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

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• 作者：Asami Hagiwara¹ ; Marion Cornu¹ ; ⁴ ; Nadine Cybulski¹ ; ⁴ ; Pazit Polak¹ ; Charles Betz¹ ; Francesca Trapani² ; Luigi Terracciano² ; Markus  ; H. Heim³ ; Markus  ; A. R&#252 ; egg¹ ; Michael  ; N. Hall¹ ; ^{m.hall@unibas.ch}
• 刊名：Cell Metabolism
• 出版年：2012
• 期刊代码：46_15504131
• 类别：med
• 出版时间：2 May, 2012
• 卷：15
• 期：5
• 页码：725-738
• 文件大小：1149 K

摘要

| Figures/TablesFigures/Tables | ReferencesReferencesml version="1.0" encoding="UTF-8"?><h3 class="h3">Summaryh3>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 m>rictorm> 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.