title: Hepatic mTORC1 Opposes Impaired Insulin Action to Control Mitochondrial Metabolism in Obesity.
abstract: Dysregulated mitochondrial metabolism during hepatic insulin resistance may contribute to pathophysiologies ranging from elevated glucose production to hepatocellular oxidative stress and inflammation. Given that obesity impairs insulin action but paradoxically activates mTORC1, we tested whether insulin action and mammalian target of rapamycin complex 1 (mTORC1) contribute to altered in vivo hepatic mitochondrial metabolism. Loss of hepatic insulin action for 2 weeks caused increased gluconeogenesis, mitochondrial anaplerosis, tricarboxylic acid (TCA) cycle oxidation, and ketogenesis. However, activation of mTORC1, induced by the loss of hepatic Tsc1, suppressed these fluxes. Only glycogen synthesis was impaired by both loss of insulin receptor and mTORC1 activation. Mice with a double knockout of the insulin receptor and Tsc1 had larger livers, hyperglycemia, severely impaired glycogen storage, and suppressed ketogenesis, as compared to those with loss of the liver insulin receptor alone. Thus, activation of hepatic mTORC1 opposes the catabolic effects of impaired insulin action under some nutritional states.
authors.affiliation: AIRC Division of Metabolic Mechanisms of Disease, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Blanka
authors.initials: B
authors.lastname: Kucejova
authors.affiliation: AIRC Division of Metabolic Mechanisms of Disease, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Joao
authors.initials: J
authors.lastname: Duarte
authors.affiliation: AIRC Division of Metabolic Mechanisms of Disease, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Santhosh
authors.initials: S
authors.lastname: Satapati
authors.affiliation: AIRC Division of Metabolic Mechanisms of Disease, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Xiaorong
authors.initials: X
authors.lastname: Fu
authors.affiliation: Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Department of Pharmacology and Cancer Biology and Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Ilkayeva
authors.affiliation: Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Department of Pharmacology and Cancer Biology and Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Newgard
authors.affiliation: Kidney Cancer Program, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: James
authors.initials: J
authors.lastname: Brugarolas
authors.affiliation: AIRC Division of Metabolic Mechanisms of Disease, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: shawn.burgess@utsouthwestern.edu.
authors.forename: Shawn C
authors.initials: SC
authors.lastname: Burgess
mesh_terms: D000818:Animals; D002952:Citric Acid Cycle; D059305:Diet, High-Fat / Q000009:adverse effects; D004789:Enzyme Activation; D005943:Gluconeogenesis; D006003:Glycogen / Q000378:metabolism; D007333:Insulin Resistance; D008099:Liver / Q000201:enzymology*; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000502:physiology*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008930:Mitochondria, Liver / Q000201:enzymology*; D009765:Obesity / Q000201:enzymology* / Q000209:etiology; D010084:Oxidation-Reduction; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; D006003:Glycogen; D011972:Receptor, Insulin; D000076222:Mechanistic Target of Rapamycin Complex 1