Leptin and Neuroendocrine Gene Regulation in Obesity

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DESCRIPTION (provided by applicant): The long-term objectives of this proposal are to understand the neuroendocrine regulation of energy homeostasis and changes in neuroendocrine axes that occur with weight loss and leptin administration. Particular focus is on the hypothalamic melanocortin and dopaminergic pathways and gastrointestinal hormones involved in the regulation of food intake. The objectives of Aim 1 are to characterize the effects of maintenance of a reduced body weight on specific neuroendocrine axes (hypothalamic-pituitary-adrenal, thyroid and growth hormone) as well as the effects of chronic low dose leptin administration on these axes in obese and weight-reduced obese individuals. This Aim is based on the premise that weight loss is accompanied by metabolic and hormonal changes that favor regain of lost weight in part due to decreased circulating concentrations of leptin and that leptin replacement will restore these parameters to those present prior to weight reduction. Aim 2 examines the changes that occur with gastric bypass and banding procedures and long-term gastric stimulation in circulating concentrations of gastrointestinal hormones that interact with the hypothalamic melanocortin system (ghrelin and PYY(3-36)). The response of these hormones to a test meal will be measured and correlated to feelings of hunger and satiety. The objectives of Aim 3 are to examine the effects of dopaminergic and antidopaminergic agents on the hypothalamic melanocortin system, body weight and glucose metabolism. The first part of this Aim characterizes the effects of these agents on food intake, body weight and composition and on Pomc and Agrp gene expression in the rat hypothalamus. The second part of this examines the effects of a long-acting dopamine agonist, cabergoline, on body weight and glucose metabolism in obese humans. Results from these studies are expected to further the understanding of the physiological responses to weight loss and to help target the development of therapies for weight reduction and the maintenance of a reduced body weight.