期刊
CELL METABOLISM
卷 10, 期 5, 页码 343-354出版社
CELL PRESS
DOI: 10.1016/j.cmet.2009.09.008
关键词
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资金
- Wellcome Trust
- Medical Research Council
- Biotechnology and Biological Sciences Research Council
- Diabetes UK
- Ludwig Institute for Cancer Research
- Queen Mary University of London
- European Molecular Biology Organization [ALTF676-2005]
- Foundation pour la Recherche Medicale [FRMSPE20051105175]
- European Union Marie Curie [MEIF-CT-2006-039676]
- MRC [G0600866, MC_U120061305, G108/551, MC_U120097114] Funding Source: UKRI
- Medical Research Council [G108/551, G0600866, MC_U120097114, G0700711B, MC_U120061305] Funding Source: researchfish
PI3K signaling is thought to mediate leptin and insulin action in hypothalamic pro-opiomelanocortin (POMC) and agouti-related protein (AgRP) neurons, key regulators of energy homeostasis, through largely unknown mechanisms. We inactivated either p110 alpha or p110 beta PI3K catalytic subunits in these neurons and demonstrate a dominant role for the latter in energy homeostasis; regulation. In POMC neurons, p110 beta inactivation prevented insulin- and leptin-stimulated electrophysiological responses. POMCp110 beta null mice exhibited central leptin resistance, increased adiposity, and diet-induced obesity. In contrast, the response to leptin was not blocked in p110 alpha-deficient POMC neurons. Accordingly, POMCp110 alpha null mice displayed minimal energy homeostasis abnormalities. Similarly, in AgRP neurons, p110 beta had a more important role than p110 alpha. AgRPp110 alpha null mice displayed normal energy homeostasis regulation, whereas AgRPp110 beta null mice were lean, with increased leptin sensitivity and resistance to diet-induced obesity. These results demonstrate distinct metabolic roles for the p110 alpha and p110 beta isoforms; of PI3K in hypothalamic energy regulation.
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