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 4

Phenotypic characteristics of control (open symbols; white bars) and PPKO (filled symbols; black bars) female mice under different dietary conditions with respect to energy homeostasis.

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Phenotypic characteristics of control (open symbols; white bars) and PPK...
(A)Average body weight of ND- (triangles) and HFD-fed (circles) female mice (n = 6–81). (B)Outward appearance of 2 control and 2 PPKO female mice of the same litter at the age of 20 weeks (17 weeks of HFD feeding). (C)Exemplary demonstration of parametrial fat pads in situ (upper panel; black diamonds) and ex situ (lower panel; white diamonds) of control and PPKO females at the age of 20 weeks. (D)Absolute parametrial fat pad weights of female control and PPKO mice on ND and HFD (n = 3–17) and relative (corrected for body weight) parametrial fat pad weights of female HFD-fed control and PPKO mice. (E)Serum leptin levels of female control and PPKO mice on ND and HFD (n = 4–30). (F)Daily caloric intake of female control and PPKO mice on HFD at the age of 10–13 weeks (n = 4–6). (G)Oxygen consumption of female mice on HFD at the age of 12 weeks (n = 7–8). (H)Locomotor activity of female mice on HFD at the age of 12 weeks (n = 7–8). Unless otherwise indicated, data were collected at 20 weeks of age. Values are mean ± SEM. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001 versus control.