The Glucagon Receptor Is Required for the Adaptive Metabolic Response to Fasting

Cell Metab. 2008 Nov;8(5):359-71. doi: 10.1016/j.cmet.2008.09.008.

Abstract

Glucagon receptor (Gcgr) signaling maintains hepatic glucose production during the fasting state; however, the importance of the Gcgr for lipid metabolism is unclear. We show here that fasted Gcgr-/- mice exhibit a significant increase in hepatic triglyceride secretion and fasting increases fatty acid oxidation (FAO) in wild-type (WT) but not in Gcgr-/- mice. Moreover fasting upregulated the expression of FAO-related hepatic mRNA transcripts in Gcgr+/+ but not in Gcgr-/- mice. Exogenous glucagon administration reduced plasma triglycerides in WT mice, inhibited TG synthesis and secretion, and stimulated FA beta oxidation in Gcgr+/+ hepatocytes. The actions of glucagon on TG synthesis and FAO were abolished in PPARalpha-/- hepatocytes. These findings demonstrate that the Gcgr receptor is required for control of lipid metabolism during the adaptive metabolic response to fasting.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / genetics
  • AMP-Activated Protein Kinases / metabolism
  • Adaptation, Biological
  • Animals
  • Cells, Cultured
  • Fasting / physiology*
  • Fatty Acids / metabolism
  • Female
  • Glucagon / pharmacology
  • Glucagon / physiology*
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism*
  • Lipid Metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Oxidation-Reduction
  • PPAR alpha / genetics
  • PPAR alpha / metabolism
  • RNA, Messenger / biosynthesis
  • Receptors, Glucagon / genetics
  • Receptors, Glucagon / physiology*
  • Triglycerides / blood
  • p38 Mitogen-Activated Protein Kinases / genetics
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Fatty Acids
  • PPAR alpha
  • RNA, Messenger
  • Receptors, Glucagon
  • Triglycerides
  • Glucagon
  • p38 Mitogen-Activated Protein Kinases
  • AMP-Activated Protein Kinases