The Institute Of Human Nutrition

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Faculty and Staff

Nutritional and Metabolic Doctoral Training Faculty

Sharon L. WardlawSharon L. Wardlaw, M.D.

Robert C and Veronica Atkins Professor of Obesity Research
in Medicine Department of Medicine-Endocrinology



Division Of Endocrinology
William Black Building
650 West 168th Street
9th Floor, Room 902
New York, NY 10032
Phone: 212 305 3725

Research Summary

Neuroendocrine control of pituitary function. Hypothalamic regulation of energy homeostasis. Neuroendocrine-immune interactions.

Research Activities

Hypothalamic regulation of energy homeostasis: This project focuses on the melanocortin neuropeptide system which plays a key role in regulating *appetite and body weight and is an important target for leptin in the hypothalamus. Studies center on the regulation of proopiomelanocortin (POMC) and the POMC-derived peptides, a-MSH, g-MSH and ß-EP, together with the newly discovered agouti related protein (AGRP) which is synthesized in the hypothalamus and is a potent antagonist of the MSH peptides. a-MSH inhibits feeding and AGRP is an orexigenic peptide which antagonizes the actions of a-MSH at specific melanocortin receptors. Ongoing studies are examining the regulation of POMC and AGRP gene expression, peptide processing and peptide release in the rat hypothalamus by both leptin and insulin as well as interactions between the POMC and AGRP neurons themselves which both express melanocortin receptors. The role of leptin in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis is also being studied. The HPA axis plays a key role in energy homeostasis and is intricately related to the obesity syndromes in leptin deficient animals. Transgenic mice which overexpress a-MSH and g-MSH have also been developed to further understand the role that these neuropeptides play in modulating feeding behavior, metabolic and endocrine responses. Current studies are characterizing the mechanisms by which the melanocortin system modulates energy expenditure, fuel oxidation and glucose metabolism in rodent models and are examining potential ways to safely activate this system for therapeutic benefit in the human.

Cytokines and Hypothalamic-Pituitary-Immune Interactions: This project focuses on inflammatory cytokines and mechanisms of HPA activation and on the modulation of cytokine and HPA responses to inflammation by leptin and the melanocortin system. There is evidence that leptin, which plays a key role in regulating energy homeostasis, can also modulate the inflammatory response. a-MSH is synthesized in the hypothalamus and in the periphery and can be regulated by leptin. a-MSH has potent anti-inflammatory properties and can antagonize many of the actions of the inflammatory cytokines. Little is known, however, about the role of the endogenous melanocortin system, consisting of a-MSH, the melanocortin receptors, and the MSH antagonist, AGRP, in modulating cytokine and neuroendocrine responses. This project will examine the role of leptin, a-MSH and AGRP in modulating pro-inflammatory (IL-1ß, IL-6, TNF-a) and anti-inflammatory cytokine (IL-1ra and IL-10) responses to endotoxin and IL-1ß in the rhesus monkey. Major goals are to determine the physiological roles that a-MSH and AGRP play both centrally and peripherally in modulating the HPA response to an inflammatory challenge and to determine if the effects of leptin on the HPA axis are mediated in part by a-MSH. A rodent model will be used to examine the effects of endotoxin on POMC and AGRP gene expression in the hypothalamus and the effects of leptin on IL-1ß-stimulated CRH release from the hypothalamus in vitro. Mice which overexpress a-MSH and agouti protein will also be utilized to study the role of the melanocortin system and of leptin in modulating cytokine and neuroendocrine responses to endotoxin.

Recent Publications - Pubmed

Savontaus E, Breen TL, Kim A, Yang LM, Chua SC, Wardlaw SL: Metabolic effects of transgenic MSH overexpression in lean and obese mice. Endocrinology 145: 3881-3891, 2004.

Breen TL, Conwell IM, Wardlaw SL: Effects of fasting, leptin and insulin on AGRP and POMC peptide release in the hypothalamus. Brain Research 1032: 141-148, 2005.

Vulliemoz NR, Xiao E, Xia-Zhang L, Ferin M, Wardlaw SL. Melanocortin modulation of inflammatory cytokine and neuroendocrine responses to endotoxin in the monkey. Endocrinology. 2006 Apr;147(4):1878-83.

Creemers JW, Pritchard LE, Gyte A, Le Rouzic P, Meulemans S, Wardlaw SL, Zhu X, Steiner DF, Davies N, Armstrong D, Lawrence CB, Luckman SM, Schmitz CA, Davies RA, Brennand JC, White A. Agouti-related protein is posttranslationally cleaved by proprotein convertase 1 to generate agouti-related protein (AGRP)83-132: interaction between AGRP83-132 and melanocortin receptors cannot be influenced by syndecan-3. Endocrinology. 2006 Apr;147(4):1621-31.

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630 West 168th Street, PH1512
Columbia University Medical Center
New York, NY 10032
(212) 305-4808