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

Ivan Nemazanyy, Guillaume Montagnac, Ryan C. Russell, Lucille Morzyglod, Anne-Françoise Burnol, Kun-Liang Guan, Mario Pende () and Ganna Panasyuk ()
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Ivan Nemazanyy: Institut Necker-Enfants Malades (INEM)
Guillaume Montagnac: Institut National de la Santé et de la Recherche Médicale (INSERM), U1170, Gustave Roussy Institute
Ryan C. Russell: University of California at San Diego
Lucille Morzyglod: Université Paris Descartes, Sorbonne Paris Cité
Anne-Françoise Burnol: Université Paris Descartes, Sorbonne Paris Cité
Kun-Liang Guan: University of California at San Diego
Mario Pende: Institut Necker-Enfants Malades (INEM)
Ganna Panasyuk: Institut Necker-Enfants Malades (INEM)

Nature Communications, 2015, vol. 6, issue 1, 1-16

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms9283

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