Glucagon and lipid interactions in the regulation of hepatic AMPK signaling and expression of PPARalpha and FGF21 transcripts in vivo.
Hepatic glucagon action increases in response to accelerated metabolic demands and is associated with increased whole body substrate availability, including circulating lipids. The hypothesis that increases in hepatic glucagon action stimulate AMP-activated protein kinase (AMPK) signaling and peroxisome proliferator-activated receptor-α (PPARα) and fibroblast growth factor 21 (FGF21) expression in a manner modulated by fatty acids was tested in vivo. Wild-type (gcgr(+/+)) and glucagon receptor-null (gcgr(-/-)) littermate mice were studied using an 18-h fast, exercise, and hyperglucagonemic-euglycemic clamps plus or minus increased circulating lipids. Fasting and exercise in gcgr(+/+), but not gcgr(-/-) mice, increased hepatic phosphorylated AMPKα at threonine 172 (p-AMPK(Thr(172))) and PPARα and FGF21 mRNA. Clamp results in gcgr(+/+) mice demonstrate that hyperlipidemia does not independently impact or modify glucagon-stimulated increases in hepatic AMP/ATP, p-AMPK(Thr(172)), or PPARα and FGF21 mRNA. It blunted glucagon-stimulated acetyl-CoA carboxylase phosphorylation, a downstream target of AMPK, and accentuated PPARα and FGF21 expression. All effects were absent in gcgr(-/-) mice. These findings demonstrate that glucagon exerts a critical regulatory role in liver to stimulate pathways linked to lipid metabolism in vivo and shows for the first time that effects of glucagon on PPARα and FGF21 expression are amplified by a physiological increase in circulating lipids.
Berglund
Eric D
ED
Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Kang
Li
L
Lee-Young
Robert S
RS
Hasenour
Clinton M
CM
Lustig
Daniel G
DG
Lynes
Sara E
SE
Donahue
E Patrick
EP
Swift
Larry L
LL
Charron
Maureen J
MJ
Wasserman
David H
DH
D000263:Adenylate Kinase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D019540:Area Under Curve; D001786:Blood Glucose / Q000378:metabolism; D002395:Catecholamines / Q000097:blood; D005217:Fat Emulsions, Intravenous / Q000378:metabolism*; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D005346:Fibroblast Growth Factors / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D005934:Glucagon / Q000378:metabolism*; D015309:Glucose Clamp Technique; D007328:Insulin / Q000097:blood; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D047493:PPAR alpha / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D010805:Physical Conditioning, Animal / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D018027:Receptors, Glucagon / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
D001786:Blood Glucose; D002395:Catecholamines; D005217:Fat Emulsions, Intravenous; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D047493:PPAR alpha; D012333:RNA, Messenger; D018027:Receptors, Glucagon; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D005934:Glucagon; D000263:Adenylate Kinase