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 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.
Longuet
Christine
C
Department of Medicine, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario M5G 1X5, Canada.
Sinclair
Elaine M
EM
Maida
Adriano
A
Baggio
Laurie L
LL
Maziarz
Marlena
M
Charron
Maureen J
MJ
Drucker
Daniel J
DJ
D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000220:Adaptation, Biological; D000818:Animals; D002478:Cells, Cultured; D005215:Fasting / Q000502:physiology*; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D005934:Glucagon / Q000494:pharmacology / Q000502:physiology*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010084:Oxidation-Reduction; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D018027:Receptors, Glucagon / Q000235:genetics / Q000502:physiology*; D014280:Triglycerides / Q000097:blood; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
D005227:Fatty Acids; D047493:PPAR alpha; D012333:RNA, Messenger; D018027:Receptors, Glucagon; D014280:Triglycerides; D005934:Glucagon; D048051:p38 Mitogen-Activated Protein Kinases; D055372:AMP-Activated Protein Kinases