Previous work in our laboratory, and many others, has shown that body weight is regulated. When anyone, fat or thin, tries to maintain a reduced body weight, many systems affecting energy balance (skeletal muscle, neuroendocrine, and autonomic systems) conspire to slow metabolic rate thus favoring the regain of lost weight. Individuals with leptin deficiency are remarkably similar to weight-reduced individuals. Their metabolism, thyroid hormones, and sympathetic nervous system activity are all low despite their obesity. While administration of leptin to leptin-deficient humans results in substantial weight loss and increases in energy expenditure. However, leptin administration to leptin-sufficient humans at usual body weight has little or no effect on weight unless given in doses 10-20 times what would be considered to be in the normal physiological range. This study examines the hypothesis that leptin is "read" by various systems regulating energy balance as an indicator of how much energy we have stored and that the body perceives the weight-reduced state as a condition of relative leptin insufficiency. Within this model, restoration of leptin to levels present prior to weight loss should relieve much of the metabolic opposition to keeping weight off. Preliminary studies support this hypothesis.

Healthy lean and overweight subjects are admiited to the General Clinical Research Center at Columbia University Medical College and placed on a liquid formula diet. Calories are adjusted until weight is stable and then subjects undergo testing of neuroendocrine, autonomic, and metabolic function. All subjects undergo an in-patient 10% weight reduction. Subjects are studied in a single blind placebo control design in which they are studied at usual weight and while maintaining a 10% reduced weight. At either usual weight or reduced state subjects undergo a single blind crossover placebo/control study in which they receive placebo,lepin injections while on an isocaloric diet either at usual weight or following a 10% weight loss. Leptin injections are given in doses that restored 8AM circulating leptin concentrations to those present at initial body weight.

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 weight regain; 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 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, 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. Healthy lean and overweight subjects are admiited to the General Clinical Research Center at Columbia University Medical College and placed on a liquid formula diet. Calories are adjusted until weight is stable and then subjects undergo testing of neuroendocrine, autonomic, and metabolic function. All subjects undergo an in-patient 10% weight reduction. Subjects are studied in a single blind placebo control design in which they are studied at usual weight and while maintaining a 10% reduced weight. At either usual weight or reduced state subjects undergo a single blind crossover placebo/control study in which they receive placebo,lepin injections while on an isocaloric diet either at usual weight or following a 10% weight loss. Leptin injections are given in doses that restored 8AM circulating leptin concentrations to those present at initial body weight. During each of these study periods, subjects will undergo detailed evaluation of 1.) energy expenditure (11 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); 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) 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.

• Obesity
• Weight Loss

• Drug: Placebo
  twice daily iinjections of saline in the same volume as will be used for B-2 leptin injections
• Drug: Leptin
  Leptin will be given as twice daily subcutaneous injections in doses titrated to replicate 8AM circulating leptin concentrations measured in the same subjects prior to weight loss.
• Drug: placebo
  Subjects will receive a once daily oral placebo
• Drug: Tri-iodothyronine
  Subjects will receive a once daily oral dose of T3 which will be titrated until 8AM T3 levels are similar to those measured in the same subjects prior to weight loss.
  Other Name: Cytomel

• A: No Intervention
  Subjects undergo studies at their usual body weight
• B -1: Placebo Comparator
  Subjects are studied while at a 10% reduced body weight and receiving twice daily injections of placebo for 5 weeks
  Intervention: Drug: Placebo
• B-2: Experimental
  Subjects are studied while at a 10% reduced body weight and receiving twice daily injections of "replacement" leptin for 5 weeks
  Intervention: Drug: Leptin
• C-1: Placebo Comparator
  Subjects are studied while at a 10% reduced body weight and receiving an oral placebo for 5 weeks
  Intervention: Drug: placebo
• C-2: Experimental
  Subjects are studied while at a 10% reduced body weight and receiving an oral "replacement" of thyroid hormone for 5 weeks
  Intervention: Drug: Tri-iodothyronine

• Rosenbaum M, Goldsmith R, Bloomfield D, Magnano A, Weimer L, Heymsfield S, Gallagher D, Mayer L, Murphy E, Leibel RL. Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight. J Clin Invest. 2005 Dec;115(12):3579-86.
• Rosenbaum M, Murphy EM, Heymsfield SB, Matthews DE, Leibel RL. Low dose leptin administration reverses effects of sustained weight-reduction on energy expenditure and circulating concentrations of thyroid hormones. J Clin Endocrinol Metab. 2002 May;87(5):2391-4.

Inclusion Criteria: Healthy lean or overweight males and females who have sustained their current weight for at least 6 months.

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Exclusion Criteria:Pregnancy, any illness or chronic medication that affect energy expenditure, neuroendocrine function,autonomic function or that would impair ability to tolerate a prolonged hospital stay including rapid weight reduction and vigorous exercise.

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