2503-P: The Noradrenergic System Regulates Hepatic Gluconeogenesis, Mitochondrial Oxidation, and Autophagy by CaMKII during Cold Exposure

Introduction and Objective: The molecular mechanisms by which the noradrenergic system (NES) regulates hepatic mitochondrial metabolism is poorly understood. We examined the hypothesis that the NES regulates hepatic mitochondrial oxidation and gluconeogenesis via increased autophagy mediated by activation of CaMKII during cold exposure (CE) Methods: Male C57BL/6J mice were studied before and during 6h CE (4-6ºC) under 3 conditions: Sympathectomized with 6OHDA, CaMKII antisense oligonucleotide (ASO), ATG7 ASO. Rates of hepatic mitochondrial metabolism were assessed by Q-Flux in combination with stable isotopes to assess glucose, glycerol and βOHB turnover. Results: CE increased hepatic norepinephrine (30%), plasma concentrations of glucose, fatty acids, βOHB, glucagon, corticosterone, and decreased plasma insulin concentrations. These changes were associated with increased rates of glycerol (2-fold) turnover, mitochondrial oxidation (2-fold), autophagy (2-fold) and endogenous glucose production (EGP; 2-fold), which could mostly be attributed to increased glycerol conversion to glucose (60%). 6OHDA treatment decreased hepatic norepinephrine (95%) and caused a 30-60% reduction in all of these parameters independent of changes in plasma insulin, glucagon or corticosterone. Hepatic specific knockdown of CaMKII and ATG7 mimicked all of these effects. Conclusion: These data demonstrate that cold exposure promotes increased EGP and gluconeogenesis mostly through increased glycerol conversion to glucose and supports the hypothesis that the NES regulates hepatic mitochondrial oxidation and gluconeogenesis via increased autophagy mediated by activation of CaMKII. Disclosure H.N. Morgan: None. R. Calais Gaspar: None. A. Schavinski: None. A.P. Assis: None. J. Zheng: None. S. Parikh: None. S. Dufour: None. M. Kahn: None. A. Nasiri: None. M. Perelis: Employee; Current; Ionis Pharmaceuticals. I. Kettelhut: None. L. Navegantes: None. G. Shulman: Consultant; Current; Novo Nordisk A/S. Research Support; Current; Novo Nordisk A/S. Other - collaboration; Current; Ionis Pharmaceuticals. Advisory Panel; Current; ESPERION Therapeutics, Inc. Research Support; Current; Novo Nordisk Foundation. Advisory Panel; Current; Orsobio. Research Support; Current; Orsobio. Advisory Panel; Current; Village S.S.D. Funding Sao Paulo Research Foundation (FAPESP; 2021/05848-4; 2024/03229-3), Novo Nordisk Foundation, and National Institutes of Health (R01DK119968, UC2DK134901 and P30DK045735).