Brief introduction: Leptin and insulin have been identified as fuel sensors acting in part through their hypothalamic receptors to inhibit food intake and stimulate energy expenditure.However the molecular mechanisms underlying are largely unknown.Methods: As their intracellular signaling converges at the phosphatidyl-inositol (PI) 3 kinase pathway, we used patch-clamp techniques combined with molecular biological approaches to directly study the role of PI3,4,5-trisphosphate (PIP3)-mediated signals in maintaining energy homeostasis in the transgenic mice with specific inhibition of the gene for the PIP3 phosphatase Pten specifically in hypothalamic proopiomelanocortin (POMC) neurons and NPY/AgRPP neurons.Results: POMC-specific disruption of Pten (PPKO) resulted in hyperphagia and sexually dimorphic diet-sensitive obesity.Although leptin potently stimulated Stat3 phosphorylation in POMC neurons of PPKO mice, it failed to inhibit food intake in vivo.POMC neurons of PPKO mice showed a marked hyperpolarization and a reduction in basal firing rate due to increased ATP-sensitive potassium (KATe) channel activity.Leptin was not able to elicit electrical activity in PPKO POMC neurons, but application of the PI3 kinase inhibitor LY294002 and the KATp blocker tolbutamide restored electrical activity and leptin-evoked firing of POMC neurons in these mice.Moreover, intracerebroventricular administration of tolbutamide abolished hyperphagia in PPKO mice.Conclusion: PIP3-mediated signals are critical regulators of the melanocortin system via modulation of KAP channels.