THE EFFECT OF LEPTIN IS ENHANCED BY MACROINJECTION INTO THE VENTROMEDIAL HYPOTHALAMUS

To determine whether changes in food intake produced by leptin involve targeting the hormone to distinct central nervous system regions, gui de cannulas were positioned stereotaxically into three brain regions-t he ventromedial hypothalamus (VMH) (bilaterally, n = 6), the dorsal ra phe nucleus (n = 3), and the lateral ventricle (n = 3)-of nonobese mal e rats (400-500 g). Daily food intake and body weight changes were mea sured during twice-daily injections of saline (0.1 mu l) followed by r ecombinant human leptin (0.05 mu g) for 3 days via the brain cannulas, VMH-injected rats also were followed during a postleptin saline recov ery 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, V MH-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 administrati on. VMH-injected animals fully recovered from leptin-induced effects w ithin 3 days, We conclude that small doses of leptin that do not effec t eating behavior when delivered to the ventricle or the dorsal raphe (another brain region believed to regulate feeding), suppress food int ake when injected into the VMH, These data suggest that the VMH or a b rain region in close proximity to it is a key target for the biologica l actions of leptin.