Members

Caroline Apovian, MD

Email: CAPOVIAN@PARTNERS.ORG
Categories: BWH
Institution: Brigham and Women's Hospital
Research: Nutrition and Metabolism
Grants & Publications: Harvard Catalyst
The Apovian research group primarily focuses on clinical research on human obesity and metabolism. Current research interests are weight change and its effects on adipose tissue metabolism and inflammation, obesity and cardiovascular disease, resolution of type 2 diabetes and cardiovascular disease in the bariatric surgery population, disparities in the treatment of obesity in underserved populations, and novel pharmacotherapeutic agents for the treatment of obesity. Dr. Apovian is an expert in sampling subcutaneous adipose tissue and muscle tissue in humans and has been studying the relationship between adipose tissue inflammation and obesity for over 15 years. In 2016 she was appointed the Associate Director of Clinical Research for the Boston Nutrition and Obesity Research Center (BNORC – funded by P30 DK046200); in 2019, she became the Co-Director of BNORC. In January 2021, Dr. Apovian joined the faculty in the Division of Endocrinology, Diabetes and Nutrition at Brigham and Women’s Hospital. At present, three projects are ongoing: 1) Retrospective data analysis of patients with SARS-CoV-2. Analysis of PCR-confirmed SARS-CoV-2 patients admitted to Boston Medical Center (BMC) for correlations between ICU need, mortality, body mass index (BMI), inflammatory markers, race and vitamin D status (serum 25 hydroxyvitamin D levels) in patients with and without obesity. In one analysis, we discovered an independent association between vitamin D sufficiency defined by serum 25(OH)D ≥30 ng/mL and decreased risk of mortality from COVID-19 in elderly patients and patients without obesity (Endocr Pract PMC7939977); in another we show that patients with obesity were more likely to have poor outcomes even without increased inflammation (PLoS One PMC7744045). 2) Data repository of outpatients and inpatients in an urban medically-supervised nutrition and weight management center. Our group performs disparities research in bariatric surgery looking at the difference in racial and ethnic variability on weight loss and weight maintenance. We published that African American patient had significantly more weight regain after Roux-en-Y gastric bypass than Caucasian American patients (Obesity PMCID: PMC6345597). 3) Implementation of an Online Weight Management Program in Clinical and Community Settings: The PROPS II Study: This is a PCORI-funded study under PI Heather Baer. The main objective of the proposed project is to implement the combined intervention (including the online program plus additional support) from the PROPS Study in a broader population of patients and settings.

Caroline Apovian, MD

The Apovian research group primarily focuses on clinical research on...

M. Amin Arnaout, MD

Email: AARNAOUT1@PARTNERS.ORG
Categories: MGH
Institution: Massachusetts General Hospital
Research: Biology, structure and therapeutic targeting of integrins
Grants & Publications: Harvard Catalyst

A major research focus of the Arnaout Laboratory is to elucidate the structure and function of integrins, divalent cation-dependent cell adhesion receptors that play vital roles in normal cell physiology but also in common diseases. We use the information derived from our structural studies to design and test novel and safer anti- integrin drugs targeting inflammation, thrombosis, fibrosis, autoimmunity and cancer. The Laboratory uses cell, structure and molecular biology approaches and rodent and nonhuman primate (NHP) models for testing the generated compounds. Current projects are:

1. Integrins in proteinuric kidney disease. The stoichiometric cis association of the tetraspanin CD151 with podocyte integrin α3β1 is essential for stabilizing α3β1 in an active ligand binding conformation, thus maintaining the integrity of the glomerular filtration barrier (GFB). Other studies show that activation of αvβ3 in podocytes by inflammatory mediators, growth factors or mechanical/shear stress plays a critical role in disrupting the GFB. We are investigating the cellular, structural basis of the opposing roles α3β1 and αvβ3 play in regulating GFB homeostasis both in vitro and in rodent models of proteinuric kidney disease. inactivated genetically or pharmacologically in rodent models of proteinuric kidney disease.

2. Structural basis of platelet integrin αIIbβ3 activation and its therapeutic targeting. The paradigmatic platelet integrin αIIbβ3 plays a central non-redundant role in hemostasis but also in pathologic thrombosis. αIIbβ3 is normally kept in an inactive bent conformation on circulating platelets, but rapidly switches to an active (ligand-binding) conformation in response to inside-out signaling. The ligand-occupied receptor then transmits outside-in signals via the αβ transmembrane and cytoplasmic domains that initiate platelet adhesion, a response inadvertently produced by current drugs, leading to adverse outcomes, which has limited their clinical efficacy. The structural basis of bidirectional integrin signaling remains to be clarified. Ongoing studies are aimed at elucidating the structural basis of αIIbβ3 activation and developing compounds to avoid agonism while providing effective antagonism.

3. Role of integrin CD11b in delayed graft function (DGF). DGF is a manifestation of ischemia-reperfusion injury (IRI) in the transplanted kidney allograft. DGF is an important risk factor in T-cell or antibody- mediated biopsy-proven acute rejection, and the strongest risk factor for chronic allograft dysfunction exceeding even that of pre-transplant diabetes. We have shown that the archetypal innate immune receptor leukocyte integrin CD11b/CD18 mediates IRI in native NHP kidneys, and that a first-in-class anti- CD11b monoclonal antibody (mAb107) protected IRI native kidneys from otherwise irreversible kidney failure. We are evaluating the effect of limiting IRI with mAb107 on DGF in our well-studied NHP kidney transplant model. These studies have implications on preventing IRI of allogeneic pancreatic islets, a major cause of poor engraftment or progressive loss of allogeneic islet transplants in humans.

4. Abnormal metabolism in ADPKD. A hallmark of ADPKD cells is increased cell proliferation and aerobic glycolysis with upregulation of the glycolytic enzymes HK, PFK and PKM2 and down-regulation of LKB1/AMPK. Competitive inhibition of glycolysis with the non-metabolizable glucose analog 2-deoxy-D- glucose (DG) slowed disease progression in Pkd1 knockout mice. Yet the primary effector(s) that connects the underlying genetic defect in ADPKD to aberrant proliferation and Warburg metabolism remains to be identified. We now show that Warburg metabolism in the Pkd1 null mouse cells is β1 integrin-dependent and requires an extramitochondrial Plasma Membrane Electron Transport (PMET) redox system, which converts excess NADH back to NAD+ to fuel aerobic metabolism. We are evaluating the role of integrin β1 and PMET in energy utilization in tamoxifen-inducible mouse and human primary ADPKD cells, identify the β1 integrin signaling intermediates involved and the effect of PMET inhibition on rapid and slow kidney cyst growth in an inducible Pkd1 knockout mouse model.

M. Amin Arnaout, MD

A major research focus of the Arnaout Laboratory is to...

Jodie Babitt, MD

Email: Babitt.Jodie@mgh.harvard.edu
Categories: MGH
Institution: Massachusetts General Hospital
Research: Iron homeostasis in health and disease
Grants & Publications: Harvard Catalyst

The Babitt laboratory focuses on understanding the molecular underpinnings of iron homeostasis in health and disease. We previously discovered that the bone morphogenetic protein (BMP)-SMAD signaling pathway plays a crucial role in regulating systemic iron homeostasis by coordinating the regulation of the iron hormone hepcidin in the liver. Indeed, we previously determined that HJV (encoding hemojuvelin), the gene most commonly mutated in the severe juvenile onset form of the iron overload disorder hereditary hemochromatosis, is a BMP co-receptor, and that hemojuvelin-mediated BMP signals control hepcidin transcription in the liver. We also showed that BMP signaling pathway activators and inhibitors modulate hepcidin expression and systemic iron balance in vivo. More recently, we discovered that BMP6 and BMP2 are the main BMP ligands involved in hepcidin regulation and iron homeostasis, and that Bmp6 global or endothelial knockout (KO) mice and endothelial Bmp2 KO mice develop a similar iron overload phenotype as Hjv KO mice. Additionally, we demonstrated that the SMAD signaling pathway is not only critical for hepcidin regulation to control body iron balance, but also plays an independent protective role against tissue injury and fibrosis caused by iron excess.

Diabetes mellitus is a common complication of hemochromatosis and other iron overload disorders. Even in apparently healthy populations, increased dietary iron, especially heme iron, and high body iron stores, as measured by serum ferritin, are associated with an increased risk of type 2 diabetes mellitus and other insulin resistance states. A causative role for iron in the development of diabetes mellitus is supported by the fact that body iron reduction by phlebotomy or iron chelators improves glycemic control in these patients. Although the mechanisms by which iron contributes to the pathogenesis of diabetes and diabetic complications are not fully understood, oxidative stress induced by iron excess is thought to play a role. Evidence also suggests that the BMP signaling pathway itself plays a role in glucose homeostasis. For example, BMP9 has been proposed to play a role as a hepatic insulin sensitizing substance. Additionally, BMP ligands and the BMP receptors are expressed in pancreatic islet cells, and mice heterozygous for mutations in the BMP type I receptor ALK3 develop abnormal glucose metabolism with impaired insulin secretion.

A new focus in the laboratory is to use our novel genetic mouse models of impaired BMP signaling and hemochromatosis to explore the role of BMP-SMAD signaling and iron in islet cell physiology, pathology, and glucose metabolism.

Jodie Babitt, MD

The Babitt laboratory focuses on understanding the molecular underpinnings of...

Alexander Banks, PhD

Email: asbanks@bidmc.harvard.edu
Categories: BIDMC
Institution: Beth Israel Deaconess Medical Center
Research: Improvement of insulin sensitivity by modulation of the nuclear hormone receptor PPARy
Grants & Publications: Harvard Catalyst

Obesity-linked insulin resistance is the most common precursor to the development of type 2 diabetes. Our previous work has shown that phosphorylation of PPARy at serine 273 stimulates a pattern of gene expression in obese adipose tissues associated with insulin resistance and type 2 diabetes. Inhibition of this modification is a major therapeutic mechanism for anti-diabetic drugs acting on PPARy, such as the thiazolidinediones (TZDs) and partial/non-agonists. Despite being powerful insulin sensitizing agents, the side effect profile of the TZDs limits their clinical utility. We would like to understand how the insulin sensitizing properties of the TZDs are linked to their ability to block PPARy phosphorylation in order to rationally target this pathway using safer new approaches.

Development of new tools for obesity research: The Banks lab also directs the Energy Balance Core to study metabolic alterations which lead to obesity in mice. This equipment includes an indirect calorimeter containing gas exchange sensors to measure rates of conversion O2 into CO2, and sensitive scales to measure food intake. The large datasets produced by indirect calorimetry previously produced a statistical bottleneck. Our group developed CalR, a free indirect calorimetry data analysis tool now used on more than 30,000 experiments. We are continuing to develop new software tools for metabolic analysis.

Alexander Banks, PhD

Obesity-linked insulin resistance is the most common precursor to the...

Sudha Biddinger, MD, PhD

Email: sudha.biddinger@childrens.harvard.edu
Categories: Children's
Institution: Children's Hospital
Research: Defining the Effects of Insulin on the Liver
Grants & Publications: Harvard Catalyst

Insulin is the most powerful anabolic hormone in the body, transitioning it from the fasted to the fed state. The dysregulation of insulin signaling, or insulin resistance, plays a central role in the development of diabetes, cardiovascular disease and non-alcoholic fatty liver disease. In the liver, the gluconeogenic genes are key targets of insulin, and insulin suppression of the gluconeogenic genes is important for maintaining glucose homeostasis. However, numerous other targets exist. The mission of the Biddinger Lab is to define the other key targets of insulin and determine how they contribute to disease. We expect that our studies, by providing a more complete and granular understanding of insulin action, will lead to better therapies for insulin resistance and its sequelae.

Lab website

Sudha Biddinger, MD, PhD

Insulin is the most powerful anabolic hormone in the body,...

Joseph Bonventre, MD, PhD

Email: joseph_bonventre@hms.harvard.edu
Categories: BWH
Institution: Brigham and Women's Hospital
Research: Lipotoxicity - mediated proximal tubule injury in the pathogenesis of diabetic kidney disease
Grants & Publications: Harvard Catalyst

Increasing evidence suggests that the kidney tubule plays an important role in diabetic kidney disease, and we have reported that tubulointerstitial injury may contribute to glomerular changes in diabetes. We have focused on the roles of kidney injury-related molecules, mainly surface receptors of renal tubular epithelia, in both acute and chronic tubular degeneration, inflammation and fibrosis. Kidney injury molecule–1 (KIM-1) was identified originally in our laboratory as an early marker of proximal tubule injury. We reported that KIM-1 acts as a novel epithelial phosphatidylserine and scavenger receptor and that its levels in urine are a very good predictor of the progression of albuminuria in patients with type 1 diabetes. We have also reported that the plasma levels of KIM-1 are predictive of progression of diabetic nephropathy in Type I and Type II diabetic patients. These findings indicate that proximal tubule injury and dysfunction hold a critical role in the progression of diabetic kidney disease (DKD). This is further supported by other recent findings from our laboratory that: 1. injured proximal tubule cells undergo cell cycle arrest in G2M phase and assume a pro-inflammatory and pro-fibrotic secretory phenotype as a consequence of maladaptive response, and 2. repetitive targeted proximal tubule injury alone triggers interstitial fibrosis and secondary glomerulosclerosis in a non-diabetic mouse model.

Proximal tubular KIM-1 expression and urinary KIM-1 levels are increased in an animal model of DKD and correlate with the degree of tubulointerstitial and glomerular pathology. KIM-1 functions as a receptor for endocytosis of advanced glycation endproducts (AGEs) and oxidized low-density lipoproteins (oxLDLs), Free fatty acids (FFAs), all of which are known to be elevated in patients with diabetes, and triggers pro- inflammatory and pro-fibrotic responses. A diabetic mouse with a deletion of the mucin domain of KIM-1 (KIM- 1Δmucin), is protected from proximal tubular uptake of AGEs, oxLDLs, and FFAs, albuminuria, and development of DKD.

In a recent manuscript published in Cell Metabolism we have reported that KIM-1 mediates proximal tubule uptake of free fatty acids (FFAs), particularly the long chain fatty acid, palmitic acid (PA), leads to tubule injury with mitochondrial fragmentation, interstitial inflammation and fibrosis, and glomerulosclerosis in mouse models of diabetes. In proximal tubule cells, KIM-1-dependent internalization of FFAs enhances cell death and DNA damage response (DDR), transforms tubule cells into a pro-fibrotic secretory phenotype, and activates NLRP3 inflammasomes. Mice with a KIM-1 gene mucin domain deletion are protected from DKD and from injury caused by FFA. Inhibition of KIM-1-mediated FFA uptake by our newly identified compound prevented injury both in vitro and in vivo. Thus, in DKD, sustained proximal tubular KIM-1 expression results in uptake of FFAs in a mucin domain-dependent manner and promotes tubule cell death, pro-inflammatory and pro-fibrotic responses leading ultimately to tubule atrophy, interstitial fibrosis and secondary glomerulosclerosis. Our findings support KIM-1 as a new therapeutic target for DKD and introduces a new therapeutic agent (TW-37) which prevents PT from KIM-1-mediated endocytosis of FFA and protects the kidney against injury. In ongoing experiments, we crossed Six-2GFP-Cre transgenic mice (129/B6) with iDTR mice (C57BL/6) to obtain bigenic offspring (DTR), and then crossed with heterozygous C57BL/6-Ins2+/C96Y mice to obtain AkitaDTR mice. The AkitaDTR and control mice were studied with and without unilateral nephrectomy and on a regular diet or HFD, exposed to diphteria toxin injection and followed for 4 months. Kidney disease was evaluated by injury biomarkers, histology, and immunofluorescence staining. The targeted acute tubular injury (ATI) in AkitaDTR mice fed a HFD resulted in long-term albuminuria and azotemia, prolonged DNA damage, tubulointerstitial fibrosis and secondary glomerulosclerosis. In vitro, mechanistic studies have been carried out with LLC-PK1 kidney epithelial cells exposed to normal and high glucose and palmitic acid in the presence or absence of fatty acid oxidation (FAO) modulators and analyzed for phosphorylation of acetyl-CoA carboxylase (p-ACC) and DNA damage. p-ACC was upregulated in high glucose media. Promoting FAO with the ACC inhibitor PF- 05175157 after acute injury ameliorated DDR.

In conclusion diabetes increases susceptibility of the kidney to lipotoxicity. One episode of tubular injury in the setting of reduced renal mass and a high saturated fat diet leads to chronic kidney disease with tubulointerstitial fibrosis. Inhibition of FAO in tubular epithelial cells exposed to injury aggravates DNA damage and maladaptive repair.

Joseph Bonventre, MD, PhD

Increasing evidence suggests that the kidney tubule plays an important...

Dennis Brown, PhD

Email: Brown.Dennis@mgh.harvard.edu
Categories: MGH
Institution: Massachusetts General Hospital
Research: Regulation of Protein/Vesicle Trafficking in Epithelial Cells in Health and Disease
Grants & Publications: Harvard Catalyst

Dennis Brown is Director of the MGH Program in Membrane Biology (PMB) within the MGH Division of Nephrology. The overarching goal of the Program is to understand how epithelial cells respond to physiological cues, including the antidiuretic hormone vasopressin, to regulate their function in the kidney and other organs. The group studies how the processes of exo- and endocytosis work together to regulate the cell surface expression of critical cell membrane proteins, including aquaporin water channels and proton pumping H+ATPases. These proteins are central to organ function and systemic body fluid and acid base homeostasis. The role of cytoskeletal proteins such as tubulin, actin and accessory proteins in this process is a focus, as well as clathrin-mediated endocytosis. The role of hormonally induced phosphorylation of aquaporin 2 and other trafficking proteins, and identification and regulation of the kinases and phosphatases that regulate protein trafficking and kidney function in response to vasopressin is a central theme.

The experimental systems used in the PMB cover a wide range, moving from dissecting protein-protein interactions at the molecular level, through in vitro cell systems expressing normal and mutated purified proteins, to whole animal models including transgenic and knockout mice. The aim is to understand the physiological and hormonal regulation of fluid and electrolyte homeostasis in the context of renal function and disease. Representative projects include: 1) discovering new drugs and strategies to correct defective vasopressin receptor signaling that leads to increased (diabetes insipidus) or decreased (hypertension) urine output in disease; 2) dissecting the pathways and proteins involved in the recycling of a vacuolar (V-type) H+ATPase to regulate acid-base secretion, urinary tract acidification and proximal tubule function; 3) a new project to understand the role of inflammation mediated by collecting duct intercalated cells in the pathogenesis of acute kidney injury (AKI).

Dennis Brown, PhD

Dennis Brown is Director of the MGH Program in Membrane...

Clary Clish, PhD

Email: clary@broadinstitute.org
Categories: Broad
Institution: Broad Institute
Research: Metabolomics of diabetes, metabolic diseases, and early disease indicators

Our work focuses on the development and application of technologies to comprehensively analyze the complement of small molecules in biological specimens, the metabolome. We have created a robust platform that uses a combination of liquid chromatography tandem mass spectrometry (LC-MS)-based methods to enable analyses of hundreds of compounds associated with cardiometabolic traits and diseases. Compounds measured by the platform broadly cover the metabolome and range from polar metabolites, such as lactate and organic acids, to nonpolar lipids. The methods also measure thousands of signals from yet to be identified metabolites and potentiate discovery of novel metabolites. Ongoing technology development efforts include creation of new analytical techniques and refinement of software tools to support metabolomics informatics workflows. Our research in diabetes and metabolic diseases is highly collaborative, with several ongoing studies of human cohorts that aim to identify early metabolic changes associated with risk of incident disease, including impact of the microbiome, diet and other potential modifiers such as lifestyle. Complementing the human cohort studies, the lab’s metabolomics capability is leveraged to dissect the roles of specific metabolites and pathways in biological models of diabetes and metabolism, including the use of stable isotope tracers. Our overall goal is to contribute to discovery of new markers of disease, factors that reduce disease risk, and avenues for therapeutic intervention.

Clary Clish, PhD

Our work focuses on the development and application of technologies...

Saumya Das, MD, PhD

Email: SDAS@mgh.harvard.edu
Categories: MGH
Institution: Massachusetts General Hospital
Research: Role of extracellular vesicles and their cargos as biomarkers and mediators of cardiometabolic diseases
Grants & Publications: Harvard Catalyst

The Das laboratory focuses on extracellular vesicles (EVs) and their molecular cargoes as biomarkers in cardiovascular and metabolic diseases and seeks to determine their functional role in mediating phenotypes associated with cardiometabolic diseases including diastolic dysfunction, atrial fibrillation and insulin resistance. The laboratory uses a combination of human subject research including isolation of EVs from subcutaneous or visceral fat in patients undergoing bariatric surgery to profile their contents and assess their function on organ-on-chip platforms. In addition, we have characterized novel murine models that allow for tracking of EVs to assess intercellular communication and the functional effects of EV targeting.

Saumya Das, MD, PhD

The Das laboratory focuses on extracellular vesicles (EVs) and their...

Sandeep Datta, MD, PhD

Email: srdatta@hms.harvard.edu
Categories: HMS
Institution: Harvard Medical School
Research: Encoding appetitive food preferences
Grants & Publications: Harvard Catalyst

Food-seeking behavior is driven by the interplay of internal state and cues from the external world; while remarkable progress has been made in understanding the neuroendocrinological mechanisms that translate metabolic states into motivational states, little is known about how sensory information representing state- appropriate appetitive objects in the world is represented in the brain, or how this information is merged with internal state data to drive adaptive behaviors such as foraging. We have developed a suite of molecular genetic and neural tracing methods that are enabling our lab to identify specific sensory channels in the olfactory epithelium that are crucial for innate odor-driven behaviors such as foraging for food or approaching mates, and to trace the flow of information from the nose through the olfactory cortex into limbic, striatal and hypothalamic regions of the brain responsible for driving innate behaviors and altering energy balance and expenditure. These experiments will reveal the neural basis for behaviors that play critical roles in normal energy homeostasis, and potentially identify neural substrates that are affected as part of the pathophysiology of obesity and diabetes.

Sandeep Datta, MD, PhD

Food-seeking behavior is driven by the interplay of internal state...

Linda Delahanty, MS, RDN

Email: Delahanty.Linda@mgh.harvard.edu
Categories: MGH
Institution: Massachusetts General Hospital
Research: Nutrition and Lifestyle Interventions for Obesity, Diabetes and Prediabetes
Grants & Publications: Harvard Catalyst

My research program is focused on translating evidence-based nutrition and lifestyle interventions into real world clinical and community settings and understanding the psychological and behavioral factors that influence weight and activity outcomes. I have expertise in the design, implementation, and evaluation of lifestyle interventions that target weight loss and increased activity and the co-occurring problems of diabetes, prediabetes, hyperlipidemia, and hypertension. My 25+ years of clinical research experience has focused on understanding drivers of health and disease-specific quality-of-life in patients with hyperlipidemia, prediabetes, diabetes, and obesity including depression, distress, diet, and medication treatment, and to probe real-world barriers to effective care. I have designed and adapted lifestyle interventions that can promote clinically significant weight loss; improve diabetes self-management and prevent diabetes; and improve emotional well- being, quality of life and other health related outcomes in adults with diabetes, and prediabetes. My current translational intervention research in diabetes emphasizes sustainable, patient-centered approaches that have potential for wide dissemination. In Real Health-Diabetes, we are evaluating the reach, engagement, and cost- effectiveness of a lifestyle program delivered in-person or via telephone conference call (a scalable delivery format) compared with medical nutrition therapy. In Food is Medicine: a Randomized Clinical Trial of Medically Tailored Meals for Individuals with Type 2 diabetes Mellitus and Food Insecurity, we will evaluate the durability of effectiveness of a medically tailored meal intervention program that includes a lifestyle change component for individuals with type 2 diabetes on glycemic control, food insecurity, hypoglycemia, diabetes distress, diabetes self-efficacy and health-related quality of life compared with a food subsidy group. In Food as Medicine for HIV: A Randomized Trial of Medically Tailored Meals and Lifestyle Intervention, we will evaluate mechanisms whereby a food insecurity intervention may improve management of type 2 diabetes and examine the role of both nutritional improvement and health-related behavior change in doing so. The knowledge to be gained will help improve diabetes-related outcomes for patients with HIV and food insecurity.

My translational research is focused on bridging the gap between the clinical efficacy evidence base for nutrition and lifestyle intervention treatment efforts for diabetes and its implementation in real-world practice and community settings. My approach to lifestyle intervention for the treatment and prevention of diabetes is informed by behavioral science theory and empirical evidence, seeks multi-stakeholder input and collaboration and focuses on evaluating interventions that are scalable and have the potential for widespread dissemination.

Linda Delahanty, MS, RDN

My research program is focused on translating evidence-based nutrition and...

Hans Dooms, PhD

Email: hdooms@bu.edu
Categories: BU
Institution: Boston University
Research: Dysregulation of autoreactive T cells in Type 1 Diabetes

The Dooms laboratory focuses on understanding how autoreactive, islet-specific T cells, which are present in healthy people without causing harm, acquire their pathogenic functions and cause Type 1 Diabetes (T1D) when present in genetically susceptible individuals. The broad hypothesis is that faulty exposures and/or responses of T cells to microenvironmental factors such as cytokines and metabolites compromise immunoregulatory mechanisms and promote activation, differentiation and expansion of autoreactive T cells. The lab uses the non-obese diabetic (NOD) mouse model and patient samples to study this question in T1D. Currently, there are two active T1D projects in the lab:

Mechanisms underlying the role of Interleukin-7 in T1D: Interleukin-7 (IL-7) is a cytokine with critical functions in many aspects of T cell biology, from early T cell development to mature T cell homeostasis and function (1). Evidence for a critical role of the IL-7/IL-7Rα axis in the pathogenesis of multiple autoimmune diseases, including T1D, is accumulating (1), and, as a result, clinical trials targeting IL-7Rα are underway. We first demonstrated that a monoclonal antibody blocking IL-7Rα prevented T1D development and reversed established disease in NOD mice by inhibiting memory T cells (2). Mechanistically, we showed that treatment with anti-IL-7Rα antibodies increased expression of co-inhibitory receptors such as PD-1, affecting T cell effector functions (3). Our current research efforts are centered around the hypothesis that aberrant IL-7 signaling due to genetic variations in signaling and/or increased exposure in the steady-state and at the inflammatory site promotes metabolic fitness and prevents exhaustion in diabetogenic T cells. In addition, we are interested in developing new strategies to utilize IL-7Rα blockade in combination with autoantigen vaccination for the treatment of T1D (4).

The dietary fatty acid linoleic acid promotes pathogenic T cells in T1D: The incidence of T1D has globally been rising over the last 30 years, up to 5.3% annually in the United States, indicating that changing environmental conditions contribute to enhanced disease risk in genetically susceptible individuals. The nature of these environmental drivers, as well as the mechanisms by which they operate, remain largely undefined. The Western diet is one external factor that has emerged as a plausible candidate to promote autoimmune diseases, including T1D. One component of this diet that has garnered attention is the essential ω-6 polyunsaturated fatty acid linoleic acid (LA), which is present at increasingly high levels in the diet and has been associated with pro-inflammatory cytokine production. Our current research efforts are focused on our findings that exposure of autoreactive T cells to LA during activation changes their cytokine production profiles promoting a more diabetogenic phenotype. Thus, increasing levels of LA may promote the autoimmune response in T1D.

Hans Dooms, PhD

The Dooms laboratory focuses on understanding how autoreactive, islet-specific T...

Denise Faustman, MD, PhD

Email: DFAUSTMAN@mgh.harvard.edu
Categories: MGH
Institution: Massachusetts General Hospital
Research: TNF Superfamily Receptors and Clinical trials using BCG in type 1 diabetes, Alzhemier’s and COVID-19
Grants & Publications: Harvard Catalyst

As Director of the Immunobiology Laboratory at Massachusetts General Hospital (MGH), my research objective is to introduce new therapeutic concepts to treat autoimmune diseases and, more recently, cancer. I have been working in the fields of autoimmunity and immunology for nearly three decades, with a particular interest in identifying new biological processes that may be related to human disease and most frequently on the TNFR2 signaling pathway. The TNF receptor is center to Treg balance with overuse in cancer and underuse in autoimmunity. In the Immunobiology Lab, I lead teams that work to uncover the basic molecular and immunological mechanisms behind human and murine immune pathogenesis as it relates to TNF and translate these new innovations to the clinic. In various forms of autoimmunity (e.g., type 1 diabetes, Sjögren’s syndrome), we found that restoring tumor necrosis factor (TNF, TNFR2 signaling) can selectively eliminate pathogenic T cells and induce beneficial regulatory T cells (Tregs). Our findings have led to the establishment of global and collaborative clinical trial programs using repeat BCG vaccination, a known potent inducer of host TNF, in diverse autoimmune diseases including an effort to decrease the inflammation of Alzheimer’s. At MGH, this nearly century-old, safe and inexpensive vaccine is also being tested for other off-target effects such as for COVID-19 prevention. BCG vaccinations are also being tested in Italy in Phase III clinical trials in patients with multiple sclerosis. In 2015, we gained FDA approval for our protocol for Phase II testing of BCG vaccination in long-term diabetics and also established two new GMP/FDA approved manufacturing processes for BCG. In total, over 7 advanced trials are ongoing in the Immunobiology Labs. In 2018 we published the Phase I efficacy of repeat BCG vaccines in stably restoring blood sugars to the near normal range in long term diabetic subjects, a feat not feasible with insulin alone with safety. The pathway for tolerance induction in humans with TNF appears to be driven strongly by TNFR2 and now this is a target for both agonistic and antagonistic antibodies for the clinic.

Denise Faustman, MD, PhD

As Director of the Immunobiology Laboratory at Massachusetts General Hospital...

Christiane Ferran, MD, PhD

Email: cferran@bidmc.harvard.edu
Categories: BIDMC
Insitution: Beth Israel Deaconess Medical Center
Research: Deciphering the role of the anti-inflammatory gene TNFAIP3/A20 in regulating glucose metabolism in models of type I diabetes
Grants & Publications: Harvard Catalyst

In recent studies from our laboratory, we discovered that liver-directed A20-based therapies in mouse models of T1D and T2D, restored or significantly improved glycemic control in ways that fulfilled safety criteria. Bioengineering mouse livers to overexpress A20, led to unexpected reversal of hyperglycemia (i.e., diabetes), or at the very least to significant improvement of glycemic control in diabetic mice. A20, also known as TNFAIP3, is a gene that we showed, over 2 decades ago, to be a critical component of our physiologic anti- inflammatory defense mechanisms1. Previously established effects of A20 in the liver, mostly reported by our group, related to its anti-inflammatory, anti-apoptotic, and pro-regenerative functions, but there was no indication that it could also improve glucose metabolism, until our recent discovery. Mechanistically, we documented that overexpression of A20 in the liver positively impacted local hepatic glucose metabolism, and also systemically improved the regulation of glucose metabolism in other organs and tissues, mostly skeletal muscle. Liver-expressed A20 restored euglycemia and normalized glucose tolerance test (GTT) by decreasing hepatic gluconeogenesis and increasing peripheral glucose uptake. Importantly, A20 restored glycemic control in an insulin-independent manner, and without causing hypoglycemia, even under fasting conditions, including in the NOD mouse model of auto-immune diabetes. Additional benefits of hepatic expression of A20 include A20’s positive impact on lipid metabolism, which led to improved non-alcoholic fatty liver disease (NAFLD) in a mouse model of type II diabetes The case for A20 is further supported by our previously published data showing that physiologic protein levels of endogenous A20, whether in blood vessels or in the liver, are significantly decreased in the presence of high glucose levels i.e. badly controlled diabetes, hence the need to restore its expression through gene therapy in these conditions. We are currently exploring means to develop modified A20 constructs that could resist glucose, and hence reduce the level of gene therapy necessary to achieve glycemic control.

Currently, our goals are geared towards better understanding of the molecular basis for A20’s effects on glycemic control and performing key experiments to facilitate clinical translation of this novel A20-based gene therapy. Specifically, we wish to
1) Characterize the molecular basis that support the ability of liver-expressed A20 to regulates glucose metabolism.
2) Document A20’s effect on glucose uptake, hyperinsulinemic euglycemic clamps, insulin signaling.
3) Optimize AAV-based gene therapies, specifically promoter selection and enhancer elements, to ensure safe and sustained expression of A20 in livers of diabetic animals.
4) Perform pre-clinical toxicology and biodistribution studies in rodents using the optimal AAV-based gene therapy vector identified
5) Engage in additional proof-of-concept studies using a large animal model of T1D, in prelude to clinical implementation.

Christiane Ferran, MD, PhD

In recent studies from our laboratory, we discovered that liver-directed...

Michael Fitzgerald, PhD

Email: MFITZGERALD@CCIB.mgh.harvard.edu
Categories: MGH
Institution: Massachusetts General Hospital
Research: Cardiovascular disease, lipoprotein metabolism and innate immunity
Grants & Publications: Harvard Catalyst

Our lab seeks to understand at the mechanistic level how atherosclerotic cardiovascular disease is driven by dysregulation of lipoprotein metabolism and inappropriate activation of innate immunity. The tools we used to investigate these questions include cellular models of macrophage biology, construction and analysis of mouse models of atherosclerosis, and bioassay development to interrogate clinical sample material from trials studying CVD risk in people living with HIV. We have made important contributions to these areas including one of the first descriptions of the role of the microRNA-33 in regulating ABCA1 expression and HDL biogenesis, and how diets high in fat and refined carbohydrates can trigger innate immune driven inflammation through a mechanism involving epigenetic remodeling and the activity of the NLRP3 inflammasome. To carryout aspects of this work we have extensively used the services of the MGH Cell Biology Core for our advanced imaging needs. We have also made use of Kahn-BIDMC Metabolic Physiology Core to obtain cellular and mouse model reagents.

Michael Fitzgerald, PhD

Our lab seeks to understand at the mechanistic level how...

Jason Flannick, PhD

Email: flannick@broadinstitute.org
Categories: Children's
Institution: Children's Hospital
Research: Statistical and computational genetic approaches to understand type 2 diabetes
Grants & Publications: Harvard Catalyst

The Flannick lab focuses on learning what large-scale genetic and genomic datasets can teach us about type 2 diabetes (T2D). We focus on techniques ranging from software engineering to statistical method development to genetic data analysis. Through these approaches, we hope to identify insights into diabetes only apparent once we combine the necessary datasets, develop the necessary methods, apply the necessary analyses, and present the necessary results in ways that any researcher can interpret. We have three major projects ongoing in the lab:

Rare coding variants and their contribution to T2D. Genome wide association studies (GWAS) of common variants are the dominant genetic study design for complex diseases like T2D. Complementary to these studies are whole exome sequence analyses, which allow us to directly implicate genes in T2D based on aggregate associations observed for the collection of rare coding variants within them. We aggregate and analyze whole exome sequence for T2D understand T2D’s genetic basis (Nature, PMC5034897), evaluate the extent to which rare coding variant associations exist throughout the genome (Nature, PMC6699738), and use rare coding variants to personalize diagnosis for T2D (Under review at Nature Genetics)

Methods to evaluate the contribution of a gene to T2D or related traits. Our work suggests that rare coding variant associations are present for many T2D-relevant genes, but they are too weak to detect with statistical significance for the foreseeable future. We develop statistical methods to model the probability that a gene is involved with T2D, given its observed rare coding variant and GWAS associations (Under review at Cell Metabolism). We are extending these methods to incorporate other non-genetic information as well as information from multiple traits to provide the best possible picture – given currently available genetic data – of if and how a gene is involved in T2D.

Disseminating the results of T2D genetic analyses to the world. Our group maintains the Type 2 Diabetes Knowledge Portal (T2DKP), which seeks to make genetic and genomic datasets for T2D and related traits more publicly accessible (Submitted to AJHG). The portal consists of a web-interface and underlying software platform that integrates numerous genomic datasets with bioinformatic methods for predicting relationships among diseases, variants, genes, and pathways. The T2DKP is the world’s clearinghouse for T2D-related genetic data and provides a foundation for numerous T2D-related genetic analyses.

Jason Flannick, PhD

The Flannick lab focuses on learning what large-scale genetic and...

Mark Fleming, PhD

Email: Mark.Fleming@childrens.harvard.edu
Categories: Children's
Institution: Children's Hospital
Research: Iron Metabolism
Grants & Publications: Harvard Catalyst

My laboratory is primarily interested in investigating how mammals acquire and utilize iron. In mammals, erythrocytes typically contain greater than 70% of the organism’s iron in the form of heme in hemoglobin. Over the past several years, many of the transporter and accessory proteins involved in intercellular iron metabolism have been described. However, many proteins involved in intracellular iron metabolism beyond the basic components of the transferrin cycle remain elusive. Furthermore, the enzymatic components of heme biosynthesis are well characterized, but accessory transporters and other proteins required to shuttle heme precursors between mitochondria and the cytoplasm are unknown. To investigate these areas, we are taking two general approaches. First, we are using modern genetic techniques to identify and characterize the genes underlying mouse and human hereditary defects in erythroid iron and heme metabolism that lead to congenital forms of anemia. Second, using targeted mutagenesis in the mouse, we are studying proteins implicated in systemic, intracellular, and erythroid iron homeostasis. In particular, we are interested in the pathogenesis in a group of bone marrow disorders known as sideroblastic anemias, in which erythroid precursors develop pathologic mitochondrial iron deposits. At present, we are working on three ongoing projects:

1) Congenital sideroblastic anemia (CSA): We have developed a growing repository of >250 CSA probands and are using positional cloning and next generation sequencing to define new disease genes. We have identified five novel disease genes and are now modeling these and other previously characterized phenotypes in mouse models.
2) In a multi-institutional collaborative RC2 grant we are systematically evaluating the genetics and genomics of inherited and acquired bone marrow failure disorders, including aplastic anemia, congenital cytopenias, and myelodysplastic syndromes in children.
3) The ubiquitin-proteasome system (UPS) in erythropoiesis: in collaboration with Dr. Dan Finley at Harvard Medical School, we are discovering the targets of UPS components in developing red blood cells.

Mark Fleming, PhD

My laboratory is primarily interested in investigating how mammals acquire...

Jose C. Florez, MD, PhD

Email: jcflorez@partners.org
Categories: MGH
Institution: Massachusetts General Hospital
Research: Clinical Translation of Genetic Predictors for Type 2 Diabetes
Grants & Publications: Harvard Catalyst

The Florez lab aims to bring the treatment of diabetes and its complications into the new era of molecular medicine, using genetic and metabolomic approaches. To achieve these objectives, the lab undertakes the following set of activities:

1. Genetic discovery via high-throughput approaches. We have leveraged genome-wide association studies and whole-exome sequencing to discover genetic determinants of type 2 diabetes, related traits and downstream complications in diverse populations

2. Functional characterization of genetic association signals. Through fine-mapping and functional genomics we have begun to elucidate the molecular, cellular and physiological consequences of nucleotide changes in DNA sequence associated with type 2 diabetes in humans

3. Physiological assessment of glycemic and metabolic traits affected by genetic variation. In observational cohorts, clinical trials and dedicated physiological studies we have explored how type 2 diabetes- associated genetic variants impact glucose regulation in humans

4. Clinical translation of genetic findings. We have leveraged newly discovered genetic variation to understand the heterogeneity of type 2 diabetes, predict disease onset, or evaluate response to different treatment modalities

Jose C. Florez, MD, PhD

The Florez lab aims to bring the treatment of diabetes...

Irene Georgakoudi, PhD, MSc

Email: Irene.Georgakoudi@tufts.edu
Categories: Tufts
Institution: Tufts University
Research: Label-free, high resolution, non-destructive imaging of metabolism in living specimens

The Georgakoudi laboratory focuses on the development of label-free, microscopic imaging methods to assess metabolic function in living specimens. We rely on multi-photon imaging approaches that rely for contrast on endogenous fluorescence from molecules such as NAD(P)H, FAD, retinol, and lipofuscin to assess changes in the activity of key metabolic pathways and oxidative stress. We have also shown that NAD(P)H-based two- photon images can be analyzed to quantitatively characterize changes in mitochondrial organization in vivo and without the need for an exogenous label. The goal is to use such techniques to monitor functional metabolic changes in three-dimensional tissues dynamically to improve understanding of their role during development, the function of different adipose tissue types, and in the context of several diseases, including cancer and neurodegeneration/traumatic brain injury. Relevant ongoing projects include the following:

1) Label-free, metabolic function imaging-based detection of cervical pre-cancers in humans. We have shown that a combination of metrics of metabolic function as a function of depth within human cervical epithelial tissue models and freshly excised biopsies can be used to discriminate cervical pre-cancerous tissues from healthy epithelia. Enhanced levels of glycolysis and decreased levels of metabolic function variations within different epithelial tissue layers are main biomarkers of cervical pre-cancers. Metabolic heterogeneity variations are also important discriminators. Our goal is to develop and test a system that enables us to acquire such measurements in humans to assess diagnostic and potentially prognostic performance and ultimately enable accurate detection of pre-cancerous lesion without a biopsy at the time of imaging.
2) Dynamic monitoring of metabolic interactions in engineered brain tissue models during development and following traumatic brain injury. We have shown that label-free, two photon imaging can be used to monitor metabolic function of differentiating stem cells and different brain cell populations. We have also shown that our imaging approaches can identify subpopulations of cells with distinct metabolic function and responses to treatment in three-dimensional engineered tissue models of glioblastoma. Our current studies focus on exploiting such tools to monitor metabolic interactions between neurons, astrocytes, and microglia in engineered brain tissue models of traumatic brain injury to improve our understanding of their role in disease development and responses to potential treatments.

Irene Georgakoudi, PhD, MSc

The Georgakoudi laboratory focuses on the development of label-free, microscopic...

Robert Gerszten, MD

Email: rgerszte@bidmc.harvard.edu
Categories: BIDMC
Institution: Beth Israel Deaconess Medical Center
Research: Biochemical Profiling of Human Cardiometabolic Diseases and “Retro-translation” to the Bench
Grants & Publications: Harvard Catalyst

Our laboratory focuses on the nexus of cardiac and metabolic diseases with a particular interest in exercise biology and inter-organ communication. To expand the novelty and clinical impact of our studies, we have developed and incorporated emerging metabolomics and proteomic technologies towards the discovery of new biomarkers and pathways. We make observations in humans and then turn to cell and animal-based systems to test for causal relationships. Because metabolites and proteins are downstream of genetic variation and transcriptional changes, they serve as “proximal reporters” of physiology and may be highly relevant biomarkers for human diseases. At the same time, we leverage human genetics to understand the genetic architecture of circulating factors for pathway elucidation. Our multi-disciplinary research incorporates basic molecular and cell biology, genetics, chemistry, mass spectrometry and bioinformatics, all with a foundation in clinical medicine.

Robert Gerszten, MD

Our laboratory focuses on the nexus of cardiac and metabolic...

Anna Greka, MD

Email: AGREKA@BWH.HARVARD.EDU
Categories: BWH
Institution: Brigham and Women's Hospital
Research: Mechanisms of cellular homeostasis
Grants & Publications: Harvard Catalyst

The mission of the Greka laboratory is to define fundamental aspects of membrane protein biology and dissect mechanisms of cellular homeostasis. The laboratory complements this cell biology-focused program with tools from molecular biology, genomics, proteomics, and chemical biology. Combining expertise in ion channel biology with the study of kidney podocytes, the Greka laboratory uncovered a pathway linking TRPC5 ion channel activity to cytoskeletal dysregulation and cell death. Based on these discoveries, TRPC5 inhibitors are now being tested in the clinic for difficult-to-treat kidney diseases.

More recently, the Greka laboratory made a key discovery of a general mechanism that monitors the quality of membrane protein cargoes destined for the cell surface by studying a proteinopathy in the kidney, caused by a mutation in MUC1. Specifically, the Greka lab identified a mechanism for membrane protein quality control that is operative in diverse cell types and tissues, such as kidney epithelial cells and retina photoreceptors. The study of cargo quality control is now a major focus of the laboratory.

The Greka laboratory is also interested in dissecting the fundamental mechanisms of cellular homeostasis across the lifespan, with implications for many degenerative human diseases.

Anna Greka, MD

The mission of the Greka laboratory is to define fundamental...

Steven Grinspoon, MD

Email: SGRINSPOON@mgh.harvard.edu
Categories: MGH
Institution: Massachusetts General Hospital
Research: Metabolic Regulation of Ectopic Adipose Tissue
Grants & Publications: Harvard Catalyst

Dr. Grinspoon is Chief of the Metabolism Unit and his research group focuses on understanding the metabolic consequences of abnormal fat distribution in lipodystrophy, and strategies to reduce ectopic adipose tissue and related inflammation. NAFLD is major consequence of dysfunctional adipose tissue and associated with insulin resistance and diabetes in lipodystrophy.

1) The group has shown reduced DICER in relationship to altered brown fat and metabolic regulation of adipose tissue and altered miRNA’a in this group. Of note the adipose DICER knockout demonstrated a lipodystrophic phenotype with severe insulin resistance, suggesting this pathway may be involved in regulating glucose regulation in lipodystrophy.

2) Dr. Grinspoon’s group has demonstrated reduced growth hormone pulsatility among lipodystrophic patients with excess visceral adipose tissue, strongly related to liver fat and has developed a novel hypothalamic peptide to augment endogenous GH pulsatility which was shown to reduce liver fat and visceral adiposity, while preventing liver fibrosis progression, in lipodystrophy, as well as selectively reducing VAT in generalized obesity. In Phase III trials for visceral adiposity, the therapy was associated with a 20% relative reduction in VAT vs. placebo and the larger the reduction in VAT, the lower the A1C, demonstrating the important relationship of this compartment to glucose control. Using banked tissue, the group has shown that IGF-I transcription is progressively reduced with advancing stages of liver disease, and is inversely related to glucose parameters, independent of circulating IGF-I, with implications for glucose control in NAFLD.

3) In a third set of studies, the group has shown that the renin angiotensin system is turned on in relationship to excess VAT ion lipodystrophy. Key studies investigating effects of RAAS blockade on this axis have shown reduced inflammatory proteins and reduced ectopic adipose tissue, but with a low BNP. Studies are ongoing to investigate effects of a dual strategy of blocking the RAAS with a neprilysin inhibitor to simultaneously augment BNP.

Steven Grinspoon, MD

Dr. Grinspoon is Chief of the Metabolism Unit and his...

Marcia Haigis, PhD

Email: Marcia_Haigis@hms.harvard.edu
Categories: HMS
Institution: Harvard Medical School
Research: Mitochondrial Metabolism and Aging
Grants & Publications: Harvard Catalyst

The Haigis laboratory aims to elucidate how basic regulatory mechanisms of mitochondrial metabolism impact human health, aging and age-related diseases, such as diabetes. We utilize a cross-disciplinary platform that integrates biochemical, cell biological, and organismal approaches to study mitochondrial metabolism with a goal to identify new mechanisms that regulate mitochondrial metabolism and apply this knowledge of regulation to deepen our understanding of fundamental cell biology and relevance to diseases. To achieve these goals, the Haigis lab has employed an orthogonal approach of multi-omics technology combined with an in-house platform of metabolomics, signaling, mitochondrial biochemistry (in lab Seahorse respirometer and 3 mass spectrometers for metabolomic studies), and cell biology to identify novel metabolic nodes relevant to cellular metabolism. This approach is exemplified in ongoing projects

1. Aging, obesity and immunity. The Haigis lab has discovered new molecular mechanisms that contribute to our understanding of the role of metabolism in T cells and the importance of these pathways in during physiological states, such as aging and obesity. We have discovered that one carbon metabolism was blunted during the activation of aged T cells, and that addition of one carbon intermediates could enhance T cell activation (PMC6310842). Most recently, we investigated the effects of systemic stresses, such as obesity on immunity. Our studies identifying metabolic liabilities that metabolic rewiring of fatty acids to impact immunity during obesity was recently published in Cell in 2020 (PMCID in progress).

2. Post-translational regulation of metabolism in mitochondria. We have identified new molecular mechanisms that contribute to our understanding of how fuels are oxidized in the mitochondria by sirtuins and prolyl hydroxylases. For example, we mapped the mitochondrial sirtuin interactome and determined that SIRT3 mediates membrane potential homeostasis during stress (PMC5134900). Next, we discovered that the proline hydroxylase, PHD3, hydroxylates acetyl coA carboxylase 2 to regulate lipid metabolism in skeletal muscle (PMCID in progress). This work led us to establish novel assays of lipid metabolism and place PHD3 in a new signaling pathway relevant to metabolic homeostasis and physiology.

Marcia Haigis, PhD

The Haigis laboratory aims to elucidate how basic regulatory mechanisms...

Naomi Hamburg, MD, MS

Email: nhamburg@bu.edu
Categories: BU
Institution: Boston University
Research: Endothelial Phenotype in Cardiometabolic Disease

The Hamburg laboratory focuses on understanding the development and clinical relevance of vascular dysfunction in patients with type 2 diabetes and obesity. The lab uses translational research approaches that combine the measurement of vascular function in patients with characterization of endothelial phenotype at the cellular level to identify pathways that have potential to protect the vasculature from the accelerated aging induced by metabolic diseases. At present three projects are ongoing:

1) Mechanisms of endothelial dysfunction in patients with type 2 diabetes and obesity. Patients with type 2 diabetes experience accelerated vascular aging, premature atherosclerotic cardiovascular disease, and increased cardiovascular risk. Alterations in endothelial function promote atherosclerotic development in type 2 diabetes. We have identified signaling pathways that promote inflammation, oxidative stress and mitochondrial dysfunction in endothelial cells isolated from patients with type 2 diabetes. Using isolated endothelial cells, we have demonstrated several novel targets and therapies that may improve nitric oxide bioavailability. We have developed approaches to characterize coding and non-coding RNA in endothelial cells from patients with diabetes and are relating to measures of vascular aging to identify their functional relevance.

2) Mechanisms linking novel therapies for type 2 diabetes with vascular protection. Considerable enthusiasm exists for newer agents including GLP-1 agonists and SGLT2 inhibitors in reducing cardiovascular events in type 2 diabetes. Improvement of endothelial cell signaling and phenotype may serve as a marker for novel therapeutic interventions to improve cardiovascular health. We are conducting clinical intervention studies to evaluate whether novel diabetes medications will restore endothelial cell non-coding RNA expression and function.

3) ER stress and mitochondrial function in the obesity and diabetes. Metabolic stressors including elevated glucose and obesity impact endothelial cell metabolism characterized by ER stress and increased mitochondrial oxidative stress. We are evaluating the impact of therapies targeted at reducing ER stress and restoring mitochondrial health on vascular function in patients with diabetes.

Naomi Hamburg, MD, MS

The Hamburg laboratory focuses on understanding the development and clinical...

Joel Hirschhorn, MD, PhD

Email: joel.Hirschhorn@childrens.harvard.edu
Categories: Children's
Institution: Children's Hospital
Research: From Genetics to Biology of Obesity, Height, Diabetic Kidney Disease, and Other Polygenic Traits
Grants & Publications: Harvard Catalyst

I am a human geneticist and clinically active pediatric endocrinologist and have a long and successful track record in research. My group uses genetics to identify and understand the causal biology of polygenic diseases and traits. My main areas of focus relate to endocrinology, including two major unmet medical needs (obesity and diabetic kidney disease), height (the classical model polygenic trait), and metabolomics. Over the last decade, our work has provided multiple insights into the genetics of obesity and other polygenic traits, and provided early, compelling genetic evidence for two different signatures of recent human evolution/selection.

I have substantial expertise in human genetics and an extensive track record of productivity that has had an impact on the field. I was an early leader in shaping the design of genome-wide association studies (GWAS) showing that meta-analysis of genetic association studies with stringent statistical thresholds would be a successful route to robust genetic associations1,2. I organized and continue to lead the GIANT consortium, which has discovered nearly all the variants known to be associated with measures of obesity and height). I co- lead the GENIE consortium, which has discovered the common variants known to be associated with kidney disease in individuals with type 1 diabetes5,6.

We have developed computational methods that integrate multiple data types to translate genetic discoveries into new biologic insights. We have also developed methods that allow us to extend metabolomics to unknown signals from untargeted profiling data9 and have combined genetic and metabolomics data to study causal relationships with diet, obesity, and diabetes related outcomes. We are now performing genetic studies of rarer variation in large populations and individual families, including whole exome and whole genome sequencing, and studies of metabolite levels and their relationship to obesity. We are also engaged in functional follow up of genes and variants emerging from GWAS. My lab has discovered multiple new genes and rare variants that are responsible for single gene disorders related to pediatric endocrine phenotypes. I have mentored >25 trainees, with consistently successful publication records and career trajectories.

Joel Hirschhorn, MD, PhD

I am a human geneticist and clinically active pediatric endocrinologist...

Marie-France Hivert, MD, MMSc

Email: MHIVERT@PARTNERS.ORG
Categories: HMS, MGH
Institution: Harvard Medical School, Massachusetts General Hospital
Research: Heterogeneity of Gestational Diabetes and Pathophysiologic Pathways of Fetal Metabolic Programming leading to Transgenerational Risk of Diabetes
Grants & Publications: Harvard Catalyst

Marie-France Hivert, MD is an Associate Professor in the Department of Population Medicine at Harvard Medical School and Harvard Pilgrim Health Care Institute. She is a clinical investigator with primary focus on the etiology and primordial prevention of obesity and related co-morbidities, particularly type 2 diabetes and gestational diabetes. Her interests also include fetal metabolic programming mechanisms and the integration of genetics, epigenetics, and environmental factors contributing to obesity and related disorders. She is currently involved in many international consortia investigating the genetics determinants of glycemic regulation during and outside of pregnancy.

Dr. Hivert is the PI of a prospective cohort called Genetics of Glucose regulation in Gestation and Growth (Gen3G). Gen3G research team recruited women in 1st trimester of pregnancy, collected biologic samples and detailed phenotypes during pregnancy (including oral glucose tolerance test) and at delivery. Gen3G research team completed follow-up mother-child pairs at 5 years post-birth, and is in the process of the 12 years old follow-up visit. Gen3G has a rich dataset of glycemic markers, adipokines, and anthropometric measures during and after pregnancy for the mothers and in offspring, in addition to genotypes and DNA methylation arrays in placenta and offspring blood (birth and 5y). Gen3G has also completed microRNA and RNA sequencing of placenta samples. This extensive multi-omics dataset allows investigations of determinants of glycemic regulation and pregnancy, as well as investigations of mechanisms linking maternal hyperglycemia and metabolic consequences in the offspring.

Dr. Hivert is also co-PI of Project Viva (PI = Oken) which is a prospective pre-birth cohort that was established between 1999-2002 and has been following up mothers and children throughout childhood and adolescence, collecting data and samples to investigate child health and common conditions (asthma, obesity, neurodevelopment, etc.). Project Viva research team is now following mother-child pairs >20 years post-birth. Project Viva also has an extensive amount of genotyping (mothers and children), epigenetics (cord blood, blood cells at 3yo and 8yo, blood and nasal cells at 12 yo), untargeted metabolomics (cord blood, blood at 8yo, 12yo, and 18yo), and longitudinal measures for many of their phenotypes. This allows many investigations from prenatal up to adolescence with a deep lifecourse approach.

Dr Hivert has been an active member of the genetic working group within the Diabetes Prevention Program. She has led many project and manuscripts help to understand the interaction between genetics and lifestyle in determinants of diabetes. Dr Hivert also continues to be an active member of multiple international consortia in the field of genetics and epigenetics of diabetes related traits (e.g. MAGIC, CHARGE), and early life determinants of adiposity and metabolic traits (e.g. EGG, PACE).

Marie-France Hivert, MD, MMSc

Marie-France Hivert, MD is an Associate Professor in the Department...

Gökhan Hotamisligil, MD, PhD

Email: ghotamis@hsph.harvard.edu
Categories: HMS
Institution: Harvard Medical School
Research: Immunometabolism and Organelle Homeostasis in Health and Disease
Grants & Publications: Harvard Catalyst

The Hotamışlıgil Lab at the Sabri Ülker Center studies innate adaptive pathways involved in metabolic health and disease clusters such as obesity, diabetes, and cardiovascular disease. For the past 25 years, our lab has made important contributions to the burgeoning field of “immunometabolism”, studying the interactions between metabolic and immune responses as critical drivers of numerous chronic diseases. Our current overall approach has been organized in two pillars: organelle structure and homeostasis and lipid signaling, hormones and metabolism. Using biochemical, genetic, and physiological studies, we aim to find novel pathways and preventive, therapeutic solutions to today’s greatest threats to global human health.

Organelle function and structure have profound effects on cellular and metabolic integrity and its dysfunction is causal to metabolic diseases. In this context, our main focus has been on the endoplasmic reticulum, a cellular compartment comprised of a vast network committed to protein and lipid synthesis, maturation, and trafficking, as well as calcium homeostasis. Our laboratory is particularly interested in the mechanisms by which this organelle integrates nutrient-sensing with metabolic responses and endocrine networks. The ER forms dynamic physical and functional interactions with all other subcellular components of the cells and the architecture of these are central to homeostasis. For example, we find an abnormal increase in MAM formation, contributing to impaired metabolic homeostasis. We are interested in how these inter-organelle interactions and structural organization can shape metabolic regulation. We also explore the molecular mechanisms underlying the metabolic biology of the ER, including calcium homeostasis which is impaired in obesity and diabetes. We have identified the ER-resident transcription factor erythroid 2 related factor-1 (Nrf1/Nfe2L1) as a critical sensor and regulator against excessive cholesterol exposure and adipocyte function. We explore the mechanisms by which ER-resident proteins such as Nrf1.

Lipid signaling, hormones, and metabolism. Lipids, whether dietary or endogenously produced, have a profound influence on several vital physiological and metabolic pathways and are involved in the pathogenesis of many critical metabolic diseases such as fatty liver disease, diabetes, and atherosclerosis. We approach the molecular basis of these interactions by focusing on fatty acid-mediated signaling events and transcriptional regulation and the biological role of lipid hormones and escort proteins, such as fatty acid-binding proteins (FABP), as molecules involved in intracellular lipid trafficking in immune and metabolic cells and in the whole organism. Using systemic approaches and quantitative lipidomics, we identified a fatty acid hormone or a lipokine, regulated by adipose tissue lipid chaperones which regulates lipid metabolism in the liver. We are investigating the biology of this lipid hormone in several metabolic diseases in experimental models and humans and exploring the mechanisms underlying its specific endocrine actions. We have also demonstrated that FABPs are central to many components of metabolic syndrome, including obesity, insulin resistance, type 2 diabetes, fatty liver disease, and cardiovascular disease. These proteins are proximal to the generation of stress and inflammatory responses upon exposure to lipids. More recently, we have discovered that FABP4 is secreted from adipocytes in response to lipolytic signals and acts on beta cells and hepatocytes to control insulin secretion and glucose metabolism. In exploring the mechanism of action and physiological and

pathological importance of this unique adipokine, we most recently discovered a novel hormone complex named Fabkin, a structure formed by FABP4 and two extracellular nucleoside kinases, ADK and NDPK. When assembled, this hormone regulates ATP/ADP ratios and signals through purinergic receptors on beta cells to control insulin secretion. The levels of these proteins are markedly elevated in diabetes and cardiovascular disease in both preclinical models and in humans. We also developed prototype antibody-therapeutics to target Fabkin and demonstrated that both type 1 and type 2 diabetes could be treated with this molecule in preclinical models. We are now exploring mechanistic and translational pathways to develop and test these therapeutic entities for their clinical applications.

Gökhan Hotamisligil, MD, PhD

The Hotamışlıgil Lab at the Sabri Ülker Center studies innate...

Nawfal Istfan, MD

Email: nistfan@bwh.harvard.edu
Categories: BWH
Institution: Brigham and Women's Hospital
Research: Nutrition and metabolism
Grants & Publications: Harvard Catalyst

The Istfan research lab primarily focuses on clinical research on human obesity and metabolism. His past research interests have focused on metabolic regulation of nutrients including protein, fat and omega-3 fatty acids and their role in cancer cell proliferation. His current research is primarily related the metabolic problems that accompany obesity such as insulin resistance and type 2 diabetes. Of particular importance is understanding how the body handles excessive nutrient loads and how acute overfeeding contributes to disease and cardiovascular risk.

Dr. Istfan has practiced obesity medicine and weight management for the past 25 years. He has vast experience in helping patients improve their metabolic health by diet and use of pharmacologic agents. His most recent publications have focused on the problem of weight regain and racial disparities after bariatric surgery. He has specific expertise in helping patients prevent and reduce weight regain following successful weight loss. In January 2021, Dr. Istfan joined the faculty in the Division of Endocrinology, Diabetes and Nutrition at Brigham and Women’s Hospital. At present, one project is ongoing:

1) Data repository of outpatients and inpatients in an urban medically-supervised nutrition and weight management center. Our group performs disparities research in bariatric surgery looking at the difference in racial and ethnic variability on weight loss and weight maintenance. We published that African American patients had significantly more weight regain after Roux-en-Y gastric bypass than Caucasian American patients
2) Dual Sugar Challenge Test for Assessment of Metabolic Overfeeding. The primary objective of this study is to determine the time course of cytoplasmic and mitochondrial redox changes in response to a challenge of glucose/fructose solution administered orally in normal weight participants and participants with obesity. Redox couple measurements will be entered into a model to estimate the cellular energy charge and predict the occurrence of metabolic overfeeding (MOF) at a sugar consumption level of 0.75 grams/kilogram (g/kg) and 1.75 g/kg.

Nawfal Istfan, MD

The Istfan research lab primarily focuses on clinical research on...

Barbara Kahn, MD

Email: bkahn@bidmc.harvard.edu
Categories: BIDMC
Institution: Beth Israel Deaconess Medical Center
Research: Mechanisms Underlying Insulin Resistance and Type 2 Diabetes
Grants & Publications: Harvard Catalyst

The overall goal of research in my lab is to determine the cellular and molecular mechanisms for insulin resistance in obesity and type 2 diabetes. Major research areas include:

1) discovering the mechanisms by which novel adipocyte-associated molecules alter insulin action and fuel metabolism in other tissues;
2) determining the molecular mechanisms that render obesity a risk factor for type 2 diabetes;
3) understanding the regulation and biological activities of a novel class of anti-diabetic and anti-inflammatory lipids that we discovered and named branched Fatty Acid Esters of Hydroxy Fatty Acids.

Our work has had a major impact on understanding the important role of the adipocyte as an endocrine organ and as a metabolic “factory” consuming nutrients and substrates and producing metabolites that have systemic effects on insulin action, energy balance and inflammation. We use genomic and metabolomics approaches in mouse models we have genetically engineered mice to discover novel adipocyte-associated molecules which have provided important markers and mechanisms for insulin resistance and diabetes in humans. For example, we demonstrated that retinol binding protein 4 levels are elevated in insulin-resistant people and that elevated retinol binding protein 4 causes insulin resistance by activating both the innate and adaptive immune systems in adipose tissue. Lab members also showed that de novo lipogenesis in adipocytes has a major role in regulating systemic insulin sensitivity. These studies focused our interest on identifying novel metabolites which regulate glucose homeostasis.

Glut4 is the major insulin-regulated glucose transporter and is expressed at highest levels in skeletal and cardiac muscle and brown and white adipocytes. Reduced levels of Glut4 in adipocytes is associated with insulin resistance in humans and is a risk factor for developing type 2 diabetes. To understand the role of Glut4 and glucose transport specifically in adipocytes on glucose homeostasis, we engineered mice to have adipose-specific overexpression of Glut4. These mice have markedly enhanced glucose tolerance in spite of obesity. This improved glucose tolerance depends on increased lipogenesis in adipose tissue driven Carbohydrate Response Element Binding Protein, a transcription factor that regulates de novo lipogenesis and glycolysis. Knocking out Carbohydrate Response Element Binding Protein from adipose-specific Glut4- overexpressing mice reverses their enhanced glucose tolerance.

Since plasma fatty acids were elevated in the adipose-specific Glut4-overexpressing mice, we sought to determine whether specific lipids were being synthesized that have beneficial metabolic effects. With Dr. Alan Saghatelian, we used a global lipidomic platform and discovered a novel class of lipids that are made in human tissues, correlate highly with insulin sensitivity in humans, and have anti-diabetic and anti-inflammatory effects. These lipids lower glycemia and improve insulin sensitivity in insulin-resistant obese mice and protect against inflammatory diseases including autoimmune Type 1 diabetes in a mouse model. We are investigating the biology and pharmacokinetics of these lipids and the pathways that regulate their levels and mediate their effects. Because of the constellation of beneficial effects of these lipids and their favorable safety profile, they could lead to new therapeutic agents to prevent and treat diabetes and immune-mediated diseases.

Barbara Kahn, MD

The overall goal of research in my lab is to...

Ursula Kaiser, MD

Email: UKAISER@BWH.HARVARD.EDU
Categories: BWH
Institution: Brigham and Women's Hospital
Research: Neuroendocrine Control of Reproduction and Metabolism
Grants & Publications: Harvard Catalyst

Diabetes mellitus and other metabolic and nutritional disorders can lead to a number of complications, which include a major impact on reproductive maturation and fertility. We are interested in the intersection of neuroendocrine control of reproductive development and function with that of metabolism. The hypothalamic pathways by which gonadotropin-releasing hormone (GnRH) neurons are reactivated at puberty and by which the precise periodic pulsatile release of GnRH is regulated are closely intertwined with those that sense energy balance and regulate appetite and metabolism. As one example, congenital leptin deficiency is associated with severe obesity as well as with hypogonadotropic hypogonadism that responds to leptin administration. Furthermore, leptin administration to women with hypothalamic amenorrhea improves reproductive function. Similarly, many other genes implicated in hypothalamic pathways of appetite and energy metabolism are also associated with hypogonadotropic hypogonadism when deleted or mutated in patients or in animal models. We are interested in dissecting the pathways by which central regulation of metabolism and reproduction interconnect. A recent avenue of our investigation is the characterization of the functional roles of kisspeptin and neurokinin B in the regulation of GnRH release and in the neuroendocrine regulation of reproductive function. Studies have demonstrated that kisspeptin and its receptor are downstream of leptin, as administration of kisspeptin in leptin-deficient animal models results in recovery of gonadotropin secretion. We are interested in mapping the neural pathways that link leptin action to kisspeptin and/or GnRH neurons. An additional area of interest is polycystic ovarian syndrome, a reproductive disorder associated with obesity and insulin resistance in which GnRH pulse frequency is increased, resulting in altered ratios of luteinizing hormone and follicle-stimulating hormone secretion and hence irregular menses, anovulation and infertility. Treatment with insulin sensitizing agents results in improvement in these reproductive parameters. It is expected that these studies will provide new insights into the links between energy balance and reproductive function, and lead to improved management of disorders of reproductive function.

Ursula Kaiser, MD

Diabetes mellitus and other metabolic and nutritional disorders can lead...

Shingo Kajimura, PhD

Email: skajimur@bidmc.harvard.edu
Categories: BIDMC
Institution: Beth Israel Deaconess Medical Center
Research: Metabolic Adaptation and Reprogramming
Grants & Publications: Harvard Catalyst

The Kajimura laboratory focuses on the molecular mechanisms of metabolic adaptation to stress. In this regard, fat cells (adipocytes) serve as a unique model because adipose tissue comprises a dynamic organ that remodels its cellular size and composition in response to a variety of hormonal cues, nutritional changes (e.g., overeating or fasting), and temperatures. Such metabolic adaptation, involving lipolysis, lipogenesis, adipogenesis, mitochondrial biogenesis/clearance, and thermogenesis, plays a central role in the regulation of energy homeostasis. We apply the most cutting-edge technologies and multidisciplinary approaches (biochemistry, genetics, bioinformatics, molecular biology, engineering, etc.) to generate a blueprint for engineering regulatory circuits of adaptive responses and restoring metabolic health by defined factors. This approach will have a profound impact on the prevention and treatment of metabolic disorders, cancer, aging, and beyond.

1) Metabolite compartmentalization via mitochondrial transporters: A notable metabolic change during cold adaptation is fuel utilization from glucose to fatty acids and amino acids. We recently found that, besides glucose and fatty acids, brown/beige fat cells actively uptake branched-chain amino acids (BCAA) in the mitochondria, thereby enhances systemic BCAA clearance. This is highly significant because increased BCAA levels – due to impaired BCAA oxidation in metabolic organs – are tightly associated with human diabetes. By studying the fuel switch mechanisms, we identified SLC25A44 as the first mitochondrial transporter for BCAA (Yoneshiro et al. Nature 2019). We aim to explore the biological roles of this newly identified mitochondrial BCAA transporter SLC25A44 as well as other uncharacterized transporters in health and disease.

2) Cellular and functional heterogeneity in adipose tissues: Historically, it has been considered that mammals possess “two types” of adipose cells – brown and white fat cells. However, emerging evidence suggests that adipose cell origins and composition are far more complicated than merely two types. In fact, we and others showed that beige adipocytes- an inducible form of thermogenic fat cells – exist in mice and humans (e.g., Shinoda et al. Nature Med 2015). More recently, we found that myogenic progenitors in the subcutaneous WAT give rise to a glycolytic form of beige fat (termed “g-beige” fat) in the absence of �-adrenergic receptor signaling (Chen et al. Nature 2019). It is conceivable that adipose tissues contain diverse progenitors that differentially respond to external and hormonal stimuli (e.g., exercise, tissue injury, cancer cachexia, and intermittent fasting), and each of them gives rise to developmentally and functionally distinct mitochondria- enriched adipocytes. We aim to generate a complete lineage/functional map of adipose cells in mice and humans.

3) Metabolic engineering to improve metabolic health: The “browning” of white fat – enhanced beige fat biogenesis – is accompanied by a substantial improvement in metabolic health, including improved glucose tolerance, insulin sensitivity, lipid profile, and cardiovascular health. The conventional dogma was that these metabolic effects are through UCP1-mediated thermogenesis; however, surprisingly, we demonstrated that a large part, if not all, of the anti-diabetic actions of beige fat is UCP1-independent (Ikeda et al. Nature Medicine 2017; Haseawa et al. Cell Metabolism 2017). We aim to explore this unexpected observation by 1) uncovering the mechanisms of UCP1-independent anti-diabetic actions, and 2) reconstitution of such anti-diabetic effects of beige fat in adipose tissues, i.e., fat-specific “cold mimetics.”

Shingo Kajimura, PhD

The Kajimura laboratory focuses on the molecular mechanisms of metabolic...

Nada Kalaany, PhD

Email: Nada.Kalaany@childrens.harvard.edu
Categories: Children's
Institution: Children's Hospital
Research: Effects of systemic metabolic alterations on cancer growth
Grants & Publications: Harvard Catalyst

The broad interest of the Kalaany lab is to define the role of systemic metabolism in cancer initiation and progression using a combination of genetics, in vivo transplant models, cell biology and metabolic approaches. Our studies are focused on identifying metabolic vulnerabilities in cancers growing under distinct systemic metabolic states, including obesity, insulin resistance, dietary restriction, and cachexia. Current ongoing projects in the lab:

Role of insulin/IGF-1 signaling in Kras-driven lung cancer. Our lab addressed a long-standing question in KRAS-driven lung cancer and identified a metabolic vulnerability that could be exploited therapeutically using drugs available in the clinic. Although KRAS direct binding to and activation of PI3K had been known to be required for KRAS-driven lung cancer formation, the contribution of insulin receptor (IR) and IGF-1 receptor (IGF1R), in the context of mutant KRAS, had remained largely controversial. We provided robust genetic evidence that lung-specific dual ablation of insulin receptor substrates (IRS1/IRS2), which mediate insulin and IGF-1 signaling, strongly suppresses lung tumor initiation in a mouse model with KRAS activation and p53 loss. We also showed that inhibition of IR/IGF1R in KRAS-mutant human non-small cell lung cancer (NSCLC) cells decreases the uptake of amino acids, generating a metabolic dependency on protein degradation processes, including autophagy and the proteasome. (Published in Proc Natl Acad Sci USA PMCID: PMC5910837). We are currently investigating the role of insulin/IGF-1 signaling in KRAS-driven lung cancer- associated body wasting or cachexia.

Nitrogen metabolism as a dependency in obesity-associated pancreatic cancer. Obesity is an established risk factor for pancreatic ductal adenocarcinoma (PDA); yet the metabolic dependencies of obesity-associated PDA have remained largely unexplored. We showed that similar to AKT-activated PDA, obesity-driven PDA exhibits increased growth and a striking transcriptional enrichment for pathways regulating nitrogen metabolism. Specifically, we found that the mitochondrial, extrahepatic form of arginase (ARG2), which hydrolyzes arginine into ornithine and urea, is induced. This induction is accompanied by enhanced nitrogen flux into the urea cycle and is required for PDA growth. Analysis of resected tumors from PDA patients indicated that ARG2 levels correlate with body mass index (BMI) or with activated AKT independent of BMI. The specific dependency of PDA on ARG2, which unlike ARG1 is not associated with human diseases, opens a new therapeutic window for the treatment of pancreatic cancer in overweight patients as well as lean patients carrying tumors with AKT- activating mutations, independent of obesity (Published in Nat Commun PMCID: PMC5556090). We are currently investigating the role of another nitrogen-dependent pathway, i.e. polyamine biosynthesis, in pancreatic cancer progression.

Adaptation of pancreatic cancer cells to nutrient deprivation. In this work, we selected for clonal human pancreatic ductal adenocarcinoma (PDA) cells that survive and adapt to limiting levels of both glucose and glutamine. We found that adapted clones exhibit increased growth in vitro and enhanced tumor-forming capacity in vivo. Mechanistically, adapted clones use amino acids for de novo glutamine and nucleotide synthesis. They also display enhanced mTORC1 activity that prevents the proteasomal degradation of glutamine synthetase (GS), the rate-limiting enzyme for glutamine synthesis. This phenotype is notably reversible, with PDA cells acquiring alterations in open chromatin upon adaptation. Silencing of GS suppresses the enhanced growth of adapted cells and mitigates tumor growth. These findings identify nongenetic adaptations to nutrient deprivation in PDA and highlight GS as a dependency that could be targeted therapeutically in pancreatic cancer patients. (Published in Proc Natl Acad Sci USA PMCID: PMC7958225, available 09/02/2021). We are currently exploring the epigenetic basis of the regulation of pancreatic cancer cell adaptation to nutrient deprivation.

Nada Kalaany, PhD

The broad interest of the Kalaany lab is to define...

Konstantin Kandror, MD

Email: kkandror@bu.edu
Categories: BU
Institution: Boston University
Research: Insulin regulation of adipose functions

Adipocytes, skeletal myocytes and some neurons express a specific isoform of the glucose transporter protein, Glut4. Under basal conditions this transporter is localized in intracellular membrane vesicles which fuse with the plasma membrane upon insulin administration. Translocation of Glut4 plays a major role in post-prandial glucose clearance and, more generally, in glucose sensing and metabolic homeostasis in the body. For a number of years, my lab has been involved in the dissection of the “Glut4 pathway” in various insulin-sensitive cells.

Another key physiological function of insulin is to inhibit lipolysis and to promote storage of triglycerides in fat tissue. We have discovered two novel pathways of regulation of lipolysis by insulin. One of these pathways is mediated by the insulin- and nutrient-sensitive mammalian Target of Rapamycin Complex 1, while the other is mediated by the transcription factor FoxO1. Currently, we are engaged in the dissection of both pathways at the molecular level.

Fat represents an important secretory tissue in the body. Unlike typical endocrine and exocrine cells, adipocytes produce and secret several physiologically important proteins, such as leptin, adiponectin, lipoprotein lipase, etc. and switch the secretory process from one protein to another in response to changing metabolic conditions. We are exploring connections between food intake, obesity and secretion of adipokines in order to understand the central role of fat tissue in the orchestrating the overall response of the organism to changing metabolic conditions.

Konstantin Kandror, MD

Adipocytes, skeletal myocytes and some neurons express a specific isoform...

Masao Kaneki, MD, PhD

Email: MKANEKI@HELIX.MGH.HARVARD.EDU
Categories: MGH
Institution: Massachusetts General Hospital
Research: Stress-induced insulin resistance and metabolic derangements

The Kaneki laboratory has been working on stress (e.g., burn injury)-induced insulin resistance, mitochondrial dysfunction and muscle wasting. In the attempt to clarify the underlying molecular mechanisms and help develop a clinical trial in burn patients, the lab uses genetically engineered mice, pharmacological approaches and cell culture system. In addition, the PI conducted a pilot clinical study of coenzyme Q10 in burn patients, based on the data in burned mice. At present, related to stress-induced insulin resistance and metabolic derangements the following project is ongoing:

Mechanisms by which burn injury induces insulin resistance and metabolic derangements. Metabolic derangements, including insulin resistance, mitochondrial dysfunction and hyperlactatemia, are a major complication of burn injury and negatively affect clinical outcomes of burn patients. However, the molecular mechanisms by which burn injury induces these metabolic derangements remain to be clarified. We have shown that: (1) burn injury increases farnesyltransferase expression and farnesylated proteins; and (2)

farnesyltransferase inhibitor (FTI) prevents burn-induced insulin resistance (which parallels reversal of increased basal [insulin-unstimulated] mTORC1 activation), mitochondrial dysfunction in mouse skeletal muscle and hyperlactatemia. We have also shown that burn injury induces the Warburg effect in mouse skeletal muscle, as indicated by increases in expression of hypoxia-inducible factor (HIF)-1α and its downstream glycolytic genes, which is prevented by FTI. Moreover, we have recently shown that FTI prevents sepsis-induced mitochondrial damage in mice. (Sepsis is a leading cause of mortality in burn patients.) In addition, we have reported that treatment with coenzyme Q10 prevents burn-induced metabolic aberrations (i.e., insulin resistance, mitochondrial dysfunction and hyperlactatemia) in mice. Based on these data, the PI conducted a pilot clinical study in burn patients (ClinicalTrials.gov Identifier: NCT02251626).

Masao Kaneki, MD, PhD

The Kaneki laboratory has been working on stress (e.g., burn...

Young-Bum Kim, PhD

Email: ykim2@bidmc.harvard.edu
Categories: BIDMC
Institution: Beth Israel Deaconess Medical Center
Research: Metabolic actions of Rho-kinase, ApoJ and LRP in obesity and diabetes
Grants & Publications: Harvard Catalyst

Identifying ROCK1 as a novel regulator of insulin signaling, glucose homeostasis, and lipogenesis: My works suggested that Rho-kinase positively regulates insulin-stimulated glucose transport and signaling via either IRS-1 serine phosphorylation or active polymerization, establishing a new mechanism for the regulation of glucose transport. My works also demonstrated that inhibition of Rho-kinase causes insulin resistance in vivo. Our studies also revealed that adipose ROCK1 isoform plays an inhibitory role for the regulation of insulin sensitivity in diet-induced obesity in vivo. Recent our work established a ROCK1-AMPK signaling axis that regulates de novo lipogenesis, providing a unique target for treating obesity-related metabolic disorders such as NAFLD. Identification of ROCK1 as a key player of glucose and lipid metabolism has a major impact on the understanding of the pathogenesis of diabetes and has significantly advanced the diabetes field.

Discovery of Rho-kinase as a key regulator of leptin action: Our recent works also have established the critical roles of the serine threonine kinase ROCK1 on regulation of leptin signaling and action in hypothalamus in vivo, using transgenic mouse models. Our study establishes a new hypothesis that ROCK1 regulates energy balance by targeting leptin receptor signaling, suggesting ROCK1 as a key regulator of leptin action. In fact, genetic disruption of ROCK1 in either POMC or AgRP neurons increases body weight and adiposity. Mice lacking ROCK1 in POMC neurons show hyperphagia and hypoactivity. However, AgRP neuron-specific ROCK1-deficient mice display lower oxygen consumption and locomotor activity. The molecular mechanism for this is involved in ROCK1-mediated JAK2 phosphorylation, which promotes downstream signaling pathways of leptin, including STAT3 and PI3K signaling, ultimately leading to the control of energy balance. This model provides a new mechanism that advances our understanding of central leptin action and energy homeostasis.

ApoJ is a new metabolic signal controlling energy homeostasis and glucose metabolism: Identification of a new molecule that cures potentially eating disorder has been a key subject of obesity field. Our recent work discovered ApoJ as a novel anorexigenic molecule that regulates appetite and energy balance. Like leptin, ApoJ treatment caused anorexia, weight loss, and hypothalamic Stat3 activation. These effects were most likely mediated by a cellular mechanism that was dependent on a physical interaction between functional leptin receptors and LRP (low-density lipoprotein receptor-related protein). However, peripheral actions of ApoJ in the context of glucose metabolism are unknown. Our studies demonstrated that ApoJ functions as a hepatokine targeting insulin signaling and glucose metabolism in skeletal muscle, which is mediated via the LRP signaling cascade. Taken together, our works identify the ApoJ ® LRP signaling axis as a novel metabolic signaling pathway that is central for the maintenance of normal glucose homeostasis and energy balance.

Young-Bum Kim, PhD

Identifying ROCK1 as a novel regulator of insulin signaling, glucose...

Dong Kong, PhD

Email: Don.Kong@childrens.harvard.edu
Categories: Children's
Institution: Children's Hospital
Research: Brain-controlled Blood Glucose Homeostasis
Grants & Publications: Harvard Catalyst

The long-term interest of our laboratory is to bridge molecular, cellular, and system approaches to decipher the neuronal modulatory and circuitry mechanisms underlying diabetes and obesity. By leveraging and combining a battery of cutting-edge technologies, including genetically engineered mouse models, recombinant viral vectors and viral tracing system, optogenetic and pharmacogenetic approaches, patch-clamp electrophysiology, 2-photon laser scanning microscopy, and 2-photon laser uncaging methods (2PLSM/2PLU), we are interrogating the following questions: 1) how neurons in the central nervous system translate their intrinsic firing properties to the controlling of energy and glucose homeostasis, and what circuits are involved; 2) how metabolic signals, including circulating metabolites, hormones, and neuropeptides, act on circuit neurons, shape their firing outputs, and modulate related synaptic neurotransmission; and 3) what kinds of receptors, ion channels, or cellular signaling molecules are rooted to bear these physiological processes and how their dysfunctions contribute to the pathogenesis of diabetes and the related complications. Understanding these above questions will provide novel insights on the treatment and prevention of diabetes.

Dong Kong, PhD

The long-term interest of our laboratory is to bridge molecular,...

Aaron Leong, MD

Email: asleong@mgb.org
Categories: MGH
Institution: Massachusetts General Hospital
Research: Hemoglobin A1c genetics in Diabetes Diagnosis and Patient Care
Grants & Publications: Harvard Catalyst

My research program is focused on the application of complex trait genetics to clinical practice. I am to rigorously test strategies for translating type 2 diabetes (T2D) and hemoglobin A1c (A1C) genetics to precision medicine in controlled, real-world research settings. I take genetic findings from largescale genome-wide association analyses of T2D and A1C to pharmacogenetic clinical studies involving detailed phenotyping and pharmacologic interventions, and patient-oriented outcomes research using biobanks and electronic health records. Ongoing research studies in my lab include 1) a study funded by the American Diabetes Association to examine host genetics underlying diabetes and COVID-19 severity (Principal Investigator), 2) a study funded by the American Diabetes Association to characterize the beta cell function and sulfonylurea response of individuals at the extremes of polygenic scores (Site Investigator), and 3) an examination of the association of genetics with A1C-glycemia mismatches funded by the Boston Area Diabetes Endocrinology Research Center (BADERC) Pilot and Feasibility Program and a Doris Duke Foundation Clinical Scientist Development Award (Principal Investigator). I play both leadership and participatory roles in genetic discovery efforts within national and international genetics consortia – Meta-Analysis of Glycemic and Insulin-related Traits Consortium (MAGIC), Trans-Omics for Precision Medicine (TOPMed) Program, Cohorts of Heart and Aging in Genomic Epidemiology (CHARGE) and the Million Veteran Program (MVP). Additionally, I have published studies on novel approaches to diabetes population screening using health administrative databases and population-based surveys, and on Mendelian randomization approaches to evaluate causal relationship between risk factors and cardiometabolic disease.

Aaron Leong, MD

My research program is focused on the application of complex...

Peter Libby, MD

Email: PLIBBY@BWH.HARVARD.EDU
Categories: BWH
Institution: Brigham and Women's Hospital
Research: Inflammation and Atherosclerosis
Grants & Publications: Harvard Catalyst

The links between the major theme of the Libby laboratory, inflammation in cardiovascular diseases, to metabolic diseases including diabetes and obesity have become increasingly apparent. Work from Libby laboratory has explored the interface between adipose tissue, adaptive immunity, and atherosclerosis. We showed that T cells regulate aspects of biology of adipose tissue, defined a role for the Th1 cytokine gamma interferon in regulating insulin sensitivity in obese mice, and in new studies have explored the mechanisms of T cell recruitment to adipose tissue. We have also explored the interface between adiponectin and aspects of the immune and inflammatory response related to atherothrombosis. These studies can benefit from the use of proteomic and RNA profiling facilities available through BADERC. Dr. Libby as a true translational investigator contributed to the study that first demonstrated the link between statin treatment and incident diabetes and explored the risk factors for this relationship. Dr. Libby has moreover instigated and co-led the large-scale cardiovascular outcome trial (CANTOS) that targets interleukin-1 beta that prespecified incident diabetes as a secondary endpoint. He is currently a supervisor of PROMINENT, a large-scale clinical outcomes trial in diabetic individuals with hypertriglyceridemia evaluating a novel selective PPARa agonist.

Peter Libby, MD

The links between the major theme of the Libby laboratory,...

Stephen J. Liberles, PhD

Email: Stephen_Liberles@hms.harvard.edu
Categories: HHMI, HMS
Institution: HHMI, Harvard Medical School
Research: Internal and external senses
Grants & Publications: Harvard Catalyst

We study internal sensory systems using molecular and genetic approaches. The vagus nerve is an essential body-brain communication axis that controls vital functions of the respiratory, cardiovascular, digestive, and immune systems. Despite their importance, vagal sensory mechanisms are largely unresolved. We led efforts to (1) chart vagal sensory neuron diversity, (2) adapt genetic tools to map, image, control, and ablate different sensory neuron types, and (3) identify neuronal sensory receptors involved in interoception. We characterized a myriad of sensory neurons that innervate the lungs, stomach, intestine, heart, arteries, and larynx, and control breathing, protect airway integrity, detect blood pressure changes, and monitor meal volume and content. In a collaborative effort with Ardem Patapoutian, we identified a critical role for Piezo mechanoreceptors in the sensation of airway stretch and neuronal sensation of blood pressure underlying the baroreceptor reflex. We also used similar approaches to chart brainstem neurons that mediate nausea-related behaviors. Identifying neurons and receptors that control autonomic physiology builds an essential foundation for mechanistic study and therapy design.

Olfaction is one of our five basic external senses, and a principal mechanism by which we perceive the external world. Sensory receptors define our capacity for perception, and we identified novel olfactory receptor families (TAARs, FPRs), opening up new avenues of research to probe the neuronal basis of perception and behavior. We discovered ligands for many TAARs, including ethological odors derived from carnivores, male mice, and carrion that evoke innate aversion or attraction responses. We also identified a pheromone of juvenile mice that inhibits adult sexual behavior, and uncovered a noncanonical mechanism for sweet taste detection in hummingbirds that involved transformation of the ancestral umami receptor. Together, our work provides a molecular framework for understanding how sensory inputs are processed to evoke variable and complex behaviors.

Stephen J. Liberles, PhD

We study internal sensory systems using molecular and genetic approaches....

Bradford Lowell, MD, PhD

Email: blowell@bidmc.harvard.edu
Categories: BIDMC
Institution: Beth Israel Deaconess Medical Center
Research: Neural control of hunger, energy balance, metabolism and autonomic function
Grants & Publications: Harvard Catalyst

We utilize genetic engineering techniques in mice, electrophysiology, optogenetics, chemogenetics, rabies mapping, ChR2-assisted circuit mapping, in vivo assessments of neuronal activity, and single neuron transcriptomics to elucidate neural circuits controlling hunger and energy balance, neuroendocrine regulation and autonomic function. Neuron-specific recombinase driver mice are used in conjunction with recombinase-dependent AAVs expressing various genetically encoded “tools” to selectively (in a neuron cell type-specific fashion): a) map connectivity between neurons to establish their “wiring diagrams”, b) manipulate neuron firing rates in vivo to determine their roles in regulating behavior and physiology, and c) measure neuron activity in vivo to establish their responses to discrete behavioral and physiologic perturbations. These three parameters are key to understanding how neurons and their circuits control of behavior and physiology.

The above-mentioned approaches are powerful. However, their impact is sometimes limited by the fact that we do not know the different neurons that make up each “homeostatic” brain region (i.e., the “parts list”), and related to that, we do not have the “enabling” recombinase mice that would provide experimental access to these important, but presently unknown, neurons. We are addressing this by: 1) performing single-neuron transcriptomics on “homeostatic” brain regions to reveal: i) the different neurons that exist in each of these brain sites (i.e., the “parts list”), and ii) the genetic markers that specify each of the unique “parts” (i.e., the neurons). 2) We then use these genetic markers and CRISPR genetic engineering to rapidly generate mice expressing recombinases in each of the interesting, novel neurons. 3) Finally, we use these mice to uncover the wiring diagrams and determine the role these novel neurons play in regulating energy homeostasis and autonomic function.

Lab Website

Bradford Lowell, MD, PhD

We utilize genetic engineering techniques in mice, electrophysiology, optogenetics, chemogenetics,...

James Meigs, MD

Email: JMEIGS@mgh.harvard.edu
Categories: MGH
Institution: Massachusetts General Hospital
Research: Precursors to Type 2 Diabetes
Grants & Publications: Harvard Catalyst

Dr. Meigs has been a practicing primary care general internist at MGH for over 30 years, during which time his lab has focused on the cause and prevention of type 2 diabetes and cardiovascular disease using biochemical, genetic epidemiology and health services translational research approaches. He is a senior leader of many major large international T2D genomics consortia, including MAGIC, DIAGRAM, AAGILE, CHARGE- and TOPMed-diabetes, NIDDK T2D AMP/CMD and the VA’s MVP cardiometabolic work group. Dr. Meigs is also an experienced research mentor of over 50 early career investigators, including nine K-award recipients.

Current projects include:
TOPMed Omics of T2D, Quantitative Traits: We aim to use whole genome sequence and blood omic biomarkers in the NHLBI Trans-Omics for Precision Medicine (TOPMed) study to illuminate the pathobiology of type 2 diabetes (T2D) and its quantitative traits fasting glucose, insulin and hemoglobin A1c. We will integrate TOPMed results with beta cell-, liver-, fat- and muscle-specific omics and epigenomic annotation in the Accelerating Medicine Partnership (AMP) T2D Diabetes epiGenome Atlas and with hundreds of additional genomic trait associations in the AMP T2D Knowledge Portal for ‘in silico variant-to-function’ and phenomic studies aimed to find new approaches to address the global epidemic of T2D.

TOPMed Omics of CVD in T2D : We aim to use blood omic biomarkers in the NHLBI TOPMed study to illuminate the pathobiology of cardiovascular disease (CVD) in T2D. T2D is driving a major global epidemic of CVD, where CVD events occur over twice as frequently in people with T2D as without. The reasons for this excess risk are unknown but likely involve perturbations across multiple omic dimensions, including whole genome sequence variation and whole blood methylation, transcription, proteomics and metabolomics, where individually and together they contribute to novel pathways to CVD in T2D.

eMERGE Phase IV Clinical Center at Mass General Brigham: The discovery and clinical use of polygenic risk scores (PRS) for complex traits promises to dramatically change the practice of medicine. Our eMERGE IV grant will leverage a large Biobank and a rich electronic medical record to define the clinical impact of PRS derived from diverse populations and the clinical impact of returning these results along with family history and clinical risk information to participants and their healthcare providers.

Development of Polygenic Risk Scores for Diabetes and Complications across the Life Span in Populations of Diverse Ancestry: T1D and T2D, gestational diabetes (GDM) and related complications are excellent disease models to study the utility of polygenic risk scores (PRS) for predicting heterogenous and complex health outcomes in a setting where dramatic racial/ethnic and socioeconomic disparities exist. To address the disparities in PRS across ancestries, we have assembled a multi-disciplinary team to aggregate and analyze the largest existing genetic data from more than 1.8 M individuals (35% non-European) with T1D, T2D, GDM and glycemia-related complications and quantitative traits to improve the PRS prediction of diabetes and progression across the lifespan in diverse ancestries. Accomplishing the aims of this proposal will demonstrate how genomic data can inform more efficient and targeted preventive strategies within healthcare systems and across ethnically diverse populations

James Meigs, MD

Dr. Meigs has been a practicing primary care general internist...

Juan Melero-Martin, PhD

Email: Juan.MeleroMartin@childrens.harvard.edu
Categories: Children's
Institution: Children's Hospital
Research: Bioengineering and engraftment of microvascular networks
Grants & Publications: Harvard Catalyst

Our laboratory is interested in understanding how vascular networks are formed and the mechanisms by which vascular networks engraftment occurs upon transplantation. Every year, millions of grafting procedures are performed in the United States to replace damaged and/or diseased tissues, including pancreatic islets, skin, bones, nerves, blood vessels, and fat. The success of these procedures closely depends on achieving adequate revascularization of the grafts. However, inadequate revascularization remains a common outcome, leading to various degrees of graft resorption and failure. As a result, patients often require additional grafting, which imposes added donor site morbidity, operating room time, and cost. Moreover, repetitive grafting is limited by donor tissue availability. Thus, the search for new approaches to improve graft revascularization continues to be a pressing clinical need.
We specialize in the biology of human Endothelial Colony-Forming Cells (ECFCs). These ECFCs are progenitors of endothelial cells that circulate in cord blood and adult peripheral blood and have enormous potential in Regenerative Medicine because they can generate large amounts of autologous endothelial cells for vascular therapies. We also specialize in methods to bioengineer functional microvascular networks in vivo. Our approach combines human endothelial cells with human mesenchymal stem cells (MSCs) into a biocompatible hydrogel to form organized vascular networks that when implanted into immunodeficient mice join with the host vasculature. This model is ideally suited for studies on the cellular and molecular mechanisms of human vascular network formation and for developing strategies to improve microvascular engraftment in surgical grafting. In addition, our model allows us to study the mechanisms by which the endothelium modulates the activity of co-transplanted stem cells and to elucidate how tissue-specific endothelial cells influence the cross-talk that occurs between these stem cells and the vasculature.

In addition, an important part of our research relies on having high quality human pancreatic islets to study different strategies for vascularization and engraftment. For human islets, we worked with the Pancreatic Islet Isolation Core at the Massachusetts General Hospital. The service is provided through the Boston Area Diabetes Endocrinology Research Center (BADERC); this service has been exceptional and critical for our research progress. The islets we obtain through BADERC are of exceptional high quality as they are similar to those intended for transplantation and are isolated by standard clinical methods.

Lab website

Juan Melero-Martin, PhD

Our laboratory is interested in understanding how vascular networks are...

Vamsi Mootha, MD

Email: Mootha.Vamsi@mgh.harvard.edu
Categories: MGH
Institution: Massachusetts General Hospital
Research: Systems Approaches to Metabolism and Mitochondrial Biology
Grants & Publications: Harvard Catalyst

The research program is aimed at utilizing the new tools of genomics and computational biology to understand mitochondrial biology and metabolism. We are particularly interested in the rare mitochondrial disorders – collectively the largest class of inborn errors of metabolism. Major efforts in the group are aimed at identifying all of the protein components of mitochondria, discovering the regulatory networks that control their expression and assembly, and discovering genetic variants that disrupt these proteins and networks in human disease. We have found that an elevated NADH/NAD+ ratio, or reductive stress, is an important driver of mitochondrial disease. Ongoing work is aimed at targeting this parameter. Some of our work has implications for type 2 diabetes.

Vamsi Mootha, MD

The research program is aimed at utilizing the new tools...

Raul Mostoslavsky, MD, PhD

Email: RMOSTOSLAVSKY@MGH.HARVARD.EDU
Categories: MGH
Institution: Massachusetts General Hospital
Research: Understanding the crosstalk between epigenetics, metabolism, and cancer
Grants & Publications: Harvard Catalyst

The Mostoslavsky laboratory is interested in understanding the influence of chromatin on nuclear processes (gene transcription, DNA recombination and DNA repair) and the relationship between chromatin dynamics and the metabolic adaptation of cells. One of our interests is on the study of a group of proteins called SIRTs, the mammalian homologues of the yeast Sir2. Sir2 is a chromatin silencer that functions as an NAD-dependent histone deacetylase to inhibit DNA transcription and recombination. In the past few years, we have been exploring the crosstalk between epigenetics and metabolism. In particular, our work has focused on the mammalian Sir2 homologue, SIRT6. In recent years, we have identified SIRT6 as a key modulator of metabolism. Mice lacking SIRT6 exhibit severe metabolic defects, including hypoglycemia and hypoinsulinemia. SIRT6 appears to modulate glucose flux inside the cells, functioning as a histone H3K9 deacetylase to silence glycolytic genes acting as a co-repressor of Hif1alpha, in this way directing glucose away from to reduce intracellular ROS levels. This function appears critical for glucose homeostasis, as SIRT6 deficient animals die early in life from hypoglycemia. More importantly, SIRT6 acts as a tumor suppressor in colon cancer, regulating cancer metabolism through mechanisms that by-pass known oncogenic pathways.

Cancer cells prefer fermentation (i.e., lactate production) to respiration. Despite being described by biochemist and Nobel laureate Otto Warburg decades ago (i.e., the Warburg effect), the molecular mechanisms behind this metabolic switch remained unknown for decades. Our work identified SIRT6 as a critical modulator of the Warburg effect in both colon and skin cancer, providing a long-sought molecular explanation to this phenomenon. Further, our recent studies indicate that metabolism in cancer is a highly heterogeneous feature, with only a handful of cells (so called tumor propagating cells) adapted for glycolytic metabolism. We have also uncovered key roles for SIRT6 in DNA repair (anchoring the chromatin remodeler SNF2H to DNA breaks) and early development (acting as a repressor of pluripotent genes), indicating broad biological functions for this chromatin deacetylase. In addition, we identified SIRT6 as a robust tumor suppressor in pancreatic cancer, where it silences the oncofetal protein Lin28b, protecting against aggressive tumor phenotypes. As such, SIRT6 represents an example of a chromatin factor modulated by cancer cells to acquire “epigenetic plasticity”. Lastly, we more recently started expanding our research. We are exploring novel metabolic liabilities in cancer, including assessing the ability of cells to adapt to extreme nutrient conditions, and the unique epigenetic/metabolic adaptations of metastatic cells. On the other hand, we are looking into broader chromatin roles in DNA repair, using unique combinations of chromatin libraries and DNA repair assays where we can perform high throughput screenings.

Specific Projects:
1. Determining the role of SIRT6 in tumorigenesis using mouse models
2. Elucidating the role of histone modifications and chromatin dynamics in DNA repair
4. Determining molecular crosstalk between epigenetics and metabolism
5. Assessing metabolic liabilities in cancer and metastases.

Raul Mostoslavsky, MD, PhD

The Mostoslavsky laboratory is interested in understanding the influence of...

David Nathan, MD

Email: DNATHAN@mgh.harvard.edu
Categories: MGH
Institution: Massachusetts General Hospital
Research: Clinical Research in Type 1 and Type 2 Diabetes
Grants & Publications: Harvard Catalyst

Dr. Nathan directs the MGH Diabetes Center, which provides clinical care to patients with diabetes and focuses on the development and evaluation of innovative therapies for type 1 and type 2 diabetes and their complications. Dr. Nathan and the Diabetes Center have played a leadership role in the conduct of numerous NIH and Foundation supported multi-center trials that have defined modern-day diabetes prevention and treatment. These include: the Diabetes Control and Complications Trial (DCCT) and its ongoing follow-up study, the Epidemiology of Diabetes Interventions and Complications (EDIC) study, which demonstrated the primacy of intensive metabolic control in preventing the development of complications in Type 1 diabetes; the Diabetes Prevention Program (DPP) and DPP Outcomes Study (DPPOS) which established the means of preventing Type 2 diabetes; the Look AHEAD study which examined the role of a lifestyle intervention as a means of preventing heart disease in type 2 diabetes; the Immune Tolerance Network Study which explored islet transplantation as a treatment of type 1 diabetes; the TODAY study, exploring the treatments of type 2 diabetes in children and adolescents; the A1c-Derived Average Glucose Study (ADAG) which established the definitive translation of HbA1c into average glucose levels; and most recently GRADE, a comprehensive comparative effectiveness study of type 2 diabetes therapies. Dr. Nathan chairs (or chaired) DCCT/EDIC, DPP/DPPOS, ADAG and GRADE. Other current single center studies have promoted the translation of laboratory results into new therapies, such as the development of GLP-1 receptor agonist class of drugs and new techniques for islet transplantation, the development of an artificial pancreas for the treatment of type 1 diabetes, the immune basis of type 1 diabetes, cardiovascular disease prevention, and means of optimizing the care of type 2 diabetes by primary care practitioners. Epidemiological studies in collaboration with the Framingham Heart Study, Baltimore Longitudinal Study of Aging, and Nurses and Physicians Health Studies have explored the risk factors of diabetes and its complications and in particular the relationship between
glycemia and heart disease. A host of genetics and pharmacogenetic and quality improvement studies are also ongoing.

David Nathan, MD

Dr. Nathan directs the MGH Diabetes Center, which provides clinical...

Victor Navarro, MD

Email: VNAVARRO@BWH.HARVARD.EDU
Categories: BWH, HMS
Institution: Brigham and Women's Hospital, Harvard Medical School
Research: Neuroendocrine Regulation of Metabolism and Reproduction
Grants & Publications: Harvard Catalyst

The Navarro lab focuses on the neuronal mechanisms that control reproductive function and metabolism, from the events that participate in the sexual differentiation of the brain during perinatal periods to the acquisition and maintenance of reproductive behavior and fertility, as well as the metabolic cues that control each of these critical processes.

Reproduction is coordinated by neuro-endocrine communication between the brain and gonads. The hypothalamus is the nodal point for the action of central and peripheral factors that control the secretion of neurons that produce gonadotropin-releasing hormone (GnRH). GnRH stimulates the pituitary to secrete LH and FSH, which then act on the gonads to induce gametogenesis and create sex steroids, which in turn feedback to the hypothalamus to control GnRH release. Although we understand the basic principles that govern reproduction, we know far less about the cellular and molecular mechanisms that control GnRH secretion. Thus, the focus of the Navarro Lab is to understand how hormones and neurotransmitters initiate the onset of puberty, regulate reproductive cycles, and integrate metabolism and reproduction with special attention to the Kiss1 system.

Kisspeptins, encoded by the Kiss1 gene, bind to a G protein-coupled receptor, Kiss1r (formerly called GPR54). The importance of this signaling pathway became evident in 2003, when inactivating mutations in the Kiss1r gene were linked to hypogonadotropic hypogonadism in humans and mice. GnRH neurons are direct targets for the action of kisspeptin, which is a potent secretagogue for GnRH. The Navarro Lab continues the line of research that initially demonstrated that the expression of Kiss1 and Kiss1r in the hypothalamus is induced in association with the onset of puberty and that the administration of kisspeptin to prepubertal animals can initiate precocious puberty, suggesting that the kisspeptin activation of GnRH neurons plays a key role in gating pubertal maturation. Additionally, these initial studies showed that the expression of the Kiss1 gene of the adult is influenced by the steroid milieu during the neonatal critical period, when the brain undergoes sexual differentiation.
We are also interested in elucidating the hypothalamic pathways that regulate the action of the Kiss1 system. Specifically, the action of dynorphin (encoded by Pdyn) and tachykinins (Substance P, neurokinin A and neurokinin B, encoded by Tac1 and Tac2) on Kiss1 neurons. Many of these neurotransmitters are co- expressed in the same neurons of the hypothalamic arcuate nucleus and are suggested to participate in the shaping of kisspeptin pulses, which in turn control GnRH pulsatility.

Victor Navarro, MD

The Navarro lab focuses on the neuronal mechanisms that control...

Valentina Perissi, PhD

Email: vperissi@bu.edu
Categories: BU
Institution: Boston University
Research: Regulation of metabolic adaptation and nuclear-mitochondria communication

The overarching theme in the Perissi Lab is dissecting the molecular mechanisms that control metabolic adaptation in response to nutrients availability, cell differentiation and oxidative stress. Current projects focus on two main areas:

1) Mechanisms regulating mitochondria-nuclear communication. We have recently identified a novel nuclear- mitochondrial communication pathway based on the translocation of a transcriptional cofactor, called G- Protein Pathway Suppressor 2 (GPS2), from the mitochondria to the nucleus to regulate the expression of nuclear-encoded mitochondrial genes. Our data indicate that GPS2-mediated retrograde signaling is critical for responding to acute mitochondrial stress by depolarization, and for sustaining mitochondrial biogenesis during adipocyte differentiation (Cardamone et al., Molecular Cell, 2018).
2) Dissecting the role of non-proteolytic K63 ubiquitination in the regulation of metabolic reprogramming. This stems from the identification of G-Protein Suppressor 2 (GPS2) as a specific inhibitor of the ubiquitin- conjugating enzyme Ubc13 (Lentucci et al., JBC, 2017). Investigating the role of the GPS2-Ubc13 module within different cellular compartments has led us to describe unexpected roles for GPS2 as a suppressor of PI3K/AKT signaling downstream of the insulin receptor and as an inhibitor of TLR and TNFR pro- inflammatory signaling pathways (Cardamone et al., Molecular Cell, 2012; Cederquist et al., Molecular Metabolism, 2016; Lentucci et al., JBC, 2017). Ongoing studies investigate novel targets of regulation, in addition to addressing the relevance and synergism among these functions in the context of obesity- associated inflammation/insulin resistance and breast cancer.

Valentina Perissi, PhD

The overarching theme in the Perissi Lab is dissecting the...

Anastassios Pittas, MD, MS

Email: apittas@tuftsmedicalcenter.org
Categories: Tufts
Institution: Tufts University
Research: Prevention and management of type 2 Diabetes

The program focuses on the role of vitamin D in prevention and treatment of type 2 diabetes (vitamindfordiabetes.org). The program is funded by NIH and ADA to conduct observational and randomized trials on prevention of type 2 diabetes. We have completed a large multi-center trial on vitamin D supplementation for prevention of type 2 diabetes (www.d2dstudy.org) and recently completed a second smaller 2-site trial on vitamin D supplementation for treatment of established type 2 diabetes. Tufts Medical Center also served as a clinical site for both trials.

Anastassios Pittas, MD, MS

The program focuses on the role of vitamin D in...

Camille Powe, MD

Email: Camille.Powe@MGH.HARVARD.EDU
Categories: MGH
Institution: Massachusetts General Hospital
Research: Physiology and Genetics of Metabolic Disease Affecting Women in Pregnancy and Postpartum
Grants & Publications: Harvard Catalyst

The Powe clinical research group focuses on studying diabetes and the glucose metabolism of women who are pregnant or recently postpartum. Studies aim to improve our understanding of metabolic disease affecting this population by focusing on endocrine physiology and genetics. Current studies focus on detailed longitudinal characterization of glycemic physiology in pregnancy and examining approaches to parse heterogeneity among women with gestational diabetes (GDM). We have defined physiologic subtypes of gestational diabetes and are investigating translation of our findings to personalize therapy for women with gestational diabetes. Selected projects include:

1) GO MOMs – Glycemic Observation and Metabolic Outcomes in Mothers and Offspring. GO MOMs is a multicenter prospective longitudinal study designed to characterize the glycemic profile of pregnancy using continuous glucose monitoring (CGM) technology in order to develop criteria using CGM measurements and/or early pregnancy oral glucose tolerance testing (OGTT) that are predictive, along with clinical factors, of adverse pregnancy outcomes in mothers and their newborns.
2) SPRING – Study of Pregnancy Regulation of Insulin and Glucose. SPRING aims to characterize pregnancy-associated changes in insulin secretion and sensitivity, compare insulin secretion and sensitivity in high-risk women who do and do not develop GDM, examine the contribution of maternal genetics to glycemic physiology, and discover proteins secreted by the placenta that affect glycemia.
3) HINT-GDM – Heterogeneity Informed Nutritional Therapy for Gestational Diabetes Mellitus. HINT-GDM aims to develop dietary interventions to minimize glycemic excursions in distinct physiologic subtypes of GDM and prospectively confirm previously observed associations between physiologically-defined GDM subtypes and hyperglycemia-associated adverse outcomes.
4) MHC – The MGH Maternal Health Cohort. The MHC is a large electronic medical record-based cohort that collects medical and health information from women seen for prenatal care at MGH to study the effects of chronic diseases on pregnancy outcomes and pregnancy’s impact on women’s health. Pregnancy is an understudied area, so this protocol aims to examine risk factors that affect maternal and neonatal outcomes which will help inform future interventions designed to improve women’s health. A subset of women in MHC provided blood samples during their pregnancy which are available for
5) MGH2 – The MGH Maternal Genetics and Health Study. MGH2 will add genetic data to the MHC cohort to examine genetic determinates of maternal and infant health. Initial work will focus on the genetics of GDM.

Camille Powe, MD

The Powe clinical research group focuses on studying diabetes and...

Pere Puigserver, PhD

Email: Pere_Puigserver@dfci.harvard.edu
Categories: Dana-Farber
Institution: Dana-Farber Cancer Institute
Research: Control of Nutrient and Energy Metabolism
Grants & Publications: Harvard Catalyst

Nutrient Sensing and Diabetes: Mammalian cells sense nutrients signals to reprogram energetic metabolism and trigger tissue specific responses within the context of whole animal physiology. For example, nutrient fluctuations during fed/fasting or diabetic conditions define specific metabolic functions in central and peripheral tissues. We have used the family of PGC-1 coactivators, key proteins in remodeling glucose and lipid metabolism, as a “scaffold” bait to identify nutrient sensing components. We have identified a new regulatory nutrient/metabolite pathway that impinges on the hyperacetylation of PGC-1s. Central sensing components within this pathway include metabolite sensitive enzymes such as the acetyl transferase GCN5 (responds to Acetyl-CoA levels), the deacetylase SIRT1 (responds to NAD+ levels) and components of the canonical cAMP pathway, and insulin/amino acid cell cycle components (Lee et al. 2014). We have also identified small molecules that control “acetylation” components with anti-diabetic effects (Sharabi et al. 2017). In the context of cell cycle components linked to obesity/diabetes, we have recently identified a specific vulnerability (Cyclin D1/CDK4) in liver tumors formed in obese/diabetic conditions (Luo et al. 2020). We have also identified NADPH regulatory pathways that are controlled by metabolic enzymes such ME1 (Balsa et al. 2020). Studies in cells and mouse models have shown that manipulation of these pathways is dysregulated in type 2 diabetes linked to obesity.

Mitochondrial Biology and Energy Metabolism: Energy expenditure is a key component of energy balance that, at the cellular level, requires oxidative metabolism through mitochondrial respiratory activities. We are interested in defining the regulatory control of how mitochondrial mass is formed, assembled and activated to generate energy and heat dissipation. We use traditional approaches in biochemistry, cellular biology and physiology in combination with new screening technologies, genetic/epigenetic and disease models. We have applied bioinformatic and genetic/proteomic tools to identify transcription factors that are pivotal to mitochondrial biology including the zinc finger YY1 and the co-activator PGC-1s and signaling kinases including Clk2 (Verdeguer et al. 2015; Hattings et al. 2017) and PERK (Balsa et al 2019; Latorre-Muro et al. 2021). In addition, we uncouvered new mechanisms whereby tetracyclines and mitochondrial translation rescue mitochondrial dysregulation and mutations in cells and mouse pre-clinical models (Perry et al. 2021).

Pere Puigserver, PhD

Nutrient Sensing and Diabetes: Mammalian cells sense nutrients signals to...

Melissa Putman, MD, MS

Email: MSPUTMAN@PARTNERS.ORG
Categories: MGH
Institution: Massachusetts General Hospital
Research: Advancing the Diagnosis and Care of Cystic Fibrosis Related Diabetes
Grants & Publications: Harvard Catalyst

Leveraging the large patient population with cystic fibrosis (CF) cared for by the MGH CF Center and the Boston Children’s Hospital CF Center, the goal of this research program is to improve our understanding and treatment of CF-related diabetes (CFRD). With funding from the NIDDK and the Cystic Fibrosis Foundation (CFF), we are investigating the application of diabetes technology to the screening, diagnosis, and treatment of CFRD as well as the impact of nutrition on glycemic control and clinical outcomes. Utilizing resources from the clinical research core led by Dr. Nathan, we recently completed a clinical study investigating the use of continuous glucose monitoring (CGM) in the diagnosis of CFRD, finding that average glucose derived from CGM correlates well with A1c. We are also exploring the use of continuous glucose monitoring to the screening and diagnosis of CFRD. Funded by the NIDDK, we are leading studies investigating the safety and efficacy of artificial pancreas technology (the bionic pancreas) in children and adults with CFRD, with plans to expand our single-site clinical trial to multiple sites across the country with funding from the CF Foundation. We are also leading the Maternal and Fetal Outcomes in the Era of Modulators (MAYFLOWERS) CGM substudy, collecting comprehensive CGM data in pregnant women with CF throughout pregnancy at 30 CF centers across the US. We are also leading a multicenter planning grant to design a study investigating novel assessments of nutritional status in adults with CF and advanced lung disease. Lastly, funded by a competitive revision from the NIDDK to R01119699, we are investigating the use of CGM in hospitalized patients during the COVID-19 pandemic. This program has supported the career development of multiple junior investigators, including (1) Dr. Jordan Sherwood, a pediatric endocrinologist supported by CF Foundation Shwachman Career Development Award investigating artificial pancreas technology in patients with CF referred for lung transplant; (2) Dr. Laura Brenner, a pulmonologist awarded a K23 from the NIDDK investigating the impact of the bionic pancreas on lung and gut microbiome; (3) Dr. Luz Castellanos supported by a diversity supplement to R01DK119699; (4) Dr. Mollie Sands, a second year endocrine fellow at MGH, and (4) Dr. Kevin Scully, a pediatric endocrine junior faculty at Boston Children’s Hospital investigating diabetes technology in CFRD.

Melissa Putman, MD, MS

Leveraging the large patient population with cystic fibrosis (CF) cared...

Eugene Rhee, MD

Email: EPRHEE@PARTNERS.ORG
Categories: MGH
Institution: Massachusetts General Hospital
Research: Metabolomics of CKD and Diabetes
Grants & Publications: Harvard Catalyst

One of my lab’s major interests is the application of LC-MS based metabolomics to epidemiologic and physiologic studies of kidney disease, including diabetic nephropathy. We have spearheaded the first published studies of metabolomics to study the effects of the hemodialysis procedure, identify novel markers of death in end-stage renal disease, identify predictors of new onset CKD, and differentiate individuals with established CKD who do or do not progress. A key feature of these studies has been the integration of physiologic investigation—more specifically, collection of samples from the aorta and renal vein using invasive catheterization—to characterize how the human kidney modulates hundreds of molecules, providing insight on why select metabolites are deranged in renal failure. In parallel, my laboratory is interested in lipid metabolism in the kidney and beyond. In conjunction with Drs. Robert Gerszten (BIDMC) and Clary Clish (Broad Institute), we showed that lipid highly unsaturated fatty acid (HUFA) content can change rapidly, increasing in plasma triglycerides within 2 hours of various glycolytic stimuli, including oral glucose ingestion, sulfonylurea administration, and exercise. In follow up, we recently elucidated the biochemistry that underlies these human observations, identifying HUFA synthesis as a novel mechanism of glycolytic NAD+ recycling, analogous to lactate fermentation. The relevant desaturases are highly expressed in the kidney and liver, where their role in NAD+ recycling is acutely adaptive during acute stress, including acute kidney injury, but may contribute to dyslipidemia over time. In addition, these findings highlight a key biologic role for lipid desaturation independent of the HUFA end products and provide insight into genetic studies linking lipid desaturation with human disease, including diabetes.

Eugene Rhee, MD

One of my lab’s major interests is the application of...

Evan Rosen, MD

Email: erosen@bidmc.harvard.edu
Categories: BIDMC
Institution: Beth Israel Deaconess Medical Center
Research: Transcriptional Basis of Metabolic Physiology and Pathophysiology
Grants & Publications: Harvard Catalyst

The Rosen lab strives to understand how gene expression networks control the development, function, and pathophysiology of metabolically relevant tissues, with an emphasis on adipose tissue. We employ genetic, genomic, computational, cell biological, and in vivo modeling approaches to questions related to adipogenesis, thermogenesis, insulin action, and inflammation. Current projects include:
1. Single cell approaches to human and murine adipose tissue biology. We have generated large atlases of mouse and human adipose tissue at single cell resolution from different depots and under different nutritional conditions. These atlases are being used to identify unique subpopulations of adipocytes and other cells and to generate hypotheses about cell-cell interactions within the adipose niche.

2. Understanding the role of interferon regulatory factors at the intersection of inflammation and metabolism. We have identified IRF family members as critical transcriptional regulators of adipogenesis, lipolysis, thermogenesis, hepatic glucose metabolism and fatty liver. Studies are also underway to assess the role of IRF3 in mediating leptin’s actions in the hypothalamus. Furthermore, we have identified ISGylation as a downstream effector of inflammation in adipose tissue, and we are pursuing studies to identify ISGylated target proteins.

3. Neuropeptide regulation of adipose biology. We have identified two neuropeptides, oxytocin (OXT) and neurotensin (NTS), with profound effects on adipose lipolysis and thermogenesis. Interestingly, these neuropeptides appear to be released by cells within the adipose niche. In the case of OXT, the contributing cell is a subset of sympathetic neurons, while NTS is derived from local lymphatic vessels.

Lab website

Evan Rosen, MD

The Rosen lab strives to understand how gene expression networks...

Anthony Rosenzweig, MD

Email: ROSENZWE@HELIX.MGH.HARVARD.EDU
Categories: MGH
Institution: Massachusetts General Hospital
Research: Mechanisms and novel therapeutic targets in heart failure
Grants & Publications: Harvard Catalyst

Research in the Rosenzweig laboratory is focused identifying new mechanisms and targets in heart failure. Heart failure is closely related to metabolic dysregulation in general and diabetes in particular. In addition to studying what goes wrong in heart disease, a growing area of research has been identification of pathways that keep the heart healthy, using the exercised heart as a model. Earlier studies identified intracellular signaling pathways regulating cardiomyocyte survival and function, including the first demonstration that PI3- kinase and Akt1 are critical in this context. They are also important components in insulin signaling. Subsequent work went on to demonstrate novel targets amenable to pharmacological intervention in heart failure and arrhythmia, such as SGK1, the focus of a recently funded biotech company. Studies of how exercise benefits the heart showed that growth of the heart in response to exercise is fundamentally different from that in response to pathological stimuli such as pressure overload (Cell 2010). Moreover, exercise induces cardiomyogenesis in the adult mammalian heart (Nature Comm 2018). Comprehensive genome-wide analyses have identified candidate pathways that mediate the cardioprotective and regenerative effects of exercise (Cell Metabolism 2015; Circulation 2022). Ongoing efforts seek to exploit the translation potential of targeting these pathways.

Anthony Rosenzweig, MD

Research in the Rosenzweig laboratory is focused identifying new mechanisms...

Clifford Saper, MD, PhD

Email: csaper@bidmc.harvard.edu
Categories: BIDMC
Institution: Beth Israel Deaconess Medical Center
Research: Brain circuitry for hypothalamic integrated functions
Grants & Publications: Harvard Catalyst

The Saper laboratory works on neural circuitry that underlies several basic and related hypothalamic functions, including circadian rhythms; wake-sleep cycles; thermoregulation; and feeding and metabolic control. We study brain circuitry that regulates these functions using a combination of cutting-edge neuroscience methods, including opto- and chemogenetics; fiber photometry; and use of animals with loxP sites inserted in key genes, which can then be disabled by injection of adeno-associated viral vectors that express Cre recombinase. This is combined with measuring EEG/EMG, body temperature, locomotor activity, feeding, brown adipose activation, and other physiological and behavioral measures.

Clifford Saper, MD, PhD

The Saper laboratory works on neural circuitry that underlies several...

Richa Saxena, PhD

Email: RSAXENA@PARTNERS.ORG
Categories: MGH
Institution: Massachusetts General Hospital
Research: Genetic basis of sleep, circadian rhythms and links to metabolic disease
Grants & Publications: Harvard Catalyst

My research laboratory focuses on discovery of genes and pathways underlying sleep and circadian rhythm disorders and investigates their mechanistic links with type 2 diabetes. We aim to chart a course from genetic discoveries to biological, physiologic, and clinical insights relevant to diagnosis and treatment of sleep disorders and related cardio-metabolic disease.

Illuminating the genetic and molecular basis of sleep and circadian rhythm traits and their link to cardio- metabolic disease. Our lab aims to understand the molecular basis of sleep and circadian rhythm behaviors and disorders by defining the genetic architecture, testing gene function in model organisms, and exploring shared biological pathways between these traits and cardio-metabolic disease. We have discovered hundreds of common genetic loci for morningness/eveningness preference, insomnia, sleep duration, daytime napping, and daytime sleepiness, and we find substantial heterogeneity and genetic overlap with neuropsychiatric and cardio-metabolic disease. Mendelian randomization studies suggest that insomnia contributes in a causal way to risk of type 2 diabetes. Our work has opened up novel lines of investigation and promises to yield important fundamental and translational insights and putative therapeutic targets for sleep and circadian disorders with relevance to multiple diseases.

Impact of Melatonin, MTNR1B diabetes risk gene and food timing on glucose tolerance. An estimated 5-12 million Americans use melatonin to treat sleeping problems and ~10% of working adults are shift-workers with increased diabetes risk, but the precise effect of melatonin, and its interaction with food intake on diabetes prevention and control is unknown. We found that variation in the melatonin receptor 1b gene (MTNR1B) and core clock gene cryptochrome 2 (CRY2) influence glycemic traits, implicating circadian rhythm pathways as important in glucose homeostasis and T2D. Our recent collaborative physiologic studies suggest that night eating at a time when melatonin levels are high impairs glucose tolerance, particularly in carriers of the MTNR1B risk allele. This may impact vulnerable populations of late-night eaters, shift workers or users of melatonin as a sleep-aid. We have ongoing follow-up genotype-targeted physiologic and in-vitro human pancreatic islet studies as well as epidemiologic studies to further explore mechanisms by which MTNR1B receptor variation increases risk of type 2 diabetes.

Richa Saxena, PhD

My research laboratory focuses on discovery of genes and pathways...

Guo-Ping Shi, ScD, DSc

Email: GSHI@BWH.HARVARD.EDU
Categories: BWH
Institution: Brigham and Women's Hospital
Research: Role of IL18 in obesity and diabetes
Grants & Publications: Harvard Catalyst

IL18 is a pleiotropic cytokine that is expressed in cardiovascular disease-relevant macrophages, smooth muscle cells, endothelial cells, and adipocytes. Il18-/- mice but not Il18r-/- mice showed reduced atherosclerosis. These unexplained observations inspired the discovery that IL18 uses two receptors: IL18r and NCC (Na-Cl

co-transporter), a 12-transmembrane domain ion channel protein. The role of IL18 in obesity and diabetes remains uncertain. Adipocytes, skeletal muscle, and inflammatory cells in white adipose tissues (WAT) produce IL18. Plasma IL18 levels are elevated in obese and diabetic patients, correlate with HbA1C, and predict the risk of type 1 diabetes (T1D), type 2 diabetes (T2D). Paradoxically, results from several studies indicate that IL18 deficiency exacerbated obesity and diabetes in mice. Il18-/- and Il18r-/- mice on a chow diet gained more weight than wild-type mice, suggesting that IL18 is a homeostatic regulator that is elevated in obesity to oppose excess energy, analogous to insulin and adipokine leptin. Our preliminary studies suggest that IL18r and NCC mediate IL18 activities in distinct cell types. IL18 and NCC (but not IL18r) are expressed predominantly in BAT or in beige adipocytes. Their expression was reduced in mice on a high fat diet (HFD) or increased after thermogenic stimulation with CL316243. Deficiency of NCC (but not IL18r) reduced energy expenditure and BAT or beige adipocyte thermogenic program. BAT-selective IL18 deficiency aggravated obesity and diabetes. In WAT from HFD-fed and CL316243-treated mice, and in beige adipocytes from WAT, the expression of IL18 and IL18r (but not NCC) was increased. In WAT adipocytes, IL18 induced the expression of IL18r (but not NCC) and insulin signaling. Insulin receptor (IR�) formed an immunocomplex with IL18r, but not with NCC. In pancreas, we detected selective expression of IL18 in a-cells, NCC in �-cells, and IL18r in acinar cells. In HFD-induced T2D and streptozotocin-induced T1D, NCC or IL18r deficiency reduced pancreas islet count and insulin production and signaling with concurrent increase of islet macrophage content.�-cell NCC is required for islet insulin secretion and signaling, whereas IL18r on acinar cells is required for islet insulin secretion and to block exocrine acinus macrophage accumulation. a-cell-selective IL18 depletion or �- cell-selective NCC deficiency exacerbated HFD-induced obesity or diabetes. Our current program is to test the hypothesize that NCC in BAT controls thermogenesis, IL18r in WAT controls insulin signaling, NCC in islet �- cells controls �-cell insulin secretion and signaling and islet inflammation, and IL18r in acinar cells controls exocrine acinus inflammation and indirectly controls islet insulin secretion.

Guo-Ping Shi, ScD, DSc

IL18 is a pleiotropic cytokine that is expressed in cardiovascular...

Alexander Soukas, MD, PhD

Email: asoukas@mgh.harvard.edu
Categories: MGH
Institution: Massachusetts General Hospital
Research: Metabolic Underpinnings of Obesity, Diabetes, and Aging
Grants & Publications: Harvard Catalyst

The Soukas laboratory focuses on identification and characterization of genetic pathways that promote healthy aging and reduce aging-associated metabolic diseases such as type 2 diabetes, obesity, and cancer. The lab uses a combination of genetic approaches in vertebrate and invertebrate model systems to determine how genetic pathways can be manipulated to have favorable effects on metabolism and aging. At present, three projects are ongoing:

1) Mechanisms by which metformin improves glucose and lipid homeostasis, prolongs lifespan, and blocks the growth of cancer. Metformin is the most commonly used medication for type 2 diabetes worldwide. In recent years, it has become clear that metformin also has anti-cancer properties and can prolong lifespan of model organisms. We recently published in Cell (PMC5390486) that metformin effects at mitochondria lead to alterations in nuclear transport, inactivating mTORC1, thereby, inhibiting cancer growth, and prolonging lifespan. Remarkably, this pathway is conserved from the invertebrate C. elegans to human.

2) Connecting starvation survival to obesity and type 2 diabetes. Starvation is among the most ancient of selection pressures. Starvation defenses activated when nutrients become scarce permit animals to survive until nutrients are plentiful again. We identified a thrifty genetic pathway that activates doubling to tripling of starvation survival when protein translation genes are inhibited. Turning off protein synthesis tripled fat stores and starvation survival while turning off proteasomal genes, which encode gene products that degrade proteins, led to very low body fat stores and tremendous shortening of starvation
survival. Surprisingly, the proteostasis machinery controls starvation survival by activating the master starvation regulator AMPK (Published in Cell Reports PMC5578715).

3) Manipulating insulin signaling to reduce aging-associated diseases and to promote healthy aging and healthy metabolism. Recent work in the aging field has shown that activation of autophagy, or “self-eating” is mechanistically required in almost every genetic, dietary, and pharmacologic manipulation that extends lifespan. Conversely, mutations in essential autophagy-related genes lead to human diseases such as diabetes, inflammatory bowel disease, and cancer. By studying the insulin-signaling component mTOR complex 2, we determine that it promotes health by reducing mitochondrial permeability. When mTOR complex 2 acts, it promotes mitochondrial health, permitting autophagy to have beneficial effects on longevity in invertebrates and to reduce ischemia-reperfusion injury in mTOR complex 2 signaling liver- specific knockout mice (published in Cell PMC6610881). This work has implications for metabolism, aging, heart attack, stroke, and organ transplantation. More recently, we have found that mTOR complex 2 has complicated roles in metabolism. Specifically, mTOR complex 2 promotes insulin resistance in animals fed a high fat diet by signaling through the downstream AGC family kinase Sgk1 (published in Cell Reports PMC8576737). As such inactivation of mTOR complex 2 has disparate effects on mitochondrial health and insulin resistance, so further work is dissecting how we can promote health by leveraging targets downstream of the kinase.

Alexander Soukas, MD, PhD

The Soukas laboratory focuses on identification and characterization of genetic...

Bruce Spiegelman, PhD

Email: Bruce_Spiegelman@dfci.harvard.edu
Categories: Dana-Farber
Institution: Dana Farber Cancer Institute
Research: Transcriptional Basis of Energy Metabolism in Health and Disease
Grants & Publications: Harvard Catalyst

Our lab is focused on the regulation of energy homeostasis in mammals, primarily at the level of gene transcription. This includes the problems of fat cell development, control of metabolic rates and the pathways of glucose and lipid metabolism. These studies have applications to the development of new therapies for diabetes, obesity, muscular and neurodegenerative diseases.

1. Regulation Of Fat Cell Development. We are deeply interested in the development and function of adipose cells, white, brown and beige. Our group identified the master regulator of fat development in 1994: the nuclear receptor PPARγ. Since then a major focus of our group has been to understand the pathways that control PPARγ function: its ligands, its coactivators and other transcription factors that modify its function. Since synthetic ligands to PPARγ are used clinically as anti-diabetic drugs, we are taking biochemical approaches to understanding the identity of endogenous ligands that control this receptor in vivo. We have also explored the transcriptional control of brown fat differentiation; this led to the identification of a futile cycle of creatine phosphorylation and dephosphoryation as being a critical component of adaptive thermogenesis. We have recently identified the critical creatine kinase (CKB) and creatine phosphate hydrolase (TNAP) involved in this pathway.

2. Metabolic Control Through The PGC-1 Coactivators. Biological control via gene transcription was thought to occur mainly through changes in amounts or activities of transcription factors. However, the PGC-1 coactivators have illustrated the regulation of critical metabolic programs is controlled largely via transcriptional coactivation. Brown fat-mediated thermogenesis muscle fiber type switching and hepatic gluconeogenesis are all induced via expression of PGC-α, then docks on a variety of transcription factor targets. PGC1α mRNA undergoes much control at the level of mRNA translation and we are currently exploring factors involved in this process.

3. Function and Regulation of Irisin. Irisin is a PGC1α-dependent myokine secreted into the blood of mice and humans. It influences bone development and osteoporosis in female mice; its function in motor nerves and the CNS is under study in our lab and others. We are currently studying the effects of irisin in muscular dystrophies, where diabetes is common and in ALS.

Bruce Spiegelman, PhD

Our lab is focused on the regulation of energy homeostasis...

Ali Tavakkoli, MD

Email: atavakkoli@bwh.harvard.edu
Categories: BWH
Institution: Brigham and Women's Hospital
Research: Surgical and Metabolic Research
Grants & Publications: Harvard Catalyst

Over the past several decades, obesity and its attendant metabolic disorders, in particular, type-2 diabetes have reached epidemic proportions. The field of metabolic surgery arose from the observation that procedures such as Roux-en-Y gastric bypass can significantly improve diabetes, independent of its effect on weight. While this empiric observation has been repeatedly validated in large, randomized studies, the underlying molecular mechanism of this phenomenon remains largely elusive. Our lab’s overarching thrust is to understand the mechanistic underpinnings of the anti-diabetic effects of bariatric operations and to leverage this knowledge to develop novel therapies for patients that are more effective and less invasive.

Ali Tavakkoli, MD

Over the past several decades, obesity and its attendant metabolic...

Linus Tsai, MD, PhD

Email: ltsai@bidmc.harvard.edu
Categories: BIDMC
Institution: Beth Israel Deaconess Medical Center
Research: Defining Cell type and gene networks underlying obesity and type 2 Diabetes
Grants & Publications: Harvard Catalyst

Broadly, my laboratory seeks to utilize next generation sequencing technologies and analysis to better understand the genetic, epigenetic, and tissue/cell type bases of metabolic disease. In particular, we study the biological and neural circuits and gene regulatory networks underlying obesity and type 2 Diabetes in the hypothalamus and adipose tissue of human and rodent models. Research areas include:

1. Molecular taxonomy of hypothalamic neurons. With Brad Lowell and John Campbell groups, we are systematically defining the hypothalamic neuron types underlying weight regulation, insulin resistance, and glucose homeostasis using single cell transcriptional profiling of key hypothalamic regions involved in energy balance. Starting with unbiased single cell profiling, we define a “parts” list of each region’s constituent neuron types and the genetic markers that specify each. We integrate these profiles with human GWAS data to suggest function and validate hypotheses using specific recombinase lines (many engineered from above profiling) to monitor or manipulate each’s activity and connectivity using genetic, optogenetic or pharmacogenetic approaches. My initial work on the arcuate nucleus was supported by a BADERC P&F award (2016) and resulted in publication of a seminal manuscript in the field (PMC5323293). Similar manuscripts on DMV, PVH, and LPBN have or will be submitted within the year.

2. Role of median eminence cell types in barrier function and energy balance. The arcuate-median eminence ooccupies a unique anatomical position at the nexus between the peripheral circulation, CSF of the third ventricle, and the brain parenchyma. Using single cell transcriptional profiling, we have molecularly characterized the cell types regulating communication between these compartments including: 1) specialized fenestrated endothelial cells of the ME that allow passage of signals to and from the periphery,2) β1 and β2 tanycytes that form the junction between ME, arcuate, and 3rd ventricle, and 3) neuroendocrine cells of the pars tuberalis, which lines the ME and sends signals to central brain. Using tools to induce cell-type specific activation or loss of function, we are characterizing the molecular pathways by which these cells regulate energy intake and insulin sensitivity.

3. Reconstructing the functional gene regulatory circuitry of adipocytes. In collaboration with Evan Rosen, we are systematically identifying the functional components of the human adipocyte epigenome, using histone modification ChIP-seq, ATAC-seq, RNA-seq and Hi-C to profile regulatory elements controlling gene expression across a spectrum of obesity and insulin resistance states. Bioinformatically, we reconstruct the molecular circuits underlying variation in transcription, determine adipocyte-specific eQTLS, and prioritize causal GWAS variants mediating adipocyte roles in obesity, insulin resistance, and diabetes.

4. Atlas of cell types in human and mouse adipose tissue. Adipose tissue plays a central role in the pathophysiology of obesity and diabetes, modulating satiety, glucose, and lipid homeostasis. Adipose tissue cell type content is heterogeneous, dynamic, and altered by obesity. Using single nucleus RNA-seq we assess functional cell type interactions across a variety of metabolic perturbations, including fasting, weight loss, high fat diet exposure, gastric bypass, and aging to determine how individual cell types interact to produce the adipose tissue dysfunction.

Linus Tsai, MD, PhD

Broadly, my laboratory seeks to utilize next generation sequencing technologies...

Miriam Udler, MD, PhD

Email: MUDLER@mgh.harvard.edu
Categories: MGH
Institution: Massachusetts General Hospital
Research: Genetic Subtypes of Diabetes and Metabolic Disease
Grants & Publications: Harvard Catalyst
Laboratory Website: https://www.udlerlab.org/

Our team’s research aims to identify molecular subtypes of type 2 diabetes in order to improve patient management. We interrogate genetic data across the spectrum from rare to common variation to identify novel diabetes genes and mechanisms of disease. At the rare end of the spectrum, we are part of a U54 through the NIDDK to better characterize atypical forms of diabetes using whole genome sequencing and physiological testing. At the common end of the spectrum, we are interested in leveraging the hundreds of common genetic variants identified through genome-wide association studies to identify pathways causing disease. We have employed variant-trait association clustering to identify pathways and developed pathway-specific polygenic scores to investigate how mechanistic pathways impact patient outcomes. Our research involves analyzing large-scale patient genomic data from the UK Biobank, the Mass General Brigham Biobank, and the Type 2 Diabetes Knowledge Portal. Our team participates in the ClinGen Monogenic Diabetes Expert Panel and studies the role of genetic testing in clinical practice and how to improve upon the current standard of care in endocrine clinical genetics.
References.

Miriam Udler, MD, PhD

Our team’s research aims to identify molecular subtypes of type...

Deborah Wexler, MD, MsC

Email: DWEXLER@mgh.harvard.edu
Categories: MGH
Institution: Massachusetts General Hospital
Research: Clinical effectiveness in type 2 diabetes
Grants & Publications: Harvard Catalyst

Through her research and mentorship, Dr. Wexler aims to define and achieve optimal treatment, quality of care, and quality of life for patients with type 2 diabetes using epidemiologic, clinical trial, and implementation science methodologies and through development and dissemination of guidelines and standards of care. Her expertise in this area is reflected in national leadership roles as a member of the American Diabetes Association’s Professional Practice Committee 2014-2016 and as one of five Americans invited by the ADA to draft the 2018 ADA-EASD Position Statement on Management of Hyperglycemia in Diabetes. She is currently the primary mentor of two endocrinology fellows and two junior faculty members, and a co-mentor to other fellows and junior faculty. She led the development of the MGH Diabetes Center research registry and supervises its use to promote effective recruitment into clinical trials and consults extensively with colleague to share approaches to effective recruitment and care model implementation, having successfully evaluated and implemented new care models in diabetes over the course of the last decade. She is now launching two major PCORI-funded projects.

1) GRADE (Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness) Study Role: MGH Site Principal Investigator; Member of the Executive Committee, and co-chair of the Outcomes Committee. This 37-site trial, one of the NIDDK’s major clinical trial initiatives in this decade, will evaluate the long-term metabolic and clinical effects of four classes of drugs in combination with metformin for the treatment of type 2 diabetes. It will answer the major pressing clinical questions in treatment of type 2 diabetes while also addressing novel pathophysiologic and cost-effectiveness hypotheses.
2) REAL HEALTH-Diabetes Study. This project adapted and implemented a medically supervised, evidence- based group lifestyle change program in usual care and found that it yielded clinically significant weight loss.
3) Comparative effectiveness of diabetes medications in observational databases. Complementing her work on GRADE, Dr. Wexler is collaborating with Elisabetta Patorno, of the Division of Pharmacoepidemiology at BWH, to conduct a PCORI funded analysis addressing this question using real world evidence.
4) Comparative effectiveness of SGLT2 inhibitors, GLP-1 Receptor agonists, or their combination, a pragmatic comparative effectiveness trial. Dr. Wexler is co-leader of the clinical coordinating center of PRECIDENTD (Everett BM, PI).

Deborah Wexler, MD, MsC

Through her research and mentorship, Dr. Wexler aims to define...

Gordon Williams, MD

Email: GWILLIAMS@BWH.HARVARD.EDU
Categories: BWH
Institution: Brigham and Women's Hospital
Research: Hormonal Mechanisms of Cardiovascular Injury
Grants & Publications: Harvard Catalyst

This lab is focused on understanding the regulation of steroids in the adrenal zona glomerulosa and fasciculata/reticularis at the cell, organ, and organism levels with a specific focus on genetic determinants of hypertension and/or diabetes mellitus. A variety of techniques are used: genetic modification from siRNA of cells to specific gene knockout; ex vivo single cell studies; superfusion of cells or organs; assessing steroid enzyme function in intact cells; single cell secretion and RNA sequencing; CRISPR/Cas9 gene editing; traditional molecular tools etc. Studies of In vivo and environmental factors that influence steroid secretion include the traditional (e.g., angiotensin II, potassium, ACTH, sodium, and potassium intakes) and novel (e.g., mTOR1, sex steroids, kinins, NO, cGMP, natriuretic peptides). Of particular interest has been the effect of sex, aging and genetics on adrenal function disruptions of which lead to salt-sensitive blood pressure, insulin resistance, lipid abnormalities and diabetes. Current interest includes the epigenetic factor, lysine specific demethylase 1 (LSD1) whose genetic modification in humans leads to salt sensitive hypertension, caveolin-1 deficiency associated with insulin resistance, diabetes, hypertension and the metabolic syndrome in humans and mice, and the identification of a novel ultrashort feedback loop modifying aldosterone secretion and cross talk between the zona glomerulosa and fasciculata of the adrenal cortex.

Gordon Williams, MD

This lab is focused on understanding the regulation of steroids...

Ramnik Xavier, MD

Email: xavier@molbio.mgh.harvard.edu
Categories: MGH
Institution: Massachusetts General Hospital
Research: Systems biology approaches to understand human disease signaling networks
Grants & Publications: Harvard Catalyst

The overall goal in the laboratory is to discover and understand the functions of important mediators and effectors involved in innate and adaptive immunity. Of particular interest are cellular components and regulatory networks that interact dynamically within temporal, spatial, and pathophysiological contexts of immunity. We utilize integrative systems approaches that closely couple genome-wide experimentation with high-throughput assays and computational methods.

Using the gut as a model system, we identify immune mechanisms that are perturbed in inflammatory bowel diseases (IBD) and type 1 diabetes (T1D). Recent work has focused on generating systems-wide maps within the gut that capture immune features and metabolic states at single-cell resolution. First, we transcriptionally profiled tens of thousands of individual gut epithelial cells to chart distinct cell types and their intrinsic cell states and responses to infections. We uncovered new cellular markers and programs, associated sensory molecules with cell types, and further defined principles of gut homeostasis and pathogenesis. We further utilized this data to identify intestinal stem cell (ISC) subsets enriched for MHC class II (MHCII) machinery and demonstrated that key cytokines affected MHCII+ ISC renewal and differentiation in opposing ways to orchestrate tissue-wide responses: pro-inflammatory signals promote differentiation, while regulatory cells and cytokines reduce it. A separate single-cell study examined the human colon mucosa during health and ulcerative colitis (UC), revealing 51 epithelial, stromal, and immune cell subsets. We associated inflammatory fibroblasts with resistance to anti-TNF treatment and revealed that many UC risk genes are cell type-specific and co-regulated in relatively few modules, suggesting that a limited set of cell types and pathways underlie UC. Lastly, we developed two single-nucleus RNA-sequencing methods—RAISIN-seq and MIRACL-seq—to transcriptionally profile the rare and diverse cells of the enteric nervous system (ENS) in humans at high resolution. We uncovered several neuro-epithelial, neuro-stromal, and neuro-immune interactions as well as strong expression in enteric neurons of risk genes for neuropathic, inflammatory, and extra-intestinal diseases. Collectively, these studies expose a rewiring of intra- and inter-cellular circuitry during intestinal inflammation and contribute to a more comprehensive understanding of the interplay between human genetics and mucosal immunity during health and complex diseases.

We also determine the influences of the gut microbiome on health and disease using human cohorts and computational models. Analyzing microbial strain-level variation in a longitudinal cohort of children predisposed to T1D, we revealed functional consequences of strain diversity on early microbiome development and disease susceptibility. Using the same cohort, we characterized the natural history of the early microbiome in connection to T1D diagnosis, antibiotic treatments, and probiotics. In pursuit of molecular mechanisms underlying interactions between the microbiome and the immune system, we identify microbially-derived metabolites, such as indoleacrylic acid and sphingolipids, that promote intestinal epithelial barrier function and mitigate inflammatory responses. Our metagenomic and metabolomic analyses of IBD cohorts uncovered over 2,700 gut metabolites that were differentially abundant in IBD. Furthermore, we link enzymatic activities of gut microbes to host metabolism; we recently identified cholesterol dehydrogenases harbored by a clade of bacteria that associates with lower cholesterol levels in humans. To generate unique hypotheses regarding immune mechanisms, we also established an integrative platform—an antigen prediction model coupled with high-throughput validation—to define the immunodominance landscape of microbes across a broad range of immune pathologies and an algorithm that identified bacterial genomic regions mediating host adaptation and antibiotic resistance. Together, these studies contribute to a comprehensive understanding of the functional roles played by the microbiome in maintaining mucosal homeostasis and promoting immunological disorders.

The laboratory ultimately aims to translate human genetics to functional biology and pathway medicine. Leveraging insight gained from our functional studies, we use chemical biology to test therapeutic hypotheses and inform drug discovery programs.

Ramnik Xavier, MD

The overall goal in the laboratory is to discover and...

Last Updated on May 6, 2024