Our group has tested the hypothesis that the molecules involved in the neurobiology of the stress response are key elements in the pathophysiology, treatment, and medical consequences of major depressive disorder. Leptin is implicated in the regulation of adipose tissue, body weight and homeostasis. In the first three years of this protocol we accomplished the following: (1) discovered leptin pulsatility; (2) showed that is secreted in a highly organized manner in men and women; (3) showed for the first time in humans an inverse relation between rapid fluctuations in plasma leptin concentrations in healthy volunteers and those of adrenocorticotropic hormone (ACTH) and cortisol; (4) demonstrated a complex relation between the minute-to-minute dynamics of leptin and those of luteinizing hormone and estradiol; (5) showed a striking correlation between the 24-h dynamics of leptin and those of TSH and GH; (6) demonstrated highly significant correlation between hourly fluctuations of leptin levels and those of psychometric variables such as sadness, social withdrawal, and carbohydrate craving, and (7) showed that women produce twice as much leptin per secretory event than men. By studying patients with a leptin gene mutation we showed that at least one intact copy of the leptin gene is required for the regulation of TSH function and GH architecture in humans. These results indicate that leptin, a peripherally secreted molecule, appears to modulate the secretion of hypothalamic hormones. We have therefore proposed that hypothalamic neuroendocrine transduction, a key function of the CNS, may be regulated by leptin, a peripheral pulsatile signal of nutritional status. We would like to continue and expand our studies on the interactions of leptin, fat distribution, and the pituitary-adrenal axis in normal volunteers and also in patients with depression, because depression is characterized by alterations in food intake, body weight, and neuroendocrine function. Leptin profoundly affects the regulation of these three parameters. Leptin also increases insulin resistance, being therefore a risk factor for coronary artery disease, which is more prevalent and associated with higher mortality in depressed patients than in the general population. The data to be generated by this study will provide a better understanding of pathophysiology and medical consequences of major depression.