Ofer Reizes, Ph.D. Associate Staff Department of Cell Biology Cleveland Clinic Lerner Research Institute 9500 Euclid Avenue NC-10 Cleveland, Ohio 44195 Telephone: (216) 445-0880 Fax: (216) 444-9404 reizeso@ccf.org

• Shamone Gaddy, Technician

• Role of syndecans in energy balance and obesity
• Mechanisms underlying and adipose tissue resistance to weight loss

Research

My research focuses on understanding the physiology and pathology of obesity with the underlying hypothesis that "once you buy a fat cell it is yours to keep." We are interested in studying the mechanisms leading to the accumulation of fat and fat cells as well as mechanisms that resist the reduction in fat and fat cells. More than 50% of the population in western developed nations is considered obese or overweight. Furthermore, childhood obesity is on the increase. The medical consequences of obesity include increased risk of diabetes, cardiovascular disease and cancer.

I. Function and regulation of the syndecan heparan sulfate proteoglycans (HSPGs) in development of the obese state.

A major focus of the laboratory is elucidating the role of matrix proteins such as syndecans during adipose tissue development and growth. We have been studying the syndecans, a family of cell surface heparan sulfate proteoglycans (HSPGs) that can act as coreceptors for ligand-receptor encounters. Several years ago, we showed that syndecan-3, a neural HSPG, modulates feeding behavior and body weight in rodents. Syndecan-3 is expressed at the cell surface of neurons and is regulated by cleavage of its extracellular domain in a mechanism termed shedding. The initial research brought together the fields of syndecans/HSPGs and body weight regulation. We hypothesized that shedding of the syndecan-3 may be critical in the regulation of feeding behavior and energy balance, and indeed subsequent publications supported this hypothesis. The current research direction focuses on elucidating the connection between syndecan shedding and synaptic plasticity. Shedding is recognized as an important physiological process that modulates a variety of cell surface signaling events including synaptic plasticity within the CNS. Because the process of shedding is rapid, syndecan-3 and/or other related HSPGs are well positioned to mediate the immediate changes in structure and numbers of excitatory and inhibitory synapses, and thus critical in the regulation of feeding behavior and body weight.

II. Mechanisms regulating adipose tissue and body weight resistance to weight loss.

A second focus of the laboratory is elucidating the molecular and cellular changes that occur with obesity. Exposure of mice and humans to a high fat diet leads to an increase in adipose tissue mass, a consequence of hypertrophy and hyperplasia of the fat cells. The obese adipose tissue contains both enlarged fat cells and more fat cells. We have been studying weight loss induced by pharmacological agents and diets in high fat fed diet induced obese (DIO) mice. Our studies reveal that these approaches are moderately successful yet the obese mice maintain a significant level of adipose tissue that cannot be reduced with further exposure to drug or caloric restriction. We found that the mice reduce their body weight by reducing the content of the fat cells, but the overall fat cell number in the adipose tissue remains unchanged. We hypothesize that obese mice resist a further weight loss due to excess fat cells in their adipose tissue. A concept defined by others and us as "defense of body weight" or more appropriately "defense of adipose tissue." Thus, a further aspect of the research program will focus on the adipocyte with a particular interest in elucidating the molecular and cellular mechanisms maintaining the adipose tissue and resisting weight loss in obese conditions.

Some Recent Publications

Reizes, O. , Lincecum, J., Wang, Z., Huang, L., Kaksonen, M., Goldberger, O., Ahima, R., Hinkes, M., Barsh, G.S., Rauvala, H., and Bernfield, M. (2001) Transgenic expression of syndecan-1 uncovers a novel control of feeding behavior by hypothalamic syndecan-3. Cell 106: 105-116.

Capila, I. , Lincecum, J., Park, P.W., Reizes, O. , and Bernfield, M.R. (2003) Unlocking the secrets of syndecans: Transgenic organisms as a potential key. Glycoconjugate Journal, 19: 295-304.

Reizes, O. , Benoit , S.C. , Strader, A.D., Clegg, D.J., Akunuru, S., and Seeley, R.J. (2003) Syndecan-3 modulates food intake by interacting with the melanocortin/AgRP pathway. Ann. N.Y. Acad. Sci. 994: 66-73.

Elenius, V., Götte, M., Reizes, O. , Elenius, K., and Bernfield, M. (2004) Inhibition by the soluble syndecan-1 ectodomains delays wound repair in syndecan-1 overexpressing mice. J. Biol. Chem. 279: 41928-35.

Strader, A.D*, Reizes, O.* Benoit , S.C. , Woods, S.C., and Seeley, R.J. (2004) Syndecan-3 null mice are resistant to diet induced obesity. J. Clin. Invest.114: 1354-1360. *co-first authors

Seeley, R.J., Burklow, M.L., Wilmer, K.A., Matthews, C.C., Reizes, O. , McOsker, C.C., Trokhan, D.P., Gross, M.C., and Sheldon, R.J. (2005) The effect of the melanocortin agonist, MT-II, on the defended level of body adiposity. Endocrinology 146:3732-8.

Melendez-Vasquez, C., Carey, D.J., Reizes, O. , Maurel, P., and Salzer, J.L. (2005) Differential expression of proteoglycans at central and peripheral nodes of Ranvier. Glia 52: 301-8.

Wang, Z., Götte, M., Bernfield, M., and Reizes, O. (2005) Constitutive- and accelerated shedding of murine syndecan-1 is mediated by cleavage of its core protein at a specific juxtamembrane site. Biochemistry 44: 12355-12361.

Reizes, O. , Clegg, D.J., Strader, A., and Benoit , S.C. (2006) A role for syndecan-3 in the melanocortin regulation of energy balance. Peptides. 27:274-80.

Reizes, O. , Goldberger, O., Smith, A., Xu, Z., Bernfield, M., and Bickel, P. (2006) Insulin induces shedding of syndecans from 3T3-L1 adipocytes: a role in lipoprotein lipase transport. Biochemistry. 45:5703-5711.

Reizes O, et al. The role of syndecans in the regulation of body weight and synaptic plasticity. Int J Biochem Cell Biol  2007 Jun 30 [Epub ahead of print].