期刊
NATURE COMMUNICATIONS
卷 6, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms9283
关键词
-
资金
- European Research Council
- European 7th Framework MyoAge program
- Fondation de la Recherche Medicale
- Fondation Schlumberger pour l'Education et la Recherche
- European Foundation for the Study of Diabetes
- Institut National du Cancer (INCa)
- French Muscular Dystrophy Asscoiation (AFM)
- Agence nationale de la recherche [ANR-10-Wnt-Metaboliv]
- Fondation pour la Recherche Medicale
- National Institutes of Health, U.S.A. [GM51586]
- Fondation Tourre
- EFSD
- INCa
- EMBO
- French Ministry of Research
- ATIP-Avenir Plan Cancer Programme
Defective hepatic insulin receptor (IR) signalling is a pathogenic manifestation of metabolic disorders including obesity and diabetes. The endo/lysosomal trafficking system may coordinate insulin action and nutrient homeostasis by endocytosis of IR and the autophagic control of intracellular nutrient levels. Here we show that class III PI3K-a master regulator of endocytosis, endosomal sorting and autophagy-provides negative feedback on hepatic insulin signalling. The ultraviolet radiation resistance-associated gene protein (UVRAG)associated class III PI3K complex interacts with IR and is stimulated by insulin treatment. Acute and chronic depletion of hepatic Vps15, the regulatory subunit of class III PI3K, increases insulin sensitivity and Akt signalling, an effect that requires functional IR. This is reflected by FoxO1-dependent transcriptional defects and blunted gluconeogenesis in Vps15 mutant cells. On depletion of Vps15, the metabolic syndrome in genetic and diet-induced models of insulin resistance and diabetes is alleviated. Thus, feedback regulation of IR trafficking and function by class III PI3K may be a therapeutic target in metabolic conditions of insulin resistance.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据