Diabetologie und Stoffwechsel 2006; 1 - A66
DOI: 10.1055/s-2006-943791

Enhanced PIP3 signaling in POMC neurons causes diet-sensitive obesity as the consequence of neuronal silencing via KATP channel activation

L Plum 1, X Ma 2, B Hampel 3, H Münzberg 4, M Shanabrough 5, E Rother 3, L Koch 3, R Janoschek 3, J Alber 3, BF Belgardt 3, W Krone 1, TL Horvath 5, FM Ashcroft 2, JC Brüning 3
  • 1Klinikum der Universität zu Köln, Klinik II und Poliklinik für Innere Medizin und Zentrum für Molekulare Medizin Köln (ZMMK), Köln, Germany
  • 2University Laboratory of Physiology, Oxford, United Kingdom
  • 3Institute for Genetics, Department of Mouse Genetics and Metabolism, Köln, Germany
  • 4University of Michigan Medical School, Division of Metabolism, Endocrinology and Diabetes, Ann Arbor, United States of America
  • 5Yale University School of Medicine, Department of Obstetrics, Gynecology & Reproductive Sciences and Department of Neurobiology, New Haven, United States of America

Leptin and insulin have been identified as fuel sensors acting in part through their hypothalamic receptors to inhibit food intake and stimulate energy expenditure. Both insulin and leptin receptors efficiently activate insulin receptor substrate-dependent signaling leading to activation of the phosphatidyl-inositol (PI) 3-kinase and subsequent generation of PI3,4,5-trisphosphate (PIP3). We directly addressed the role of PIP3-mediated signals in hypothalamic proopiomelanocortin (POMC) neurons by inactivating the gene for the PIP3 phosphatase Pten specifically in this cell type. Here we show that POMC-specific disruption of Pten (PPKO) paradoxically resulted in sexually dimorphic diet-sensitive obesity due to hyperphagia. Leptin potently stimulated Stat3 phosphorylation in POMC neurons of PPKO mice, but failed to inhibit food intake in vivo. Strikingly, POMC neurons of PPKO mice showed a marked hyperpolarization and a reduction in basal firing rate due to increased ATP-sensitive potassium (KATP) 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. Moreover, intracerebroventricular administration of tolbutamide abolished hyperphagia in PPKO mice. These data indicate that PIP3-mediated signals are critical regulators of the melanocortin system via modulation of KATP channels.