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

Research Summary

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.
 
BAT is of particular interest since recent studies suggest that in addition to its role in heat generation, BAT 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 rat, oxygen consumption by BAT is approximately twice the normal whole-body basal metabolic rate. In humans, it has been estimated that as little as 50g of BAT could utilize up to 20% of basal caloric needs if maximally stimulated.  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 teams from Beth Israel Deaconess Medical Center, Massachusetts General Hospital, Boston Children’s Hospital, and the Harvard School of Public Health.

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 and hormonal interventions are being evaluated to identify which ones increase BAT energy expenditure and have the potential for use as treatments for obesity and diabetes.

Biography

Aaron M. Cypess, MD, PhD, grew up in Ithaca, New York. He graduated from Princeton University with a degree in chemistry and did his postgraduate training at the Rockefeller University where he studied signal transduction of peptide hormone receptors with Thomas P. Sakmar and R. Bruce Merrifield.  After completing his medical degree in 2000 from Cornell University Medical College, Dr. Cypess devoted a year to studying medical ethics and Jewish law in Jerusalem, Israel. 

He did his residency in internal medicine and fellowship in endocrinology, diabetes, and metabolism at Beth Israel Deaconess Medical Center (BIDMC) and Joslin Diabetes Center (JDC). His postdoctoral research with C. Ronald Kahn focused on insulin receptor signaling and brown adipose tissue development. In 2006, Dr. Cypess joined the Clinical Investigator Training Program, a masters program based at Harvard Medical School (HMS) and MIT that trains physician-scientists in the techniques and processes required for patient-oriented research. His studies utilized PET/CT imaging to describe the metabolic importance of human brown adipose tissue with C. Ronald Kahn and Allison Goldfine at JDC and Gerald M. Kolodny at BIDMC.  Dr. Cypess currently has dual clinical and research appointments at JDC and BIDMC. 

He is also a member of the Institutional Review Board at Partners HealthCare through his clinical appointment at Brigham and Women’s Hospital.  Dr. Cypess is an Assistant Professor of Medicine at HMS and has served as a reviewer for Obesity, the Journal of Pediatrics, and the New England Journal of Medicine.

Page last updated: August 29, 2014