Glucagon and lipid interactions in the regulation of hepatic AMPK signaling and expression of PPARα and FGF21 transcripts in vivo

Eric D. Berglund, Li Kang, Robert S. Lee-Young, Clinton M. Hasenour, Daniel G. Lustig, Sara E. Lynes, E. Patrick Donahue, Larry L. Swift, Maureen J. Charron, David H. Wasserman

Research output: Contribution to journalArticle

74 Citations (Scopus)

Abstract

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 Thr172) 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 Thr172, 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.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume299
Issue number4
DOIs
StatePublished - Oct 2010

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Peroxisome Proliferator-Activated Receptors
AMP-Activated Protein Kinases
Glucagon
Lipids
Liver
Threonine
Glucagon Receptors
Acetyl-CoA Carboxylase
Messenger RNA
Glucose Clamp Technique
Adenosine Monophosphate
Hyperlipidemias
Lipid Metabolism
fibroblast growth factor 21
Fasting
Fatty Acids
Adenosine Triphosphate
Phosphorylation

Keywords

  • Adenosine 5′-monophosphate-activated protein kinase
  • Fibroblast growth factor 21
  • Peroxisome proliferator-activated receptor-α

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Endocrinology, Diabetes and Metabolism
  • Medicine(all)

Cite this

Glucagon and lipid interactions in the regulation of hepatic AMPK signaling and expression of PPARα and FGF21 transcripts in vivo. / Berglund, Eric D.; Kang, Li; Lee-Young, Robert S.; Hasenour, Clinton M.; Lustig, Daniel G.; Lynes, Sara E.; Donahue, E. Patrick; Swift, Larry L.; Charron, Maureen J.; Wasserman, David H.

In: American Journal of Physiology - Endocrinology and Metabolism, Vol. 299, No. 4, 10.2010.

Research output: Contribution to journalArticle

Berglund, Eric D. ; Kang, Li ; Lee-Young, Robert S. ; Hasenour, Clinton M. ; Lustig, Daniel G. ; Lynes, Sara E. ; Donahue, E. Patrick ; Swift, Larry L. ; Charron, Maureen J. ; Wasserman, David H. / Glucagon and lipid interactions in the regulation of hepatic AMPK signaling and expression of PPARα and FGF21 transcripts in vivo. In: American Journal of Physiology - Endocrinology and Metabolism. 2010 ; Vol. 299, No. 4.
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AB - 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 Thr172) 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 Thr172, 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.

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