To determine whether changes in food intake produced by leptin involve targeting the hormone to distinct central nervous system regions, guide cannulas were positioned stereotaxically into three brain regions-the ventromedial hypothalamus (VMH) (bilaterally, n = 6), the dorsal raphe nucleus (/i = 3), and the lateral ventricle (w = 3)-of nonobese male rats (400-500 g). Daily food intake and body weight changes were measured during twice-daily injections of saline (0.1 ul) followed by recombinant human leptin (0.05 ug) for 3 days via the brain cannulas. VMH-injected rats also were followed during a postleptin saline recovery interval. This small dose of leptin did not change food intake or body weight from that during the preceding saline injection period in ventricle-injected or dorsal raphe-injected rats. In sharp contrast, VMH-injected rats ate much less food (56 ± 8% basal) and lost 9 + 3 g/day or 5% of their body weight during 3 days of leptin administration. VMH-injected animals fully recovered from leptin-induced effects within 3 days. We conclude that small doses of leptin that do not effect eating behavior when delivered to the ventricle or the dorsal raphe (another brain region believed to regulate feeding), suppress food intake when injected into the VMH. These data suggest that the VMH or a brain region in close proximity to it is a key target for the biological actions of leptin. Diabetes 46:150-152, 1997 O besity and its resulting complications, such as heart disease, hypertension, dyslipidemia, and diabetes, have become increasingly significant public health concerns. The existence of a circulating satiety factor that contributes to the development of obesity has been suggested since the early parabiotic experiments of Coleman (1) showing reversal of obesity when the circulatory system of a morbidly obese (pb/ob) mouse was connected to that of a lean mouse. This hypothesis has been greatly strengthened by the recent cloning of the ob gene (2) From the Yale University School of Medicine, Department of Internal Medicine, New Haven, Connecticut.Address correspondence and reprint requests to Ralph J. Jacob, Yale University School of Medicine, Department of Internal Medicine/Endocrinology, 333 Cedar St., Box 208020, New Haven, CT 06520-8020.Received for publication 7 August 1996 and accepted in revised form 18 October 1996.CNS, central nervous system; VMH, ventromedial hypothalamus.and the identification of its product (leptin) as a 16-kDa protein secreted by adipose tissue into the circulation. In the ob/ob mouse, a mutation of the leptin gene results in the production of a truncated nonfunctional molecule. The importance of this genetic defect is underscored by data showing that systemic or intracerebroventricular (in smaller doses) administration of leptin produces reductions in food intake and body weight in leptin-deficient ob/ob mice (3-6). To produce similar effects in lean animals, much larger doses of leptin were required (3-6). Although a wide variety of tissues appear to express leptin recepto...