BBS Faculty Member - David Cohen

David Cohen

Department of Medicine
Harvard-MIT Division of Health Sciences and Technology

Brigham and Women's Hospital
Harvard Institutes of Medicine, Room 941
77 Avenue Louis Pasteur
Boston, MA 02115
Tel: 617-525-5090
Fax: 617-525-5100
Lab Members: 3 postdoctoral fellows, 2 instructors, 4 technicians
Visit my lab page here.

Our research centers on the mechanisms whereby hydrophobic lipid molecules regulate nutrient metabolism and energy homeostasis. We seek to identify new molecular targets that could be leveraged in the management of obesity and its common metabolic complications, including non-alcoholic fatty liver disease and type 2 diabetes.

Our interests include the role of steroidogenic acute regulatory transfer related (START) domain proteins in lipid and glucose metabolism. START domains bind hydrophobic ligands, including phospholipids, cholesterol and fatty acids. The laboratory has described novel roles for lipid-binding START domain proteins in metabolic control within the liver, as well as in whole body energy homeostasis.

We have demonstrated that the START domain protein StarD2, also know as phosphatidylcholine transfer protein (PC-TP) plays a critical role in governing hepatic insulin sensitivity. We have demonstrated that Pctp-/- mice are sensitized to hepatic insulin action, are relatively resistant to the development of type 2 diabetes and atherosclerosis, and exhibit more efficient brown fat-mediated thermogenesis. Milestones in this research have included cloning and characterization of the Pctp gene, expression of recombinant protein and detailed structure-function analyses, studies of cellar function, solving the crystal structure of PC-TP, identification of key PC-TP-interacting proteins and detailed phenotyping of Pctp-/- mice. We have shown the fatty acyl-CoA thioesterase superfamily member 2 (Them2) is an interacting partner of PC-TP and is activated upon binding PC-TP. We have further demonstrated that Them2 in turn plays a key role in regulating hepatic lipid and glucose metabolism, as well as energy homeostasis. Our studies suggest that a complex of Them2–PC-TP suppresses insulin signaling by reducing the activation of insulin receptor substrate 2 (IRS2), as well as by stabilizing the tuberous sclerosis 1 (TSC1)–TSC2 complex, which suppresses mTOR activity. We have gone on to identify small molecule inhibitors of PC-TP and to demonstrate their efficacy in a mouse model of type 2 diabetes. Our research suggests that PC-TP functions as a sensor of membrane phosphatidylcholine composition, which in turn regulates lipid and glucose metabolism.

In separate studies, we have demonstrated that StarD14 (synonym Them1), which is highly enriched in brown adipose tissue, plays a major role in regulating energy homeostasis. Mice lacking Them1 are highly resistant to diet-induced obesity, diabetes and inflammation. We have proposed that Them1 functions as a fatty acid sensor that controls energy expenditure in brown adipose tissue by limiting access of free fatty acids to mitochondria and by reducing thermogenic gene expression.

Most recently, we have begun to identify a key role for the gut microbiome in regulating thermogenesis and energy expenditure in mice. These studies are beginning to define how adaptations to varying ambient temperatures affect the microbiome composition, and how this in turn regulates body weight and nutrient metabolism.

Last Update: 8/11/2015


For a complete listing of publications click here.



Shishova EY, Stoll JM, Ersoy BA, Shrestha S, Scapa EF, Li Y, Niepel MW, Su Y, Jelicks LA, Stahl GL, Glicksman M, Gutierrez-Juarez R, Cuny GD, Cohen DE. Genetic ablation or chemical inhibition of phosphatidylcholine transfer protein attenuates diet-induced hepatic glucose production. Hepatology 2011; 54:664-74. PMCID: PMC3144994

Kang HW, Niepel MW, Han S, Kawano Y,
Cohen DE. Thioesterase superfamily member 2/Acyl-CoA thioesterase 13 (Them2/Acot13) regulates hepatic lipid and glucose metabolism. FASEB J 2012; 26:2209-21. PMCID: PMC3336778

Han S,
Cohen DE. Functional characterization of thioesterase superfamily member 1/acyl-CoA thioesterase 11: Implications for metabolic regulation. J Lipid Res 2012;53: 2620-31. PMCID: PMC3494255

Zhang Y, Li Y, Niepel MW, Kawano Y, Han S, Liu S, Marsili A, Larsen PR, Lee CH,
Cohen DE. Targeted deletion of Thioesterase superfamily member 1 promotes energy expenditure and protects against obesity and insulin resistance. Proc Natl Acad Sci USA 2012; 109:5417-22. PMCID: PMC3325675

Ersoy BA, Tarun A, D’Aquino K, Hancer NJ, Ukomadu C, White MF, Michel T, Manning BD,
Cohen DE. Phosphatidylcholine transfer protein interacts with thioesterase superfamily member 2 to attenuate insulin signaling. Sci. Signal. 2013;30:6:ra64.

Kang HW, Ozdemir C, Kawano Y, Vernochet C, Kahn CR, Hagen SJ,
Cohen DE. Thioesterase superfamily member 2/Acyl-CoA thioesterase 13 (Them2/Acot13) regulates adaptive thermogenesis in mice. J Biol Chem 2013:288:33376-86. PMCID: PMC3829184

Kawano Y, Ersoy BA, Li Y, Nishiumi S, Yoshida M,
Cohen DE. Thioesterase Superfamily Member 2 (Them2) and Phosphatidylcholine Transfer Protein (PC-TP) Interact To Promote Fatty Acid Oxidation and Control Glucose Utilization. Mol Cell Biol 2014; 34:2396-408. PMCID: PMC4054321

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