Members

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.

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.

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.

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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.

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.

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.

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.

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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.

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.

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.