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

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 ac...

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Bibliographic Details
Published in:Cell metabolism 2008-11, Vol.8 (5), p.359-371
Main Authors: Longuet, Christine, Sinclair, Elaine M., Maida, Adriano, Baggio, Laurie L., Maziarz, Marlena, Charron, Maureen J., Drucker, Daniel J.
Format: Article
Language:English
Subjects:
Adaptation, Biological
AMP-Activated Protein Kinases - genetics
AMP-Activated Protein Kinases - metabolism
Animals
Cells, Cultured
Fasting - physiology
Fatty Acids - metabolism
Female
Glucagon - pharmacology
Glucagon - physiology
Hepatocytes - drug effects
Hepatocytes - metabolism
HUMDISEASE
Lipid Metabolism
Male
Mice
Mice, Knockout
Oxidation-Reduction
p38 Mitogen-Activated Protein Kinases - genetics
p38 Mitogen-Activated Protein Kinases - metabolism
PPAR alpha - genetics
PPAR alpha - metabolism
Receptors, Glucagon - genetics
Receptors, Glucagon - physiology
RNA, Messenger - biosynthesis
Triglycerides - blood
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Summary: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 PPARα−/− hepatocytes. These findings demonstrate that the Gcgr receptor is required for control of lipid metabolism during the adaptive metabolic response to fasting.
ISSN:1550-4131
1932-7420
DOI:10.1016/j.cmet.2008.09.008