Abstract
Previous studies have shown that whole body deletion of the glucagon receptor suppresses the ability of starvation to increase hepatic fibroblast growth factor 21 (FGF21) expression and plasma FGF21 concentration. Here, we investigate the mechanism by which glucagon receptor activation increases hepatic FGF21 production. Incubating primary rat hepatocyte cultures with glucagon, dibutyryl cAMP or forskolin stimulated a 3-4-fold increase in FGF21 secretion. The effect of these agents on FGF21 secretion was not associated with an increase in FGF21 mRNA abundance. Glucagon induction of FGF21 secretion was additive with the stimulatory effect of a PPARα activator (GW7647) on FGF21 secretion. Inhibition of protein kinase A (PKA) and downstream components of the PKA pathway [i.e. AMP-activated protein kinase and p38 MAPK] suppressed glucagon activation of FGF21 secretion. Incubating hepatocytes with an exchange protein directly activated by cAMP (EPAC)-selective cAMP analog [i.e. 8-(4-chlorophenylthio)-2'-O-methyladenosine-3', 5'-cyclic monophosphate (cpTOME)], stimulated a 3.9-fold increase FGF21 secretion, whereas inhibition of the EPAC effector, Rap1, suppressed glucagon activation of FGF21 secretion. Treatment of hepatocytes with insulin also increased FGF21 secretion. In contrast to glucagon, insulin activation of FGF21 secretion was associated with an increase in FGF21 mRNA abundance. Glucagon synergistically interacted with insulin to stimulate a further increase in FGF21 secretion and FGF21 mRNA abundance. These results demonstrate that glucagon increases hepatic FGF21 secretion via a posttranscriptional mechanism and provide evidence that both the PKA branch and EPAC branch of the cAMP pathway play a role in mediating this effect. These results also identify a novel synergistic interaction between glucagon and insulin in the regulation of FGF21 secretion and FGF21 mRNA abundance. We propose that this insulin/glucagon synergism plays a role in mediating the elevation in FGF21 production during starvation and conditions related to metabolic syndrome.
Highlights
Fibroblast growth factor 21 (FGF21) is a newly identified hormone that plays a role in mediating adaptive changes in carbohydrate and lipid metabolism in response to nutritional stress [1,2]
Previous studies have shown that starvation increases plasma glucagon concentration and that whole body deletion of the glucagon receptor suppresses the stimulatory effect of starvation on hepatic FGF21 mRNA abundance and plasma FGF21 concentration [19,22]
In contrast to the stimulatory effect of glucagon on FGF21 secretion, glucagon caused a transient decrease in FGF21 mRNA abundance that disappeared by 12 h of treatment (Fig. 1B)
Summary
Fibroblast growth factor 21 (FGF21) is a newly identified hormone that plays a role in mediating adaptive changes in carbohydrate and lipid metabolism in response to nutritional stress [1,2]. FGF21 increases plasma glucocorticoid concentration, modulates circadian behavior, and inhibits bone growth, growth hormone sensitivity, and female fertility [8,9,10,11]. All of these effects occur during starvation, providing further evidence that FGF21 is a key mediator of the adaptive starvation response. An alternative approach to treat metabolic syndrome is to develop drugs or nutritional supplements that induce a sustained increase endogenous FGF21 production. There is a strong interest in characterizing the physiological and molecular mechanisms controlling FGF21 production
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