LEPTIN INHIBITS HYPOTHALAMIC NEURONS BY ACTIVATION OF ATP-SENSITIVE POTASSIUM CHANNELS

Leptin, the protein encoded by the obese (ob) gene, is secreted from a dipose tissue and is thought to act in the central nervous system to r egulate food intake and body weight(1,2). It has been proposed that le ptin acts in the hypothalamus(3-5), the main control centre for satiet y and energy expenditure(6). Mutations in leptin or the receptor isofo rm (Ob-R-L) present in hypothalamic neurons result in profound obesity and symptoms of non-insulin-dependent diabetes(7-10). Here we show th at leptin hyperpolarizes glucose-receptive hypothalamic neurons of lea n Sprague-Dawley and Zucker rats, but is ineffective on neurons of obe se Zucker (fa/fa) rats. This hyperpolarization is due to the activatio n of a potassium current, and is not easily recovered on removal of le ptin, but is reversed by applying the sulphonylurea, tolbutamide. Sing le-channel recordings demonstrate that leptin activates an ATP-sensiti ve potassium (K-ATP) channel. Our data indicate that the K-ATP channel may function as the molecular end-point of the pathway following lept in activation of the Ob-R-L receptor in hypothalamic neurons.