Over the last several years, an explosion of data on the role of distinct peptides in regulating food intake and energy expenditure has fundamentally altered our understanding of regulation of body weight and energy expenditure and has broadened significantly our view of the potential molecular mechanisms underlying the pathogenesis and clinical manifestations of eating disorders, including obesity and anorexia nervosa. Central to these observations was the discovery of leptin which plays a central role in signaling the amount of energy stored in adipose tissue to the central nervous system. In addition to its role in obesity, our laboratory has explored two additional central roles of leptin, i.e. the role of leptin in regulating immune function and in mediating the neuroendocrine response to states of caloric deprivation in rodents. The current proposal will provide a transition from our laboratory observations to studies in normal human volunteers. Thus, we will study the physiology of leptin's secretion in lean and obese subjects and we will investigate the potential role of leptin as a regulator of energy expenditure and immune function and as mediator of the neuroendocrine response to food deprivation in humans. We hypothesize that 1) A fall in leptin blood levels and/or a change in its pattern of secretion in response to food deprivation are associated with the food deprivation-induced neuroendocrine and/or immune changes in humans, 2) Leptin administration to fasted humans will ameliorate the immune and/or neuroendocrine changes associated with food deprivation and 3) There are differences in leptin's role between men and women as well as lean and obese subjects. To examine these three hypotheses, we will measure energy expenditure and immune function and we will perform frequent blood sampling (every 15 min.) for 24 hours to assess hypothalamic-pituitary-end organ axes in a total of 32 subjects: 8 lean men, 8 lean women, 8 obese men and 8 obese women. Subjects will be studied under three conditions: a) Baseline, i.e. normal food consumption with placebo subcutaneous injections b) Following 3 days of food deprivation with placebo leptin subcutaneous injections, and c) Following 3 days of food deprivation with recombinant human leptin subcutaneous injections (The order of b and c will be randomized and double-blind). Data derived from these studies will increase our understanding of the normal physiology of leptin and its role in regulating energy expenditure, neuroendocrine and immune response in the fed and fasted states in normal humans, In addition, these data will provide important insights into the neuroendocrine response to therapeutic dieting in obesity and elucidate the pathophysiology of the neuroendocrine changes seen in anorexia nervosa and may also provide the basis for future therapeutic interventions for obesity and anorexia nervosa.
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