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Nat Commun. 2015 Sep 21;6:8283. doi: 10.1038/ncomms9283.

Class III PI3K regulates organismal glucose homeostasis by providing negative feedback on hepatic insulin signalling.

Author information

1
Institut Necker-Enfants Malades (INEM), Cedex 14, 75993 Paris, France.
2
Institut National de la Santé et de la Recherche Médicale (INSERM), Cedex 14, U1151, 75993 Paris, France.
3
Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France.
4
Institut National de la Santé et de la Recherche Médicale (INSERM), U1170, Gustave Roussy Institute, 94805 Villejuif, France.
5
Department of Pharmacology, University of California at San Diego, La Jolla, California 92093, USA.
6
Moores Cancer Center, University of California at San Diego, La Jolla, California 92093, USA.
7
Institut National de la Santé et de la Recherche Médicale (INSERM), U1016, Institut Cochin, 75014 Paris, France.
8
Centre national de la recherche scientifique (CNRS), UMR8104, 75014 Paris, France.

Abstract

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.

PMID:
26387534
PMCID:
PMC4579570
DOI:
10.1038/ncomms9283
[Indexed for MEDLINE]
Free PMC Article

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