Fundamentals of FGF19 & FGF21 Action In Vitro and In Vivo

Abstract

Fibroblast growth factors 19 (FGF19) and 21 (FGF21) have emerged as key regulators of energy metabolism. Several studies have been conducted to understand the mechanism of FGF19 and FGF21 action, however, the data presented has often been inconsistent and at times contradictory. Here in a single study we compare the mechanisms mediating FGF19/FGF21 actions, and how similarities/differences in actions at the cellular level between these two factors translate to common/divergent physiological outputs. Firstly, we show that in cell culture FGF19/FGF21 are very similar, however, key differences are still observed differentiating the two. In vitro we found that both FGF's activate FGFRs in the context of βKlotho (KLB) expression. Furthermore, both factors alter ERK phosphorylation and glucose uptake with comparable potency. Combination treatment of cells with both factors did not have additive effects and treatment with a competitive inhibitor, the FGF21 delta N17 mutant, also blocked FGF19's effects, suggestive of a shared receptor activation mechanism. The key differences between FGF21/FGF19 were noted at the receptor interaction level, specifically the unique ability of FGF19 to bind/signal directly via FGFR4. To determine if differential effects on energy homeostasis and hepatic mitogenicity exist we treated DIO and ob/ob mice with FGF19/FGF21. We find comparable efficacy of the two proteins to correct body weight and serum glucose in both DIO and ob/ob mice. Nevertheless, FGF21 and FGF19 had distinctly different effects on proliferation in the liver. Interestingly, in vivo blockade of FGF21 signaling in mice using ΔN17 caused profound changes in glycemia indicative of the critical role KLB and FGF21 play in the regulation of glucose homeostasis. Overall, our data demonstrate that while subtle differences exist in vitro the metabolic effects in vivo of FGF19/FGF21 are indistinguishable, supporting a shared mechanism of action for these two hormones in the regulation of energy balance.

Fibroblast Growth Factor 21 (FGF21) and Glucagon-Like Peptide 1 Contribute to Diabetes Resistance in Glucagon Receptor–Deficient Mice

“…Injection of recombinant FGF21 normalizes blood glucose levels, improves insulin sensitivity, and corrects dyslipidemia in several rodent and nonrodent animal models of type 2 diabetes (12,16,17). It is highly expressed in the liver and whole-pancreas extracts, with lower expression levels in muscle and adipose tissue (18,19). Given the pleiotropic actions of FGF21 on whole-body glucose regulation, we hypothesized that FGF21 may be a factor contributing to glucose regulation in insulin-deficient Gcgr 2/2 mice.…”

Silencing of the Fibroblast growth factor 21 gene is an underlying cause of acinar cell injury in mice lacking MIST1

“…epigenetics; gene silencing; MIST1; pancreatitis; histone methylation FIBROBLAST GROWTH FACTOR 21 (FGF21) is an important regulator of metabolism, belonging to the endocrine family of FGFs, which includes FGF15/19 and FGF23 (1,24). FGF21 increases insulin production and glucose uptake (52), promotes ketogenesis (2,18), and enhances conversion of white to brown adipose tissue (14).…”

Novel Sandwich Immunoassays for The Measurement of Total and Active Fgf21

“…FGF21 activity requires nearly intact amino and carboxyl termini in order to facilitate N-terminal receptor and C-terminal KLB binding [13,14]. In one study, KLB knockout mice were shown to have stunted metabolic effects when injected with FGF21, revealing its activity dependence on KLB [15].…”

“…In one study, KLB knockout mice were shown to have stunted metabolic effects when injected with FGF21, revealing its activity dependence on KLB [15]. Additionally, deletions of N-terminal residues interfere with the FGF receptor (FGFR) activation even though KLB interaction to the C-terminal end remains uninterrupted [5,13], thus placing FGFR binding at the extreme N-terminus. In obese mice, an N-terminal truncated variant of FGF21 was administered in competition with the wild-type form.…”