biostudies-literature00520Perry RJUnited States Public Health ServiceNCATS NIH HHSNIDDK NIH HHSHoward Hughes Medical InstituteNIA NIH HHSNINDS NIH HHSNCI NIH HHS234-248.e17https://www.ebi.ac.uk/biostudies/studies/S-EPMC5766366biostudies-literatureUnknown172(1-2)The transition from the fed to the fasted state necessitates a shift from carbohydrate to fat metabolism that is thought to be mostly orchestrated by reductions in plasma insulin concentrations. Here, we show in awake rats that insulinopenia per se does not cause this transition but that both hypoleptinemia and insulinopenia are necessary. Furthermore, we show that hypoleptinemia mediates a glucose-fatty acid cycle through activation of the hypothalamic-pituitary-adrenal axis, resulting in increased white adipose tissue (WAT) lipolysis rates and increased hepatic acetyl-coenzyme A (CoA) content, which are essential to maintain gluconeogenesis during starvation. We also show that in prolonged starvation, substrate limitation due to reduced rates of glucose-alanine cycling lowers rates of hepatic mitochondrial anaplerosis, oxidation, and gluconeogenesis. Taken together, these data identify a leptin-mediated glucose-fatty acid cycle that integrates responses of the muscle, WAT, and liver to promote a shift from carbohydrate to fat oxidation and maintain glucose homeostasis during starvation.CellLeptin Mediates a Glucose-Fatty Acid Cycle to Maintain Glucose Homeostasis in Starvation.PMC5766366R01 DK040936T32 DK101019UL1 TR000142P30 DK045735U24 DK059635R01 DK113984R01 NS087568P30 DK059635UL1 TR001863UL1TR000142R00 CA215315K99 CA215315R01 DK40936R01 AG023686R01 AG23686Cline GWDufour SPetersen KFShulman GIRabin-Court ASong JDWang YZhang XMPerry RJ52falseLeptin Mediates a Glucose-Fatty Acid Cycle to Maintain Glucose Homeostasis in Starvation.The transition from the fed to the fasted state necessitates a shift from carbohydrate to fat metabolism that is thought to be mostly orchestrated by reductions in plasma insulin concentrations. Here, we show in awake rats that insulinopenia per se does not cause this transition but that both hypoleptinemia and insulinopenia are necessary. Furthermore, we show that hypoleptinemia mediates a glucose-fatty acid cycle through activation of the hypothalamic-pituitary-adrenal axis, resulting in increased white adipose tissue (WAT) lipolysis rates and increased hepatic acetyl-coenzyme A (CoA) content, which are essential to maintain gluconeogenesis during starvation. We also show that in prolonged starvation, substrate limitation due to reduced rates of glucose-alanine cycling lowers rates of hepatic mitochondrial anaplerosis, oxidation, and gluconeogenesis. Taken together, these data identify a leptin-mediated glucose-fatty acid cycle that integrates responses of the muscle, WAT, and liver to promote a shift from carbohydrate to fat oxidation and maintain glucose homeostasis during starvation.2018-01-01T00:00:00Z2018 Jan2024-11-09T17:43:57.381Z2019-03-26T22:35:26ZS-EPMC57663662930748910.1016/j.cell.2017.12.001