Obesity is a health problem of grave concern in western nations and the search for effective treatments has yet to come to fruition. The control of food intake and body weight involves peripheral (hormonal) and central (neural) mechanisms. In the brain, the hypothalamic melanocortin (MC) family of peptides is thought to play an important role in the control of food intake. Administration of MC antagonists produces robust increases in food intake, while agonists lead to decreased intake. In addition, central expression of the precursor molecule, pro-opiomelanocortin (POMC), for these peptides is regulated by signals of energy balance, including the adipocyte hormone, leptin. Importantly, recent reports have identified a novel co-receptor, called syndecan-3, which facilitates the action of melanocortin antagonists. Because POMC is critically involved in the regulation of several physiological processes (e.g., stress), syndecan-3 may represent a way to modulate melanocortin control of body weight without disrupting POMC involvement in other systems. We propose to examine the mechanisms that regulate the function of this novel syndecan-3 co-receptor and the specific ways through which it interacts with melanocortin control of food intake and body weight. First, we will assess the anatomical specificity of syndecan-3 and melanocortin receptor expression. Second, we will use pharmacological techniques to identify the enzymes responsible for syndecan-3 function. Additional experiments will assess whether drugs that influence food intake can influence syndecan-3 function, and vice-versa. Finally, we will use genetic approaches to assess the degree of syndecan-3 and melanocortin interaction in the control of energy balance. Specifically, we will cross mice with genetic disruptions of syndecan-3 function and mice that have mutant genes for melanocortin antagonists. Collectively, these experiments are designed to identify the mechanisms of syndecan-3 function as well as syndecan-3 interaction with melanocortins in the control of food intake and body weight. The results may provide important, basic insights into the control of body weight by the central melanocortin system and its recently identified co-receptor, syndecan-3.
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