Sheila Collins, Ph.D.

Adjunct Associate Professor in Psychiatry and Behavioral Sciences

Department:
Psychiatry and Behavioral Sciences

Division:
Biological Psychiatry

Email:
sheilacollinsdukeedu

Mailing Address:
, DUMC
Durham, NC 27710

Telephone:
919-684-8991

Training:
Ph.D., University of Massachusetts

Research Interests:
We are particularly interested in the molecular mechanisms whereby neurotransmitter receptors that couple to the same signal transduction pathway are expressed in the same cell, but able to activate specific responses unique to that receptor subtype.  We study the adipocyte as a model system because these cells express all three βAR subtypes, including the adipocyte-specific β3AR. Each of these βARs are coupled to the generation of intracellular cAMP, and stimulate hydrolysis of stored lipids in white fat and thermogenesis in brown fat.  Feedback control of this response involves the central nervous system by the hormone leptin, which is secreted from adipocytes in proportion to the lipid stored in the adipocyte.  Leptin "reports" on the energy reserves of the body to hypothalamic centers, which control satiety, behavior and metabolic rate.  We have shown, together with our colleagues, that leptin promotes weight loss in part by increasing sympathetic outflow to brown fat, thus stimulating thermogenesis.  Although leptin is a critical regulator of food seeking behavior and metabolic rate, most obese humans possess abundant levels of leptin. Interestingly, β3AR selective agonists are capable of preventing or reversing established obesity by essentially bypassing the leptin system and stimulating thermogenesis directly.  However, this unique metabolic response of β3AR agonists is not shared by the other subtypes (reviewed in Collins & Surwit Rec Prog Horm Res 2001; Robidoux et al Ann Rev Pharm 2004).  One unique feature of the β3AR is that it is coupled to two different signal transduction pathways simultaneously (cAMP/protein kinase A activation and ERK1/2 activation), and does not require covalent or other modifications to do so.  We are currently exploring the structural features of the receptor that control this dual signaling.  One physiological consequence of this pathway in the fat cell is to contribute to the overall stimulationof lipolysis.  

βARs in adipocytes also activate another arm of the MAPK pathway: p38 MAPK (Cao et al JBC 2001).  One of the functional consequences of this process is the cAMP-dependent increase in transcription of the brown-fat specific uncoupling protein UCP1.  The signaling cascade by which this occurs is now being defined in the lab (Cao et al MCB 2004).

Another major focus in the laboratory is the regulation of a new mitochondrial uncoupling protein (UCP-2) which appears to be genetically linked to severe obesity and type II diabetes. We generated mice here at Duke with targeted disruption of UCP-2, and this has resulted in several interesting phenotypes including effects on insulin from pancreatic β-cells and increased macrophage phagocytic and inflammatory responses.   UCP-2 appears to be a mitochondrial protein that protects against reactive oxygen species (ROS) and that can regulate the production of ROS as a signaling molecule.