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Cell. 2018 Jan 11;172(1-2):234-248.e17. doi: 10.1016/j.cell.2017.12.001. Epub 2018 Jan 4.

Leptin Mediates a Glucose-Fatty Acid Cycle to Maintain Glucose Homeostasis in Starvation.

Author information

1
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
2
Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520, USA.
3
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, CT 06520, USA; Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: gerald.shulman@yale.edu.

Abstract

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.

KEYWORDS:

HPA axis; glucose-alanine cycling; leptin; starvation

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PMID:
29307489
PMCID:
PMC5766366
DOI:
10.1016/j.cell.2017.12.001
[Indexed for MEDLINE]
Free PMC Article

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