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Aaron M. Cypess, M.D., Ph.D., M.M.Sc.

Photo of Dr. Aaron Cypess
Scientific Focus Areas: Cell Biology, Clinical Research, Molecular Biology and Biochemistry

Professional Experience

  • 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 School, 2000
  • Ph.D., Rockefeller University, 1999
  • A.B., Princeton University, 1992

Research Goal

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.

Current Research

  1. 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.
  2. 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.
  3. 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 efforts 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 endocrine organ?

Select Publications

Chronic mirabegron treatment increases human brown fat, HDL cholesterol, and insulin sensitivity.
O'Mara AE, Johnson JW, Linderman JD, Brychta RJ, McGehee S, Fletcher LA, Fink YA, Kapuria D, Cassimatis TM, Kelsey N, Cero C, Sater ZA, Piccinini F, Baskin AS, Leitner BP, Cai H, Millo CM, Dieckmann W, Walter M, Javitt NB, Rotman Y, Walter PJ, Ader M, Bergman RN, Herscovitch P, Chen KY, Cypess AM.
J Clin Invest (2020 May 1) 130:2209-2219. Abstract/Full Text
Regulation of Human Adipose Tissue Activation, Gallbladder Size, and Bile Acid Metabolism by a β3-Adrenergic Receptor Agonist.
Baskin AS, Linderman JD, Brychta RJ, McGehee S, Anflick-Chames E, Cero C, Johnson JW, O'Mara AE, Fletcher LA, Leitner BP, Duckworth CJ, Huang S, Cai H, Garraffo HM, Millo CM, Dieckmann W, Tolstikov V, Chen EY, Gao F, Narain NR, Kiebish MA, Walter PJ, Herscovitch P, Chen KY, Cypess AM.
Diabetes (2018 Oct) 67:2113-2125. Abstract/Full Text
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Research in Plain Language

Brown adipose tissue (BAT), also known as brown fat, was recently discovered to be an organ in the body that generates heat and may help regulate weight. While we are excited about the ways that activated brown fat can be used to various diseases, there are still many key features that we don't yet understand. My group uses a combination of clinical trials and basic laboratory work to help understand how brown fat works at the levels of the cells and then to translate the information into practical ways to treat people with obesity, diabetes, and other chronic illnesses.