Enhanced PIP3 signaling in POMC neurons causes KATP channel activation and leads to diet-sensitive obesity
Leona Plum, … , Frances M. Ashcroft, Jens C. Brüning
Leona Plum, … , Frances M. Ashcroft, Jens C. Brüning
Published July 3, 2006
Citation Information: J Clin Invest. 2006;116(7):1886-1901. https://doi.org/10.1172/JCI27123.
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Research Article Neuroscience

Enhanced PIP3 signaling in POMC neurons causes KATP channel activation and leads to diet-sensitive obesity

Abstract

Leptin and insulin have been identified as fuel sensors acting in part through their hypothalamic receptors to inhibit food intake and stimulate energy expenditure. As their intracellular signaling converges at the PI3K pathway, we directly addressed the role of phosphatidylinositol3,4,5-trisphosphate–mediated (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 resulted in hyperphagia and sexually dimorphic diet-sensitive obesity. Although leptin potently stimulated Stat3 phosphorylation in POMC neurons of POMC cell–restricted Pten knockout (PPKO) mice, it failed to significantly 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 (KATP) channel activity. Leptin was not able to elicit electrical activity in PPKO POMC neurons, but application of the PI3K inhibitor LY294002 and the KATP blocker tolbutamide restored electrical activity and leptin-evoked firing of POMC neurons in these mice. Moreover, icv 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.

Authors

Leona Plum, Xiaosong Ma, Brigitte Hampel, Nina Balthasar, Roberto Coppari, Heike Münzberg, Marya Shanabrough, Denis Burdakov, Eva Rother, Ruth Janoschek, Jens Alber, Bengt F. Belgardt, Linda Koch, Jost Seibler, Frieder Schwenk, Csaba Fekete, Akira Suzuki, Tak W. Mak, Wilhelm Krone, Tamas L. Horvath, Frances M. Ashcroft, Jens C. Brüning

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Figure 9

Effect of leptin and tolbutamide (Tol) on electrical activity of PPKOZ/EG POMC neurons and on food intake in vivo.

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Effect of leptin and tolbutamide (Tol) on electrical ...
(A) Representative membrane potential recording from an identified POMC neuron in an ARC slice from a PPKOZ/EG POMC neuron in the absence of drug, 11 minutes after addition of 100 nM leptin, and 4 minutes after addition of 100 nM leptin plus 200 μM tolbutamide. Note the small depolarization but absence of action potentials produced by leptin alone. A depolarization of similar magnitude (mean depolarization from –58 ± 3 mV to –54 ± 2 mV) was observed in 6 of 9 neurons tested. In the other 3 neurons, leptin caused a small hyperpolarization (from –61 ± 2 mV to –66 ± 3 mV). (B) Mean action potential frequency of PPKOZ/EG POMC neurons in the absence of drug and after incubation with leptin and/or tolbutamide (n = 6 per group). (C) Food intake and body weight of 15-week-old ND-fed control (n = 4–6) and PPKO (n = 5–9) males after icv administration of either vehicle (Veh) or tolbutamide. Injection of vehicle did not alter food intake in PPKO or control mice compared with uninjected mice (data not shown). Values are mean ± SEM. *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001.