Leptin in Human Energy and Neuroendocrine Homeostasis

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DESCRIPTION (provided by applicant): Over 50% of U.S. adults are overweight (BMI > 25 kg/m 2) and "at-risk" for adiposity-related morbidities. The failure of obesity treatments to sustain weight reduction is widely recognized. The central hypotheses of these studies are that: 1.) Energy and neuroendocrine homeostastic systems are altered during the maintenance of a reduced body weight in a manner that favors the regain of lost weight; 2.) These changes occur because weight-reduced individuals are in a state of relative leptin deficiency due to loss of body fat; and 3.) Therefore these changes energy and neuroendocrine homeostatic systems accompanying the maintenance of a reduced body weight will be reversed if circulating leptin concentrations are restored to those that were present prior to weight reduction. Maintenance of a reduced body weight is associated with integrated autonomic and neuroendocrine changes that reduce energy expenditure and increase food intake in a manner that is similar to that seen in rodents and humans who are deficient in, or resistant to, the adipocyte-derived hormone leptin. Systemic leptin administration to leptin-deficient rodents and humans reverses the metabolic (hypometabolism, hyperphagia), autonomic (increased parasympathetic and decreased sympathetic nervous system tone), and neuroendocrine (increased hypothalamic-pituitary-adrenal axis activity, decreased hypothalamic-pituitary -thyroidal and -gonadal axis activity) changes that characterize the leptin-deficient state. The proposed studies focus on the neuroendocrine, behavioral, autonomic, and metabolic changes that characterize the reduced-obese individual, and the effects on these phenotypes of restoration of circulating concentrations of leptin to levels present prior to weight loss. Obese subjects will be admitted to the Columbia University CRC and studied at 1.) usual body weight (Wtinitial), 2.) during maintenance of a 10% reduced body weight (Wt-10%), and 3.) during maintenance of a 10% reduced body weight receiving exogenous leptin at doses sufficient to restore circulating leptin to concentrations present prior to weight loss. During each of these study periods, subjects will undergo detailed evaluation of 1.) energy expenditure (10 day differential excretion of heavy isotopes of water, indirect calorimetry for resting energy expenditure, non-resting energy expenditure, and thermic effect of feeding, time spent in physical activity) and appetitive behavior (assessment of hunger and satiety); 2.) autonomic nervous system tone (serial blockade of sympathetic and parasympathetic inputs, heart rate variability analyses, and urinary catecholamine excretion); 3.) hypothalamic-pituitary -thyroid, -adrenal and -gonadal, axis function; 4.) adipose tissue gene expression; 5.) other molecules (e.g., adiponectin, ghrelin, PYY, IL-6, IL-1Ra) that may influence neuroendocrine and metabolic function. We predict that leptin administration will reverse the metabolic, autonomic, and neuroendocrine phenotypes characterizing the weight-reduced state. The results of these studies will further delineate the physiology of body weight regulation and of leptin.