Hepatic mTORC1 Opposes Impaired Insulin Action to Control Mitochondrial Metabolism in Obesity

• Published in: Cell reports (Cambridge) Vol. 16; no. 2; pp. 508 - 519
• Main Authors: Kucejova, Blanka, Duarte, Joao, Satapati, Santhosh, Fu, Xiaorong, Ilkayeva, Olga, Newgard, Christopher B., Brugarolas, James, Burgess, Shawn C.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12.07.2016; Elsevier
• Subjects: Animals; Citric Acid Cycle; Diet, High-Fat - adverse effects; Enzyme Activation; Gluconeogenesis; Glycogen - metabolism; Insulin Resistance; Liver - enzymology; Male; Mechanistic Target of Rapamycin Complex 1 - physiology; Mice, Inbred C57BL; Mice, Transgenic; Mitochondria, Liver - enzymology; Obesity - enzymology; Obesity - etiology; Oxidation-Reduction; Receptor, Insulin - genetics; Receptor, Insulin - metabolism; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2016.06.006

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. [Display omitted] •Loss of the hepatic insulin receptor (IR) stimulates oxidative metabolism in liver•Activation of mTORC1 suppresses oxidative metabolism in liver•Simultaneous IR loss and mTORC1 activation cause hyperglycemia and impaired ketosis Using in vivo stable isotope tracers, Kucejova et al. find that loss of hepatic insulin action stimulates mitochondrial metabolism and that activation of mTORC1 suppresses mitochondrial metabolism and decreases nutritional flexibility. Together, loss of insulin action and activation of mTORC1 recapitulate certain effects of diet-induced insulin resistance on mitochondrial metabolism.