title: Hepatic mTORC2 activates glycolysis and lipogenesis through Akt, glucokinase, and SREBP1c.
abstract: 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.
authors.affiliation: Biozentrum, University of Basel, CH-4056 Basel, Switzerland.
authors.forename: Asami
authors.initials: A
authors.lastname: Hagiwara
authors.forename: Marion
authors.initials: M
authors.lastname: Cornu
authors.forename: Nadine
authors.initials: N
authors.lastname: Cybulski
authors.forename: Pazit
authors.initials: P
authors.lastname: Polak
authors.forename: Charles
authors.initials: C
authors.lastname: Betz
authors.forename: Francesca
authors.initials: F
authors.lastname: Trapani
authors.forename: Luigi
authors.initials: L
authors.lastname: Terracciano
authors.forename: Markus H
authors.initials: MH
authors.lastname: Heim
authors.forename: Markus A
authors.initials: MA
authors.lastname: Rüegg
authors.forename: Michael N
authors.initials: MN
authors.lastname: Hall
mesh_terms: D000818:Animals; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D005941:Glucokinase / Q000235:genetics / Q000378:metabolism*; D005943:Gluconeogenesis; D005947:Glucose / Q000235:genetics / Q000378:metabolism; D018149:Glucose Intolerance / Q000235:genetics / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006019:Glycolysis; D022781:Hepatocytes / Q000378:metabolism; D006706:Homeostasis; D006943:Hyperglycemia / Q000235:genetics / Q000378:metabolism; D006946:Hyperinsulinism / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D050356:Lipid Metabolism; D050155:Lipogenesis; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000378:metabolism*; D010766:Phosphorylation; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors
chemical_list: D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D007328:Insulin; D046912:Multiprotein Complexes; D011506:Proteins; D051780:Sterol Regulatory Element Binding Protein 1; D015534:Trans-Activators; D014157:Transcription Factors; D005941:Glucokinase; C494922:Akt2 protein, mouse; D000071679:Glycogen Synthase Kinase 3 beta; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D038362:Glycogen Synthase Kinase 3; D005947:Glucose