Scientists

Sheila Collins, Ph.D.

Sheila Collins

Education

B.S., zoology, University of Massachusetts, Amherst, Massachusetts, 1979.
Ph.D., biology and applied biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, 1985.
Postdoctoral training, Howard Hughes Medical Institute, Duke University Medical Center, Durham, North Carolina, 1985-1991.

Research

One only has to open the newspaper or turn on the radio to hear about the epidemic of obesity in America. Not only does obesity exact a heavy toll on the population's health, but the medical costs associated with obesity, especially those related to treatment for type 2 diabetes and cardiovascular disease, are astronomical.

Our laboratory is interested in the biochemical mechanisms that regulate body weight. Accumulation of excess calories as triglycerides in adipose tissue is largely driven by insulin, and subsequent access to this stored fuel is gated by the catecholamine to stimulate lipolysis. Activation of the adrenaline receptors, specifically the members of the beta-adrenergic receptor (beta-AR) family, provides the major stimulus for the hydrolysis and release of stored lipids. There are three known beta-AR subtypes, one of which is expressed exclusively in the adipocyte: the beta3-AR. Our lab has been deciphering how the beta-ARs on fat cells are regulated and how their structural features dictate their signal transduction properties, including a process called nonshivering thermogenesis, in brown fat. Brown fat cells are specialized cells rich in mitochondria and defined by their ability to express the mitochondrial uncoupling protein UCP1, which allows the dissipation of the proton gradient in the inner mitochondrial membrane to yield heat at the expense of ATP production.

Until the mid-1990s, adipose tissue had been largely considered to be an inert storage depot for excess metabolic fuel. In the ensuing years, there has been a deeper appreciation that a fairly large number of cytokines and growth factors are secreted from adipose tissue and may play significant roles in insulin resistance and cell differentiation and growth. These discoveries, as well as the realization that a host of biochemical and environmental factors contribute to the obesity epidemic, mark a new era in understanding how organ systems communicate their energy demands and reserves to regulate body weight.

Selected Publications

Moukdar F, Robidoux J, Lyght O, Pi J, Daniel KW, Collins S (2008) Reduced antioxidant capacity and diet-induced athersclerosis in Ucp2-deficient mice. J. Lipid Res., in press.

Wikstrom JD, Katzman SM, Mohamed H, Twig G, Graf SA, Heart E Molina AJA, Corkey BE, de Vargas LM, Danial NN, Collins S, Shirihai O (2007) b-cell mitochondria exhibit membrane potential heterogeneity that can be altered bv stimulatory or toxic fuel levels. Diabetes 56: 2569-2578.

Kumar, N., Robidoux, J., Daniel, K. W., Guzman, G., Floering, L. M., and Collins, S. (2007). Requirement of vimentin filament assembly for beta3-adrenergic receptor activation of ERK MAP kinase and lipolysis. J. Biol. Chem. 282, 9244-9250.

Pi, J., Bai, Y., Zhang, Q., Floering, L. M., Wong, V., Daniel, K., Reece, J. M., Deeney, J. T., Corkey, B. E., and Collins S. (2007). Reactive oxygen species as a signal in glucose-stimulated insulin secretion. Diabetes. In press.

Pi, J., Bai, Y., Reece, J. M., William, J., Liu, D., Freeman, M. L., Fahl, W. E., Shugar, D., Liu, J., Qu, W., Collins, S., and Waalkes, M. P. (2007). Molecular mechanism of Nrf2 activation and degradation: role of sequential phosphorylation by protein kinase CK2. Free Radic. Biol. Med. 42, 1797-1806.

Robidoux, J., Kumar, N., Daniel, K. W., Moukdar, F., Cyr, M., Medvedev, A., and Collins. S. (2006). Maximal beta3-adrenergic regulation of lipolysis involves Src and epidermal growth factor receptor-dependent ERK1/2 activation. J. Biol. Chem. 281, 37794-37802.

Bai, Y., Onuma, H., Bai, X., Medvedev, A. V., Misukonis, M., Weinberg, J. B., Cao, W., Robidoux, J., Floering, L. M., Daniel, K. W., Collins, S. (2005). Persistent NF-?B activation in Ucp2-/- mice leads to enhanced nitric oxide and inflammatory cytokine production. J. Biol. Chem. 280, 19062-19069.

Robidoux, J., Cao, W., Quan, H., Daniel, K. W., Moukdar, F., Bai, X., Floering, L. M., Collins, S. (2005). Selective activation of MAP kinase kinase-3 and p38? MAP kinase is essential for cAMP-dependent UCP1 expression in adipocytes. Mol. Cell. Biol. 25, 5466-5479.

Cao, W., Daniel, K. W., Robidoux, J., Puigserver, P., Medvedev, A. V., Bai, X., Floering, L. M., Spiegelman, B. M., and Collins, S. (2004). p38 mitogen-activated protein kinase is the central regulator of cyclic AMP-dependent transcription of the brown fat uncoupling protein 1 gene. Mol. Cell. Biol. 24, 3057-3067.

Collins, S., Cao, W., and Robidoux, J. (2004). Learning new tricks from old dogs: beta-adrenergic receptors teach new lessons on firing up adipose tissue metabolism. Mol. Endocrinol. 18, 2123-2131.

Collins, S., Martin, T. L., Surwit, R. S., and Robidoux, R. (2004). Genetic vulnerability to diet-induced obesity in the C57BL/6J mouse: physiological and molecular characteristics. Physiol. Behav. 81, 243-248.

Robidoux, J., Martin, T. L., and Collins, S. (2004). ß-adrenergic receptors and regulation of energy expenditure: a family affair. Annu. Rev. Pharmacol. Toxicol. 44, 297-323.

Medvedev, A. V., Robidoux, J., Bai, X., Cao, W., Floering, L. M., Daniel, K. W., and Collins, S. (2002). Regulation of the uncoupling protein-2 gene in INS-1 beta-cells by oleic acid. J. Biol. Chem. 277, 42639-42644.

Cao, W., Medvedev, A. V., Daniel, K. W., and Collins, S. (2001). ß-adrenergic activation of p38 MAP kinase in adipocytes: cAMP induction of the uncoupling protein 1 (UCP1) gene requires p38 MAP kinase. J. Biol. Chem. 276, 27077-27082.

Collins, S. and Surwit, R. S. (2001). The ß-adrenergic receptors and the control of adipose tissue metabolism and thermogenesis. Recent Prog. Horm. Res. 56, 309-328.

Dixon, T. M., Daniel, K. W., Farmer, S. R., and Collins, S. (2001). CCAAT/enhancer-binding protein a is required for transcription of the ß3-adrenergic receptor gene during adipogenesis. J. Biol. Chem. 276, 722-728.

Medvedev, A. V., Snedden, S. K., Raimbault, S., Ricquier, D., and Collins, S. (2001). Transcriptional regulation of the mouse uncoupling protein-2 gene: double E-box motif is required for peroxisome proliferator-activated receptor-gamma-dependent activation. J. Biol. Chem. 276, 10817-10823.

Surwit, R. S. and Collins, S. (2001). Revisiting lessons from the C57BL/6J mouse. Am. J. Physiol. Endocrinol. Metab. 280, E825-826.

Arsenijevic, D., Onuma, H., Pecqueur, C., Raimbault, S., Manning, B. S., Miroux, B., Couplan, E., Alves-Guerra, M. C., Goubern, M., Surwit, R., Bouillaud, F., Richard, D., Collins, S., and Ricquier, D. (2000). Disruption of the uncoupling protein-2 gene in mice reveals a role in immunity and reactive oxygen species production. Nat. Genet. 26, 435-439.

Cao, W., Luttrell, L. M., Medvedev, A. V., Pierce, K. L., Daniel, K. W., Dixon, T. M., Lefkowitz, R. J., and Collins, S. (2000). Direct binding of activated c-Src to the ß3-adrenergic receptor is required for MAP kinase activation. J. Biol. Chem. 275, 38131-38134.

Soeder, K. J., Snedden, S. K., Cao, W., Della Rocca, G. J., Daniel, K. W., Luttrell, L. M., and Collins, S. (1999). The ß3-adrenergic receptor activates mitogen-activated protein kinase in adipocytes through a Gi-dependent mechanism. J. Biol. Chem. 274, 12017-12022.

Surwit, R. S., Wang, S., Petro, A. E., Sanchis, D., Raimbault, S., Ricquier, D., and Collins, S. (1998). Diet-induced changes in uncoupling proteins in obesity-prone and obesity-resistant strains of mice. Proc. Natl. Acad. Sci. U. S. A. 95, 4061-4065.

Collins, S., Daniel K. W., Petro, A. E., and Surwit, R. S. (1997). Strain-specific response to ß3-adrenergic receptor agonist treatment of diet-induced obesity in mice. Endocrinology 138, 405-413.

Fleury, C., Neverova, M., Collins, S., Raimbault, S., Champigny, O., Levi-Meyrueis, C., Bouillaud, F., Seldin, M. F., Surwit, R. S., Ricquier, D., and Warden, C. H. (1997). Uncoupling protein-2: a novel gene linked to obesity and hyperinsulinemia. Nat. Genet. 15, 269-272.

Collins, S. and Surwit, R. S. (1996). Pharmacologic manipulation of ob expression in a dietary model of obesity. J. Biol. Chem. 271, 9437-9440.