Vitamin D Deficiency Impairs mTORC2/Akt Signaling through Downregulating SIRT1 and Results in Increased Hepatic Gluconeogenesis

1,25(OH)2D3 as an active form of vitamin D is involved in the development of many metabolic-related diseases including diabetes. While prospective epidemiological studies have shown that vitamin D deficiency is implicated in the regulation of glucose metabolism, the specific mechanism still remains unclear. Here, we generated 1α(OH)ase-null mice and discovered that these mice developed hepatic glucose overproduction and hepatic insulin resistance accompanied by decreased expression of Sirt1. ChIP and Luciferase assay confirmed that 1,25(OH)2D3 activating vitamin D receptor (VDR) directly interacts with one vitamin D response element located in Sirt1 promoter to up-regulate its transcription, triggering a cascade of phosphorylation of Akt at S473 and FOXO1 at S256 and resulting in decreased transcription of the gluconeogenic genes glucose-6-phosphatase (G6pase) and phosphoenolpyruvate carboxykinase (PCK1), eventually hepatic glucose overproduction. We have identified a signaling pathway involving VDR, Sirt1, Rictor (a component of mTOR complex 2 [mTorc2]), Akt, and FoxO1 that regulates gluconeogenesis, and identified Sirt1 and FoxO1 as key modulators of increased gluconeogenesis induced by vitamin D deficiency. Our work demonstrates a novel mechanism of 1,25(OH)2D3 deficiency-induced hyperglycemia mediated through Sirt1 downregulation. Disclosure Q. Yuan: None. J. Yang: None. M. Sun: None. S. Tang: None. M. Dong: None. L. Mao: None. Funding National Natural Science Foundation of China (81400789)