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

Blanka Kucejova, Joao Duarte, Santhosh Satapati, Xiaorong Fu, Olga Ilkayeva, Christopher B. Newgard, James Brugarolas, Shawn C. Burgess

Research output: Contribution to journalArticle

10 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)508-519
Number of pages12
JournalCell Reports
Volume16
Issue number2
DOIs
StatePublished - Jul 12 2016

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Metabolism
Obesity
Insulin
Insulin Receptor
Liver
Chemical activation
Glycogen
Oxidative stress
Citric Acid Cycle
Gluconeogenesis
mechanistic target of rapamycin complex 1
Fluxes
Hyperglycemia
Glucose
Oxidation
Insulin Resistance
Oxidative Stress
Inflammation

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Hepatic mTORC1 Opposes Impaired Insulin Action to Control Mitochondrial Metabolism in Obesity. / Kucejova, Blanka; Duarte, Joao; Satapati, Santhosh; Fu, Xiaorong; Ilkayeva, Olga; Newgard, Christopher B.; Brugarolas, James; Burgess, Shawn C.

In: Cell Reports, Vol. 16, No. 2, 12.07.2016, p. 508-519.

Research output: Contribution to journalArticle

Kucejova, Blanka ; Duarte, Joao ; Satapati, Santhosh ; Fu, Xiaorong ; Ilkayeva, Olga ; Newgard, Christopher B. ; Brugarolas, James ; Burgess, Shawn C. / Hepatic mTORC1 Opposes Impaired Insulin Action to Control Mitochondrial Metabolism in Obesity. In: Cell Reports. 2016 ; Vol. 16, No. 2. pp. 508-519.
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