Enhanced PIP3 signaling in POMC neurons causes KATP channel activation and leads to diet-sensitive obesity
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
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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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 6

Hypothalamic neuropeptide expression and assessment of leptin sensitivity in control (white bars) and PPKO (black bars) mice.

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Hypothalamic neuropeptide expression and assessment of leptin sensitivit...
(A)Neuropeptide expression HFD-fed female mice at 6 and 20 weeks of age (n = 7–9 per group). CART, cocaine- and amphetamine-regulated transcript; AgRP, agouti-related peptide; TRH, thyrotropin-releasing hormone; CRH, corticotropin-releasing hormone. (B and C)Changes in food intake after intraperitoneal leptin treatment in ND-fed males at 15 weeks of age (B) and HFD-fed females at 10 weeks of age (C). Data represent daily food intake after a 3-day treatment with twice-daily injections of saline (–) or 2 mg/kg leptin (+; n = 4–6 per group). (D)Representative immunohistochemistry of pStat3 formation in hypothalamic neurons of male ND-fed control and PPKO mice at 12–15 weeks of age. Double immunohistochemistry of ARC neurons of COArte1 and PPKOArte1 reporter mice was performed in ad libitum–fed mice, which were intravenously injected with either saline or leptin and sacrificed 30 minutes after the injection. Red, β-gal (POMC neurons); green, pStat3. Scale bar: 100 μm. (E)Quantification of pStat3-positive POMC neurons in hypothalamic slices of male COArte1 and PPKOArte1 reporter mice on ND at the age of 12–15 weeks before (n = 1) and after (n = 3–8) leptin application (P > 0.05). Values are mean ± SEM. *P ≤ 0.05.