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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 Article has an altmetric score of 4

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

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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 11

Proposed model of insulin and leptin action in POMC neurons.

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Proposed model of insulin and leptin action in POMC neurons.
Insulin hyp...
Insulin hyperpolarizes POMC neurons via robust (solid line) activation of PI3K (p85, regulatory subunit; p110, catalytic subunit) and generation of PIP3. PIP3 activates KATP channels, resulting in hyperpolarization and a decreased neuronal firing rate. By contrast, leptin depolarizes POMC neurons, probably by opening nonspecific cation channels (36). Activation of the leptin receptor produces relatively weak (dashed line) stimulation of PI3K via IRS proteins but strong Stat3 phosphorylation via activation of Jak2, thereby leading to increased expression of POMC. KATP channel activity is also regulated by metabolically generated ATP and adenosine diphosphate (ADP) (44). This has been proposed to play a role in sensing ambient glucose concentrations (56), thereby regulating neuroendocrine sensitivity to glucose and metabolic efficiency (57). Other hormonal receptors that activate the PI3K pathway are shown by an ×. GP, glucose-6-phosphate; GK, glucokinase; PIP2, phosphatidylinositol4,5-biphosphate.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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