Leptin activates anorexigenic POMC neurons through a neural network in thearcuate nucleus

The administration of leptin(1) to leptin-deficient humans, and the analogo us Lep(ob)/Lep(ob) mice, effectively reduces hyperphagia and obesity(2,3). But common obesity is associated with elevated leptin, which suggests that obese humans are resistant to this adipocyte hormone. In addition to regula ting long-term energy balance, leptin also rapidly affects neuronal activit y(4-6). Proopiomelanocortin (POMC) and neuropeptide-Y types of neurons in t he arcuate nucleus of the hypothalamus(7) are both principal sites of lepti n receptor expression and the source of potent neuropeptide modulators, mel anocortins and neuropeptide Y, which exert opposing effects on feeding and metabolism(8,9). These neurons are therefore ideal for characterizing lepti n action and the mechanism of leptin resistance; however, their diffuse dis tribution makes them difficult to study. Here we report electrophysiologica l recordings on POMC neurons, which we identified by targeted expression of green fluorescent protein in transgenic mice. Leptin increases the frequen cy of action potentials in the anorexigenic POMC neurons by two mechanisms: depolarization through a nonspecific cation channel; and reduced inhibitio n by local orexigenic neuropeptide-Y/GABA (gamma -aminobutyric acid) neuron s. Furthermore, we show that melanocortin peptides have an autoinhibitory e ffect on this circuit. On the basis of our results, we propose an integrate d model of leptin action and neuronal architecture in the arcuate nucleus o f the hypothalamus.