Integrated Regulation of Hepatic Metabolism by Fibroblast Growth Factor 21 (FGF21) in Vivo

Abstract

Fibroblast growth factor (FGF21) plays an important role in regulating hepatic oxidation of fatty acids and gluconeogenesis in response to fasting and during consumption of a ketogenic diet. However, the metabolic pathways through which FGF21 regulates hepatic function are not well defined. To identify the effects of FGF21 on the liver in vivo, we administered FGF21 to mice and analyzed acute effects on signaling and gene expression. We found that FGF21 acts directly on the liver to stimulate phosphorylation of fibroblast growth factor receptor substrate 2 and ERK1/2. Acute FGF21 treatment induced hepatic expression of key regulators of gluconeogenesis, lipid metabolism, and ketogenesis including glucose-6-phosphatase, phosphoenol pyruvate carboxykinase, 3-hydroxybutyrate dehydrogenase type 1, and carnitine palmitoyltransferase 1α. In addition, injection of FGF21 was associated with decreased circulating insulin and free fatty acid levels. FGF21 treatment induced mRNA and protein expression of peroxisome proliferator-activated receptor-γ coactivator (PGC-1α), suggesting that PGC-1α may play a role in regulating FGF21 action. However, studies using mice with liver-specific ablation of PGC-1α revealed the same regulation of gluconeogenic gene expression by FGF21 as seen in wild-type mice, indicating that PGC-1α is not necessary for the effect of FGF21 on glucose metabolism. These data demonstrate that FGF21 acts directly on the liver to modulate hepatic metabolism. The direct effects we examined are not dependent on PGC-1α. In addition, FGF21 treatment is associated with decreased serum insulin levels that my affect hepatic function.

Retinoic Acid Receptor β Stimulates Hepatic Induction of Fibroblast Growth Factor 21 to Promote Fatty Acid Oxidation and Control Whole-body Energy Homeostasis in Mice

“…Hepatic and plasma levels of FGF21 were increased ϳ20-fold and ϳ7-fold in the fasted mice, compared with the fed mice, consistent with earlier studies (15). The fasting-inducible FGF21 might be predicted to result in enhanced fatty acid oxidation and ketogenesis via its autocrine/paracrine effects (15,19,35). In accordance with this notion, mRNA levels of CPT1␣, FIGURE 1.…”

Comparing the effects of nano-sized sugarcane fiber with cellulose and psyllium on hepatic cellular signaling in mice

“…Alternatively, FGF21 treatment has been found to induce mRNA and protein expression of PGC-1α, suggesting that PGC-1α may play a role in regulating FGF21 action. 39 However, our finding that all dietary fibers did not significantly alter PGC-1α indicates that the effect of SCF on FGF21 is not dependent on PGC-1α because SCF significantly reduced rather than increased hepatic FGF21 content.…”

Dual effects of fibroblast growth factor 21 on hepatic energy metabolism

“…Although these data provide some molecular insight, the exact mechanisms by which FGF21 induces its effects on hepatic metabolism (and in particular its effects on carbohydrate metabolism) and consequently how this then results in protection from increased hepatic lipid content in not well understood. Liver is one of the primary targets of FGF21 under both physiological (Badman et al 2007, Adams et al 2010 and pharmacological conditions (Berglund et al 2009, Fisher et al 2011) and, as indicated by our recent findings, appears to be a primary source of systemic endogenous FGF21 availability under physiological conditions (Samms et al 2014). Liver plays a crucial role in the regulation of energy metabolism and insulin action.…”