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

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(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.

CB1R antagonist increases hepatic insulin clearance in fat-fed dogs likely via upregulation of liver adiponectin receptors

“…Our finding is consistent with Heiker et al (16), who showed that increased serum adiponectin results in an increase in AMPK activation via ADRs. Our results are also consistent with glucagon-mediated activation of AMPK in the liver (4,28). We demonstrated that fasting glucagon had a tendency to be decreased in the HFDϩPL compared with the HFDϩRIM group, which is cosnsistent with the results obtained for AMPK activation.…”

Glucagon increases circulating fibroblast growth factor 21 independently of endogenous insulin levels: a novel mechanism of glucagon-stimulated lipolysis?

“…Recently, it has been shown that glucagon modulates Fgf-21 expression [12][13][14][15]. Here, we extend these observations by reporting for the first time that glucagon increases, independently of endogenous insulin levels, circulating levels of FGF-21 in humans and rodents.…”

“…* p <0.05, ** p <0.01 and *** p <0.001 vs vehicle-treated groups (indicated as -). Each experiment was repeated three times The increase of FGF-21 plasma concentration by exogenous glucagon regardless of endogenous insulin production is somehow intriguing, in view of the contradictory results of earlier studies showing that insulin regulates FGF-21 [12,15,17,30]. Exogenous insulin increased plasma FGF-21 and Fgf-21 mRNA expression in skeletal muscle in humans [30].…”

“…In rodents glucagon seems to stimulate Fgf-21 expression in vitro and in vivo [12][13][14][15], and these effects are somewhat augmented by NEFA [15]. However, another study reported that glucagon fails to stimulate hepatic Fgf-21 mRNA expression in rodents [16].…”

“…Discrepant observations were also reported regarding the role of insulin in glucagon-stimulated FGF-21 production [15]. In non-diabetic humans, an approximately sevenfold increase in circulating insulin was associated with a minimal elevation of FGF-21 [17].…”