Clinical and Cellular Biology Section
Phillip Gorden, M.D., Director Emeritus
The Clinical and Cellular Biology Section aims to study clinical conditions at a cellular level. Specific research projects include studies of patients with extreme forms of insulin resistance—for example, individuals with mutations in the insulin receptor, autoantibodies to the insulin receptor, and other related problems. Also of scientific interest are studies in patients with lipoatrophy, including genetic and acquired syndromes. These studies involve genetics, lipotoxicity, insulin resistance, and other related problems. Research includes a major clinical trial to determine the effect of leptin therapy on reducing insulin resistance in patients with complete lipodystrophy and extreme forms of insulin resistance. The Section’s work also involves investigations of organic hypoglycemia, including the diagnostic value of proinsulin in insulinoma and studies of the diagnosis, localization, and treatment of benign and malignant insulinoma.
Clinical Endocrinology Section
Monica C. Skarulis, M.D.
The Clinical Endocrinology Section conducts clinical protocols. Studies include the evaluation of treatment interventions for diseases of the pancreas and thyroid and pituitary abnormalities.
Alexxai V. Kravitz, Ph.D.
The Eating and Addiction Section focuses on a large contributor to obesity—increases in food intake. Americans consume about 25 percent more calories than they did 30 years ago. To determine why people have such a difficult time eating less, investigations concentrate on understanding how diet affects reward circuitry in the brain. Of particular interest is the idea that certain diets can alter and impair neural circuits that regulate reward processing and food consumption, similar to how drugs of abuse impair these circuits in people with addiction. Studies use a variety of approaches to examine this hypothesis, including behavioral testing, in vivo electrophysiology, and optogenetics.
Energy Homeostasis Section
Marc L. Reitman, M.D., Ph.D.
The Energy Homeostasis Section is interested in elucidating the mechanisms underlying energy homeostasis and how they impact obesity and diabetes. The major focus is on using mouse models coupled with genetics and pharmacology to understand regulation of metabolic rate and body temperature. Examples of specific research topics include brown adipose tissue, drug treatments for obesity, the role of environmental temperature, uncoupling, lipodystrophy, leptin, BRS-3 (bombesin receptor subtype-3), and melanocortins. Another interest is in using the NIH Clinical Center’s Metabolic Clinical Research Unit, with its state of the art clinical facilities, including room calorimeters. Ideally, mouse experimentation will generate hypotheses for the clinical setting and clinical observations will spur investigations in mice.
Energy Metabolism Section
Kong Y. Chen, Ph.D.
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.
Immune Tolerance Section
Kristin Tarbell, Ph.D.
The Immune Tolerance Section studies the role of dendritic cells (DCs) and regulatory T cells (Tregs) in peripheral T cell tolerance induction. Investigations focus on how these mechanisms are altered or deficient in an autoimmune setting. Researchers primarily use a mouse model of type 1 diabetes, with some studies in human peripheral blood cells. One long-term goal is to learn how to use DCs to induce autoantigen-specific tolerance for treatment of human type 1 diabetes. Specific projects concentrate on the following: (1) using a steady state DC to enhance tolerance via energy or deletion and determining whether it is possible to induce steady state tolerance in the environment of chronic autoimmune inflammation; (2) examining plasmacytoid DCs in a mouse model of type 1 diabetes; and (3) studying the immune effects of sitagliptin in healthy volunteers.
Regenerative Biology Section
Sushil G. Rane, Ph.D.
The Regenerative Biology Section developed mouse models to study cell cycle regulators (particularly Cdks) in pancreatic development and disease. A scientific focus is examining the mechanisms of islet growth and the pathways that lead to increase in beta-cell mass. Other projects investigate cell cycle regulators in obesity, diabetes, and their complications. Studies examine how cell cycle molecules and the downstream pathways become deregulated during the pathogenesis of obesity and diabetes. Of particular interest is the role of Cdk activity in the regulation of adipogenesis, muscle development and function, glucose homeostasis, glucose tolerance, and energy balance. Research in this Section also includes studies on TGF-β superfamily signaling, which is implicated in pancreatic development and pancreatic diseases associated with diabetes and obesity. These investigations use a variety of approaches—mouse models, primary cells, established cell lines, and human samples—to study the role of the TGF-beta superfamily in obesity and diabetes, particularly in the regulation of insulin gene transcription and beta-cell function.
Section on Ethnicity and Health
Anne Elizabeth Sumner, M.D.
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 when outcome 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 Krashes, Ph.D.
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 and Metabolism
Kristina Ingeborg Rother, M.D.
The Section on Pediatric Diabetes and Metabolism conducts clinical protocols. These studies examine the effectiveness of potential treatments for diabetes in youth.In the Section on Pediatric Diabetes and Metabolism, we conduct clinical studies on the pathophysiology and management of obesity and diabetes among youth. Our studies focus on artificial sweeteners and their effects on hormones, satiety, intestinal health (microbiome) and their interactions with food and medications. We also investigate lifestyle and psychosocial interventions in type 2 diabetes, and effects of bariatric surgery on incretin regulation. Additional topics of interest include the endocrine features of autoinflammatory diseases associated with lipodystrophy, e.g., dermatomyositis and CANDLE syndrome.
Section on Translational Diabetes and Metabolic Syndromes
Rebecca J. Brown, M.D., M.H.Sc., Lasker Tenure Track Investigator
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 K. Nieman, M.D.
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 from Cushing'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.
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 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 the regulate
whole body metabolism.