Hepatic mTORC2 Activates Glycolysis and Lipogenesis through Akt, Glucokinase, and SREBP1c

• DOI: 10.1016/j.cmet.2012.03.015
• Publication Date: 2012-04-19T11:45:41Z
• Authors: Asami Hagiwara; Marion Cornu; Nadine Cybulski; Pazit Polak; Charles Betz; Francesca Trapani; Luigi Terracciano; Markus H. Heim; Markus A. Rüegg; Michael N. Hall
• Keywords: Male; Physiology; Mechanistic Target of Rapamycin Complex 1; Glycogen Synthase Kinase 3; 03 medical and health sciences; Hyperinsulinism; Glucokinase; Glucose Intolerance; Animals; Homeostasis; Insulin; Molecular Biology; 0303 health sciences; Glycogen Synthase Kinase 3 beta; Forkhead Box Protein O1; Lipogenesis; Gluconeogenesis; Forkhead Transcription Factors; Cell Biology; Lipid Metabolism; Glucose; Liver; Hyperglycemia; Hepatocytes; Glycolysis

Mammalian target of rapamycin complex 2 (mTORC2) phosphorylates and activates AGC kinase family members, including Akt, SGK1, and PKC, in response to insulin/IGF1. The liver is a key organ in insulin-mediated regulation of metabolism. To assess the role of hepatic mTORC2, we generated liver-specific rictor knockout (LiRiKO) mice. Fed LiRiKO mice displayed loss of Akt Ser473 phosphorylation and reduced glucokinase and SREBP1c activity in the liver, leading to constitutive gluconeogenesis, and impaired glycolysis and lipogenesis, suggesting that the mTORC2-deficient liver is unable to sense satiety. These liver-specific defects resulted in systemic hyperglycemia, hyperinsulinemia, and hypolipidemia. Expression of constitutively active Akt2 in mTORC2-deficient hepatocytes restored both glucose flux and lipogenesis, whereas glucokinase overexpression rescued glucose flux but not lipogenesis. Thus, mTORC2 regulates hepatic glucose and lipid metabolism via insulin-induced Akt signaling to control whole-body metabolic homeostasis. These findings have implications for emerging drug therapies that target mTORC2.