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- Publisher Website: 10.1172/JCI27123
- Scopus: eid_2-s2.0-33745819212
- PMID: 16794735
- WOS: WOS:000238924900022
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Article: Enhanced PIP3 signaling in POMC neurons causes KATP channel activation and leads to diet-sensitive obesity
Title | Enhanced PIP<inf>3</inf> signaling in POMC neurons causes K<inf>ATP</inf> channel activation and leads to diet-sensitive obesity |
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Authors | Plum, LeonaMa, XiaosongHampel, BrigitteBalthasar, NinaCoppari, RobertoMünzberg, HeikeShanabrough, MaryaBurdakov, DenisRother, EvaJanoschek, RuthAlber, JensBelgardt, Bengt F.Koch, LindaSeibler, JostSchwenk, FriederFekete, CsabaSuzuki, AkiraMak, Tak W.Krone, WilhelmHorvath, Tamas L.Ashcroft, Frances M.Brüning, Jens C. |
Issue Date | 2006 |
Citation | Journal of Clinical Investigation, 2006, v. 116, n. 7, p. 1886-1901 How to Cite? |
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 PIP 3 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. |
Persistent Identifier | http://hdl.handle.net/10722/292574 |
ISSN | 2021 Impact Factor: 19.456 2020 SCImago Journal Rankings: 6.278 |
PubMed Central ID | |
ISI Accession Number ID |
DC Field | Value | Language |
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dc.contributor.author | Plum, Leona | - |
dc.contributor.author | Ma, Xiaosong | - |
dc.contributor.author | Hampel, Brigitte | - |
dc.contributor.author | Balthasar, Nina | - |
dc.contributor.author | Coppari, Roberto | - |
dc.contributor.author | Münzberg, Heike | - |
dc.contributor.author | Shanabrough, Marya | - |
dc.contributor.author | Burdakov, Denis | - |
dc.contributor.author | Rother, Eva | - |
dc.contributor.author | Janoschek, Ruth | - |
dc.contributor.author | Alber, Jens | - |
dc.contributor.author | Belgardt, Bengt F. | - |
dc.contributor.author | Koch, Linda | - |
dc.contributor.author | Seibler, Jost | - |
dc.contributor.author | Schwenk, Frieder | - |
dc.contributor.author | Fekete, Csaba | - |
dc.contributor.author | Suzuki, Akira | - |
dc.contributor.author | Mak, Tak W. | - |
dc.contributor.author | Krone, Wilhelm | - |
dc.contributor.author | Horvath, Tamas L. | - |
dc.contributor.author | Ashcroft, Frances M. | - |
dc.contributor.author | Brüning, Jens C. | - |
dc.date.accessioned | 2020-11-17T14:56:46Z | - |
dc.date.available | 2020-11-17T14:56:46Z | - |
dc.date.issued | 2006 | - |
dc.identifier.citation | Journal of Clinical Investigation, 2006, v. 116, n. 7, p. 1886-1901 | - |
dc.identifier.issn | 0021-9738 | - |
dc.identifier.uri | http://hdl.handle.net/10722/292574 | - |
dc.description.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 PIP 3 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. | - |
dc.language | eng | - |
dc.relation.ispartof | Journal of Clinical Investigation | - |
dc.title | Enhanced PIP<inf>3</inf> signaling in POMC neurons causes K<inf>ATP</inf> channel activation and leads to diet-sensitive obesity | - |
dc.type | Article | - |
dc.description.nature | link_to_OA_fulltext | - |
dc.identifier.doi | 10.1172/JCI27123 | - |
dc.identifier.pmid | 16794735 | - |
dc.identifier.pmcid | PMC1481658 | - |
dc.identifier.scopus | eid_2-s2.0-33745819212 | - |
dc.identifier.volume | 116 | - |
dc.identifier.issue | 7 | - |
dc.identifier.spage | 1886 | - |
dc.identifier.epage | 1901 | - |
dc.identifier.eissn | 1558-8238 | - |
dc.identifier.isi | WOS:000238924900022 | - |
dc.identifier.f1000 | 1049353 | - |
dc.identifier.issnl | 0021-9738 | - |