Increased hepatic glucose production, due to increased rates of gluconeogenesis, is a contributor to both fasting and postprandial hyperglycemia in patients with T2D. Recent evidence implicates a role for hepatic calcium signaling in mediating glucagon's effect to stimulate glucose production and mitochondrial oxidation; however, the cellular and molecular mechanisms by which glucagon promotes these alterations remain poorly understood. We hypothesize that an acute physiological increase in plasma glucagon concentrations will increase cytosolic and mitochondrial calcium concentrations, promoting increases in rates of hepatic mitochondrial oxidation and gluconeogenesis in a transcription-independent manner. To test this hypothesis, we used mice with a liver-specific loss of the mitochondrial calcium uniporter (MCU), which is the main transporter that allows rapid transport of calcium into the mitochondrial matrix. We found that glucagon increased oxygen consumption rate by 80% (p<0.0001) in WT hepatocytes, while this effect was abrogated in MCU KO hepatocytes. We also measured hepatic mitochondrial oxidation (VCS) in vivo using Positional Isotopomer NMR Tracer Analysis (PINTA) and found a 74% decrease in VCS (p=0.05) in MCU KO mice compared to WT mice. This suggests that tightly regulated mitochondrial calcium signaling is necessary for regulating hepatic mitochondrial oxidation. Next, we measured intrahepatic lipolysis and hepatic gluconeogenesis in vitro and in vivo. We found that glucagon increased lipolysis (p=0.05) and glucose production (p=0.024) by ∼1.5 fold in MCU KO compared to WT hepatocytes. Furthermore, in vivo PINTA results showed that glucagon increased pyruvate carboxylase flux (VPC) by 68% (p=0.08) in MCU KO mice. Taken together, these results suggest that mitochondrial calcium signaling through MCU is necessary to regulate the effect of glucagon to modulate hepatic gluconeogenesis and mitochondrial oxidation.


J. Lee: None. L. Goedeke: None. Y. Zhang: None. R.J. Perry: Research Support; Self; AstraZeneca. R. Goodman: None. V. Mootha: Advisory Panel; Self; Janssen Pharmaceuticals, Inc. Consultant; Self; 5AM Ventures. Other Relationship; Self; Raze Therapeutics. G.I. Shulman: Advisory Panel; Self; AstraZeneca, Janssen Research & Development, Merck & Co., Inc. Advisory Panel; Spouse/Partner; Merck & Co., Inc. Board Member; Self; Novo Nordisk A/S. Consultant; Self; Aegerion Pharmaceuticals, IMetabolic BioPharma Corporation, Longitude Capital, Nimbus Discovery, Inc., Staten Biotechnology B.V.


National Institutes of Health

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