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Energy Homeostasis Section
Marc L. Reitman, M.D., Ph.D.,Section Chief
The Energy Homeostasis Section is interested in a mechanistic and translational understanding of diabetes, energy homeostasis, and obesity.Obesity treatment is rarely successful for the long term. Studying the physiology of energy homeostasis should lead to advancements in the treatment of diabetes and obesity. Specific interests include studying mouse genetics and pharmacology, using mouse models to understand metabolic rate regulation, body temperature regulation and the role of BRS3 (bombesin receptor subtype-3), and exploring drug treatments for obesity. One current project involves dissecting the neuroscience of how BRS3 regulates metabolic rate, body temperature, and blood pressure. Another project explores how to improve the use of mice to evaluate candidate treatments for human obesity. A third interest is the role of brown adipose tissue and uncoupling in mouse and human thermal biology and body weight regulation.
Clinical Endocrinology Section
Ranganath Muniyappa, M.D., Ph.D.,Senior Research Physician
The Clinical Endocrinology Section conducts clinical protocols. Studies include the evaluation of treatment interventions for diseases of the pancreas and thyroid and pituitary abnormalities.
Energy Metabolism Section
Kong Y. Chen, Ph.D., MSCI,Section Chief
The Energy Metabolism Section focuses on the dissection of the components of energy expenditure in humans and an understanding of their roles in contributing to body weight regulation. The three classic components of energy expenditure are resting, thermic effect of food, and physical activity. Recently, the recognition of brown adipose tissue in adult humans confirms that the facultative component of energy expenditure may be important as a potential source for elevating energy expenditure to counter-balance food intake. Clinical studies are conducted using state-of-art whole-room indirect calorimeters at different environmental temperatures to define the capacity of nonshivering thermogenesis in lean and obese adults. These studies are also conducted using pharmacologic approaches to dissect its mechanism in humans.
Integrative Cellular Metabolism Section
Sushil G. Rane, Ph.D.,Section Chief
The Integrative Cellular Metabolism Section focuses on investigating the integrated organ system controlling glucose homeostasis. Using rodents as a model, research examines how specific organs –the pancreas, muscle, fat, and brain - integrate metabolic cues to orchestrate responses to diverse nutritional states. Investigations include understanding both the organ-centric and the integrative mechanisms that underlie the acquisition and assimilation of food. The long-term goal is to decipher the inter-organ network controlling food-seeking and food-digestion using a combination of genetic and molecular tools. Of specific interest are the neural networks through which distinct subsets of hypothalamic neurons differentially influence downstream peripheral target organs to control responses to varied nutritional states.
Neuromodulation and Motivation Section
Andrew Lutas, Ph.D., Stadtman Tenure-Track Investigator,Acting Section Chief
The Neuromodulation and Motivation Section focuses on hormone, neuropeptide, and monoamine neurotransmitter receptors that trigger molecular signaling inside neurons to control the motivation to seek or avoid food. Our current research is focused on how multiple neuromodulator signals like dopamine and neuropeptides converge on a common intracellular molecular signal, cyclic AMP (cAMP), to adjust neural circuit activity. We use optical approaches to longitudinally track and manipulate cAMP inside neurons in the intact brain. By combining these optical approaches with behavior tasks and genetic manipulations in rodents, we study how receptor-evoked molecular signals influence the overconsumption of food. Our goal is to understand principles of neuromodulation of neural circuits and uncover treatment strategies for obesity and comorbid diseases.
Section on Ethnicity and Health
Anne Elizabeth Sumner, M.D.,Section Chief
As the worldwide epidemic of obesity, diabetes, and heart disease, collectively known as cardiometabolic disease, disproportionately affects people of African descent, the Section on Ethnicity and Health is working to identify the earliest determinants of cardiometabolic disease in African Americans and African immigrants to the United States. Our research is specifically designed to determine predictors of cardiometabolic disease in people of African descent so that the most effective screening tests can be identified. Screening tests have enormous public health significance because they can lead to the initiation of an intervention at a time whenoutcome can be positively affected. Currently, screening tests for cardiometabolic disease rely on markers of insulin resistance. But the development of cardiometabolic disease requires both insulin resistance and hyperinsulinemia. Work in this Section suggests that hyperinsulinemia may be an earlier trigger in people of African descent than insulin resistance. Therefore, we are undertaking studies to rigorously identify the balance between insulin resistance and hyperinsulinemia. We will use this insight to develop screening tests that are effective in people of African descent and thereby achieve interventions that lead to a decrease in health disparities, reduced health costs, and enhanced lives. While our work focuses specifically on people of African descent, the principles of investigation are broadly applicable.
Section on Motivational Processes Underlying Appetite
Michael J. Krashes, Ph.D.,Section Chief
The Section on Motivational Processes Underlying Appetite focuses on obesity and dissecting the neural systems controlling food intake beyond metabolic need—including higher-order cognitive factors. Using rodents as a model, research examines how the rodent brain integrates peripheral senses, internal states, and experiences to orchestrate feeding. Investigations include studies of the neural systems that underlie the detection (both external and internal) and memory of stimuli associated with the acquisition of food. The long-term goal is to bridge homeostatic satiety signals emanating from the hypothalamus with those higher-order networks controlling food-seeking behavior using a combination of genetic and molecular tools to functionally unravel these circuit mechanisms. Of interest are the neuromodulatory networks through which distinct subsets of hypothalamic neurons differentially influence specific downstream target cell types and synapses to guide motivational behavior and learning and memory processing aimed at obtaining food.
Section on Pediatric Diabetes, Obesity, and Metabolism
Stephanie Chung, M.B.B.S., Lasker Tenure Track Investigator, NIH Distinguished Scholar,Acting Section Chief
The Section on Pediatric Diabetes, Obesity, and Metabolism conducts metabolic clinical trials to understand the complex association of biological, social, and environmental factors in the pathogenesis of pediatric diabetes, obesity, and metabolism. Type 2 diabetes is a leading cause of death and disability worldwide, especially in underrepresented minority groups. The transgenerational cycle of diabetes and the epidemic of childhood obesity are among the most important factors for type 2 diabetes development and contribute to a disproportionate burden of disease in youth and young adults. Moreover, current therapies for type 2 diabetes in youth are limited and response to metformin, the first-line agent in youth, is highly variable and insufficient in up to 50% of youth within 2 years of diagnosis. Current projects investigate factors associated with metformin treatment failure while evaluating innovative strategies and therapies to minimize disease burden in youth and young adults. Our long-term goals are to reduce diabetes-related health disparities across the lifespan by improving primary prevention of cardiometabolic disease. Specific interests include developing population-specific risk stratification paradigms and novel pharmacologic and pharmacogenetic targets in youth and young adults.
Section on Translational Diabetes and Metabolic Syndromes
Rebecca J. Brown, M.D., M.H.Sc., Lasker Tenure Track Investigator,Acting Section Chief
The lab conducts translational and clinical research in insulin resistance and the metabolic syndrome, focusing on pathophysiology and clinical therapeutics for rare disorders of severe insulin resistance, including lipodystrophy and genetic or acquired disorders of the insulin receptor. We apply what is learned from rare diseases to improve understanding of common disorders of insulin resistance, such as type 2 diabetes and the polycystic ovarian syndrome.
Section on Translational Endocrinology
Lynnette Nieman,Section Chief
The section on translational endocrinology conducts clinical trials to better understand disorders of cortisol excess and deficiency, such as Cushing's syndrome, glucocorticoid resistance and adrenal insufficiency. Cushing's syndrome is viewed as a model of obesity, and investigates the mechanisms by which cortisol may induce weight gain. Adrenal insufficiency is studied from the perspective of permanent disease (such as autoimmune adrenalitis) as well as reversible disorders of secondary adrenal insufficiency, such as occur after recovery fromCushing's syndrome. These models may suggest new ways to treat obesity as well as the problem of exogenous pharmacologic use of glucocorticoids. The section collaborates with others in NCI (glucocorticoid receptors; endocrine and thoracic surgery), NINDS (neurosurgery), members of the Metabolic Clinical Research Unit, Clinical Endocrinology Section, Biomedical and Metabolic Imaging Branch (BMIB), as well as with colleagues throughout the world.
Translational Physiology Section
Aaron M. Cypess, M.D., Ph.D., M.M.Sc.,Acting Section Chief
The goal of the Translational Physiology Section is to integrate a combination of in vitro, rodent, and clinical models toward finding treatments for obesity, diabetes, and other metabolic diseases. The principal area of interest is the physiology of the principal organs regulating metabolism such as fat, skeletal muscle, liver, and myocardium. One focus is on human brown adipose tissue (BAT), with the purpose of addressing three fundamental unknowns: (A) the extent to which human BAT contributes to interventions that increase energy expenditure; (B) the intracellular responses of human brown adipocytes to adrenergic stimulation and how these could impact whole-body glucose and triglyceride flux; and (C) how activated human BAT interacts with other organs in regulating metabolism. The Section collaborates with multiple groups on campus, such as members of the Metabolic Clinical Research Unit, Positron Emission Tomography Department, and the Clinical Laboratory and Mass Spectrometry Cores, as well as with colleagues throughout the world. Current projects include the use of β3-adrenergic receptor agonist drugs to activate and grow human BAT; the study of immortalized human adipocytes to determine how glucose is utilized by brown and white fat; and the leveraging of clinical samples for use in omics technologies to identify brown adipokines and how they regulate whole body metabolism.
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