The DOI matches its Crossref record; 12 of the 12 references it cites were found in a registry or an index.
Enhanced PIP3 signaling in POMC neurons causes KATP channel activation and leads to diet-sensitive obesity
Open accessAbstract
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.
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STAT3 signalling is required for leptin regulation of energy balance but not reproduction
Bates, S. H., Stearns, W. H., Dundon, T. A., Schubert, M., Tso, A. W. K., Wang, Y., Banks, A. S., Lavery, H. J., Haq, A. K., Maratos-Flier, E., et al. (2003) · Nature · doi:10.1038/nature01388 · Cited by 1,010 · cited 20×
“(D) Representative immunohistochemistry of pStat3 formation in hypothalamic neurons of male ND-fed control and PPKO mice at 12–15 weeks of age.”
BackgroundInfluentialProopiomelanocortin Neurons Are Direct Targets for Leptin in the Hypothalamus
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Membrane Phospholipid Control of Nucleotide Sensitivity of K ATP Channels
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PI3K integrates the action of insulin and leptin on hypothalamic neurons
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The Catabolic Action of Insulin in the Brain Is Mediated by Melanocortins
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“Furthermore, icv injection of insulin and leptin results in reduced expression of NPY and AgRP and increased expression of POMC (18, 19).”
Background
Cited by
Mechanisms of leptin action and leptin resistance.
Myers, M. G., Cowley, M. A., & Münzberg, H. (2008) · Annual Review of Physiology · doi:10.1146/annurev.physiol.70.113006.100707 · Cited by 1,074
Insulin Action in AgRP-Expressing Neurons Is Required for Suppression of Hepatic Glucose Production
Könner, A. C., Janoschek, R., Plum, L., Jordan, S. D., Rother, E., Ma, X., Xu, C., Enriori, P., Hampel, B., Barsh, G. S., et al. (2007) · Cell Metabolism · doi:10.1016/j.cmet.2007.05.004 · Cited by 695
Self-citationKleinridders, A., Schenten, D., Könner, A. C., Belgardt, B. F., Mauer, J., Okamura, T., Wunderlich, F. T., Medzhitov, R., & Brüning, J. C. (2009) · Cell Metabolism · doi:10.1016/j.cmet.2009.08.013 · Cited by 483
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Hill, J. W., Elias, C. F., Fukuda, M., Williams, K. W., Berglund, E. D., Holland, W. L., Cho, Y.-R., Chuang, J.-C., Xu, Y., Choi, M., et al. (2010) · Cell Metabolism · doi:10.1016/j.cmet.2010.03.002 · Cited by 391
Metadata
- Authors
- Plum, L.
- Venue
- Journal of Clinical Investigation
- Published
- 2006-07-03
- Volume
- 116
- Issue
- 7
- Pages
- 1886-1901
- ISSN
- 0021-9738 (ISSN-L)
- OpenAlex
- W2148161631
- Cited by
- 326
- References
- 12
- FWCI
- 9.92
- Type
- journal article
- Language
- en
- Open access
- bronze
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