Leptin inhibits hypothalamic neurons by activation of ATP-sensitive potassium channels

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Abstract
Leptin, the protein encoded by the obese (ob ) gene, is secreted from adipose tissue and is thought to act in the central nervous system to regulate food intake and body weight1,2. It has been proposed that leptin acts in the hypothalamus3,4,5, the main control centre for satiety and energy expenditure6. Mutations in leptin or the receptor isoform (Ob-RL) present in hypothalamic neurons result in profound obesity and symptoms of non-insulin-dependent diabetes7,8,9,10. Here we show that leptin hyperpolarizes glucose-receptive hypothalamic neurons of lean Sprague–Dawley and Zucker rats, but is ineffective on neurons of obese Zucker (fa/fa ) rats. This hyperpolarization is due to the activation of a potassium current, and is not easily recovered on removal of leptin, but is reversed by applying the sulphonylurea, tolbutamide. Single-channel recordings demonstrate that leptin activates an ATP-sensitive potassium (KATP) channel. Our data indicate that the KATP channel may function as the molecular end-point of the pathway following leptin activation of the Ob-RL receptor in hypothalamic neurons.