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Heads of Laboratories

Head shot of Paul Cohen
Paul Cohen, M.D., Ph.D.
Albert Resnick, M.D. Assistant Professor
Laboratory of Molecular Metabolism
pcohen@rockefeller.edu

Obesity has been estimated to threaten the health of more than 500 million people worldwide and more than one-third of the U.S. population. As a physician-scientist focusing on obesity and metabolic disease, Dr. Cohen investigates the molecular origins of metabolic dysfunction related to obesity with the ultimate goal of developing therapies to break the link between them.

Obesity can bring with it myriad serious and even potentially fatal health problems, including cardiovascular disease, type 2 diabetes, and cancer. But these conditions and the timing of their onset are not universal; they develop much later for some patients than others, and some escape almost entirely. A number of reasons — genetics, diet, physical activity, and type of fat — contribute to this variability. Dr. Cohen’s work focuses on understanding the molecular underpinnings of obesity-related diseases.

Epidemiological studies have shown visceral adipose tissue, stored around the abdomen, increases the risk for illness and death. Meanwhile, subcutaneous adipose deposits around the hips and buttocks do not raise these risks and may even provide protection. Evidence suggests the type of adipocytes within these two tissues is responsible for the dichotomy.

In visceral fat, white adipocytes warehouse triglycerides in large droplets. In obesity, this tissue is marked by inflammation and an increased accumulation of immune cells. However, other types of adipocytes appear to have neutral or even beneficial effects. Brown adipocytes can defend body temperature by converting the chemical energy in glucose and triglycerides into heat and may also make significant contributions to adult metabolism. Likewise, a third type, beige adipocytes, can dissipate energy just like brown adipocytes when activated by cold or certain hormones. In rodents, beige adipocytes occur in clusters surrounded by white adipocytes in subcutaneous fat, suggesting the reason for the neutral to beneficial effects of that tissue. Beige adipocytes are present in humans as well, though their location and physiological role have yet to be fully defined.

Using animal and cellular models and translational approaches in humans, Dr. Cohen investigates the transcriptional basis for the harmful and health-protecting effects of fat deposits and the adipocytes they contain. Ultimately, he hopes to develop ways to engineer healthier fat by manipulating the regulation of traits associated with different types of adipocytes.

As a postdoc, Dr. Cohen identified a promising target for this approach, PRDM16, which binds in a complex with other proteins to regulate gene expression. Dr. Cohen and colleagues found PRDM16 acts as a molecular switch that determines some of the key functional differences between visceral and subcutaneous fat. It does so by activating beige adipocytes, prompting them to burn calories rather than store them. When they knocked out the PRDM16 gene in mice, beige adipocytes no longer functioned properly, and the animals developed obesity, insulin resistance, and fatty liver. Meanwhile, their subcutaneous fat came to resemble visceral fat, both on molecular and morphological levels.

Dr. Cohen is now investigating whether a lack of PRDM16 produces the negative health effects associated with visceral fat or whether some other regulatory factor is involved. With mouse models developed as part of his work on transcriptional control, Dr. Cohen is also studying the interactions between adipocytes and conditions such as hypertension, cardiovascular disease, and cancer.


EDUCATION

A.B. in biology, 1996
Harvard College

Ph.D., 2003
The Rockefeller University

M.D., 2004
Weill Cornell Medical College

MEDICAL TRAINING

Residency in internal medicine, 2004–2007
Columbia University Medical Center

Fellowship in cardiovascular medicine, 2007–2011
Brigham and Women’s Hospital

POSTDOC

Dana Farber Cancer Institute and Harvard Medical School, 2009–2014

POSITIONS

Instructor in medicine, 2011–2014
Harvard Medical School

Assistant Professor, 2015–
The Rockefeller University

SELECTED PUBLICATIONS

Cohen, P. et al. Ablation of PRDM16 and beige adipose causes metabolic dysfunction and a subcutaneous to visceral fat switch. Cell 156, 304–316 (2014).

Ye, L. et al. Fat cells directly sense temperature to activate thermo-genesis. Proc. Natl. Acad. Sci. U.S.A. 110, 12480–12485 (2013).

Khandekar, M.J. et al. Molecular mechanisms of cancer development in obesity. Nat. Rev. Cancer 11, 886–895 (2011).

Cohen, P. et al. Role for stearoyl-CoA desaturase-1 in leptin-mediated weight loss. Science 297, 240–243 (2002).

Cohen, P. et al. Selective deletion of leptin receptor in neurons leads to obesity. J. Clin. Invest. 108, 1113–1121 (2001).


Dr. Cohen is a faculty member in the David Rockefeller Graduate Program and the Tri-Institutional M.D.-Ph.D. Program.