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

Abstract

Summary 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.

Multi-dimensional Roles of Ketone Bodies in Fuel Metabolism, Signaling, and Therapeutics

“…While ketogenesis becomes less responsive to insulin or fasting with prolonged obesity (Satapati et al, 2012), the underlying mechanisms and downstream consequences of this remain incompletely understood. Recent evidence indicates that mTORC1 suppresses ketogenesis in a manner that may be downstream of insulin signaling (Kucejova et al, 2016), which is concordant with the observations that mTORC1 inhibits PPARα-mediated Hmgcs2 induction (Sengupta et al, 2010) (also see Regulation of HMGCS2 and SCOT/ OXCT1 ).…”

Liver AMP-Activated Protein Kinase Is Unnecessary for Gluconeogenesis but Protects Energy State during Nutrient Deprivation

“…For example, inefficiencies in central oxidative metabolism induced by liver AMPK deletion may necessitate a greater reliance on glycolytic ATP production, thereby reducing G6P available for glycogen synthesis in the post-prandial state. A recent investigation has demonstrated that constitutive liver mTORC1 activation reduces liver glycogen content and glycogenolysis [61]. Thus, genetic removal of AMPK, a negative regulator of mTORC1 signaling, may enable the effects of constitutive mTORC1 signaling on glycogen metabolism.…”

Impaired ketogenesis and increased acetyl-CoA oxidation promote hyperglycemia in human fatty liver

“…Specifically, insulin continues to activate lipogenesis (38), which inhibits mitochondrial NEFA transport and β-oxidation (39). The nuanced alterations in cell signaling that give rise to elevated lipogenesis during insulin resistance can also suppress ketogenic flux by activating mTOR complex 1 (mTORC1) or activate TCA cycle flux by promoting FOXO targets (40). Indeed, the glucagon/insulin ratio had a complex relationship with hepatic β-oxidation (r S = 0.367, P = 0.030) that included a positive correlation with ketogenesis (r S = 0.445, P = 0.006) but a negative correlation with TCA cycle activity (r S = -0.584, P < 0.001).…”