TY - JOUR
T1 - Glucagon and lipid interactions in the regulation of hepatic AMPK signaling and expression of PPARα and FGF21 transcripts in vivo
AU - Berglund, Eric D.
AU - Kang, Li
AU - Lee-Young, Robert S.
AU - Hasenour, Clinton M.
AU - Lustig, Daniel G.
AU - Lynes, Sara E.
AU - Donahue, E. Patrick
AU - Swift, Larry L.
AU - Charron, Maureen J.
AU - Wasserman, David H.
PY - 2010/10
Y1 - 2010/10
N2 - 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.
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.
KW - Adenosine 5′-monophosphate-activated protein kinase
KW - Fibroblast growth factor 21
KW - Peroxisome proliferator-activated receptor-α
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U2 - 10.1152/ajpendo.00263.2010
DO - 10.1152/ajpendo.00263.2010
M3 - Article
C2 - 20663988
AN - SCOPUS:77957556136
SN - 0193-1849
VL - 299
SP - E607-E614
JO - American Journal of Physiology - Endocrinology and Metabolism
JF - American Journal of Physiology - Endocrinology and Metabolism
IS - 4
ER -