Leptin in Human Energy and Neuroendocrine Homeostasis

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.