Aaron M. Cypess, M.D., Ph.D., M.M.Sc.
Translational Physiology Section, Diabetes, Endocrinology, and Obesity Branch
BG 10-CRC RM 6-3950
10 CENTER DR
BETHESDA MD 20814
Brown adipose tissue (BAT) is an organ recently discovered to be functional in adults. In mammals, BAT contributes to the heat generated during standard physiological non-shivering thermogenesis and may also play a role in protection from weight gain and insulin resistance in both rodents and humans. At the cellular level, brown adipocytes regulate energy expenditure through their numerous, large mitochondria. In the inner mitochondrial membrane is the BAT-specific uncoupling protein 1 (UCP1), which when activated dissipates the intermembrane proton-motive force and generates heat instead of ATP.
The thermogenic capacity of BAT is impressive. In a cold-acclimatized animal models, oxygen consumption by BAT is approximately twice the normal whole-body basal metabolic rate. Until recently BAT was thought to be nonexistent and metabolically irrelevant in adult humans, in part because there were no methods to localize and quantify BAT mass and measure its activity.
Using a combination of molecular techniques and whole-body imaging, we have shown that BAT is present in adult humans in defined regions; more frequently found in women than men, and has an activity that correlates inversely with age and obesity, suggesting a potential role of brown adipose tissue in adult human metabolism.
Current translational research projects in the lab focus on brown and white adipose tissue function, energy balance, clinical physiology, and imaging in collaboration with multiple groups within the Intramural Research Program and Harvard Medical School.
- Integrative physiology: we are conducting studies in both rodents and humans to understand BAT and WAT function and teleology from the molecular and cellular through the epidemiological levels.
- Noninvasive imaging: new technologies are being developed, including PET/CT, MRI, infrared, and ultrasound, to quantify BAT mass and activity as a way of understanding its structure and function.
- Therapeutics: physiological (exposure to mild cold) and pharmacological (activators of the β3-adrenergic receptor) interventions are being evaluated to identify which ones increase BAT energy expenditure and have the potential for use as treatments for obesity and diabetes.
Applying our Research
Obesity develops when energy intake exceeds energy expenditure. This disruption of energy balance develops from a combination of increased drive to take in food and a decrease in energy expenditure. In the classical view, adipose tissue itself was considered as a passive recipient, acting as a storage depot for the excess calories, rather than an active component of disease.
Over the past two decades, this view of obesity has changed dramatically with the recognition that adipose tissue is a metabolically and hormonally active tissue, releasing free fatty acids and producing a number of hormones or adipokines acting on other tissues, including the brain, liver, and muscle to play an important role in control of food intake, energy balance, and insulin sensitivity. Moreover, adipose tissue itself is heterogeneous at multiple levels. Increased intra-abdominal fat is associated with a high risk of metabolic disease, whereas increased subcutaneous fat in the thighs and hips exerts little or no risk of metabolic disease.
Recent evidence suggests that this difference in disease risk is, at least in part, due to intrinsic differences in adipocytes in the different depots, which may be developmental in origin. In addition, it is known that not all fat is involved in energy storage. Rather, there are at least two clearly distinguishable forms of fat: white adipose tissue (WAT), which stores energy, and brown adipose tissue (BAT), which burns energy for thermogenesis.
The most recent strategic plan of the NIDDK states that we must “Determine whether human brown fat plays a major role in energy balance, and explore pharmacologic or environmental (temperature) approaches to manipulate brown fat activity to uncouple excess nutrient intake from energy storage in white fat tissue.” It is our hope that our research effots will contribute specifically toward achieving this goal.
Need for Further Study
BAT may contribute to three different facets of human physiology - energy balance, fuel utilization, and the regulation of metabolism. Answering the following three questions is the ultimate goal of our research:
- To what extent does adult human BAT contribute to increased energy expenditure?
- What is the intracellular response of human brown adipocytes to adrenergic stimulation, and how could this impact whole-body glucose and triglyceride metabolism?
- How does activated human BAT interact with other tissues as an endorince organ?
- Assistant Professor of Medicine, Harvard Medical School, 2010-2014
- Assistant Investigator and Staff Physician, Joslin Diabetes Center, 2010-2014
- Beth Israel Deaconess Medical Center, Staff Physician, 2006-2014
- M.M.Sc., Harvard Medical School, 2008
- M.D., Cornell Medical College, 2000
- Ph.D., Rockefeller University, 1999
- A.B., Princeton University, 1992
Cypess AM, Weiner LS, Roberts-Toler C, Franquet Elía E, Kessler SH, Kahn PA, English J, Chatman K, Trauger SA, Doria A, Kolodny GM. Activation of human brown adipose tissue by a β3-adrenergic receptor agonist. Cell Metab. 2015;21(1):33-8.
Cypess AM, Haft CR, Laughlin MR, Hu HH. Brown fat in humans: consensus points and experimental guidelines. Cell Metab. 2014;20(3):408-15.
Srinivasa S, Wong K, Fitch KV, Wei J, Petrow E, Cypess AM, Torriani M, Grinspoon SK. Effects of lifestyle modification and metformin on irisin and FGF21 among HIV-infected subjects with the metabolic syndrome. Clin Endocrinol (Oxf). 2015;82(5):678-85.
Mori MA, Thomou T, Boucher J, Lee KY, Lallukka S, Kim JK, Torriani M, Yki-Järvinen H, Grinspoon SK, Cypess AM, Kahn CR. Altered miRNA processing disrupts brown/white adipocyte determination and associates with lipodystrophy. J Clin Invest. 2014;124(8):3339-51.
Ussar S, Lee KY, Dankel SN, Boucher J, Haering MF, Kleinridders A, Thomou T, Xue R, Macotela Y, Cypess AM, Tseng YH, Mellgren G, Kahn CR. ASC-1, PAT2, and P2RX5 are cell surface markers for white, beige, and brown adipocytes. Sci Transl Med. 2014;6(247):247ra103.