Members

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.

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.

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).

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.

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.

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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