The effect of a HFD on mitochondrial metabolism depends on nutritional state and mTORC1 activation

• 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: 23.06.2016
• ISSN: 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. Since obesity impairs insulin action but paradoxically activates mTORC1, we tested whether insulin action and mTORC1 contribute to altered in vivo hepatic mitochondrial metabolism. Loss of hepatic insulin action for 2-weeks caused increased gluconeogenesis, mitochondrial anaplerosis, TCA cycle oxidation and ketogenesis. However activation of mTORC1, induced by 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 compared to loss of the liver insulin receptor alone. Thus, activation of hepatic mTORC1 opposes the catabolic effects of impaired insulin action under some nutritional states.