The glucagon receptor is required for the adaptive metabolic response to fasting.

Christine Longuet, Elaine Sinclair, Adriano Maida, Laurie Baggio, Marlena Maziarz, Maureen Charron and Daniel Drucker

Cell Metabolism 2008. 8: 359-71.

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.

Our Thoughts on This Paper

This paper characterizes the effects of the loss of the glucagaon receptor on lipid homeostasis. Using a combination of live animal and tissue culture experiments, they identify reduced fasting lipid oxidation and triglyceride mobilization in these mice. The authors propose that this increase in lipid oxidation causes reduced lipogenesis as well. They further characterize the mechanism of glucagon mediated lipid oxidation to require PPARa These findings are consistent with the key role of glucagon in the mobilization of fat in fasting conditions. The role of glucagon resistance in the development of steatosis has been an underexplored area and this paper provides key insights into glucagon dependent changes in fasting lipid levels.

Written by Dave Bridges on Aug. 28, 2013.

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