Abstract
Several members of the FGF family have been identified as potential regulators of glucose homeostasis. We previously reported that a low threshold of FGF-induced FGF receptor 1c (FGFR1c) dimerization and activity is sufficient to evoke a glucose lowering activity. We therefore reasoned that ligand identity may not matter, and that besides paracrine FGF1 and endocrine FGF21, other cognate paracrine FGFs of FGFR1c might possess such activity. Indeed, via a side-by-side testing of multiple cognate FGFs of FGFR1c in diabetic mice we identified the paracrine FGF4 as a potent anti-hyperglycemic FGF. Importantly, we found that like FGF1, the paracrine FGF4 is also more efficacious than endocrine FGF21 in lowering blood glucose. We show that paracrine FGF4 and FGF1 exert their superior glycemic control by targeting skeletal muscle, which expresses copious FGFR1c but lacks β-klotho (KLB), an obligatory FGF21 co-receptor. Mechanistically, both FGF4 and FGF1 upregulate GLUT4 cell surface abundance in skeletal muscle in an AMPKα-dependent but insulin-independent manner. Chronic treatment with rFGF4 improves insulin resistance and suppresses adipose macrophage infiltration and inflammation. Notably, unlike FGF1 (a pan-FGFR ligand), FGF4, which has more restricted FGFR1c binding specificity, has no apparent effect on food intake. The potent anti-hyperglycemic and anti-inflammatory properties of FGF4 testify to its promising potential for use in the treatment of T2D and related metabolic disorders.
Highlights
Several members of the fibroblast growth factor (FGF) family have been identified as potential regulators of glucose homeostasis
We found that administration of recombinant FGFs [FGF4 (rFGF4) or Recombinant FGF1 (rFGF1) induced a profound upregulation of GLUT4 transcription 2 h post administration (Supplementary Fig. 2a), which manifested in an enhancement in total GLUT4 expression that persisted for at least 6 h after administration (Fig. 2e, g and Supplementary Fig. 2b)
AMPKα activation in macrophages ameliorates adipose tissue inflammation[46], we considered the possibility that rFGF4 might act directly on these cells to attenuate the inflammatory response via activation of the AMPKα pathway
Summary
Several members of the FGF family have been identified as potential regulators of glucose homeostasis. Two endocrine FGFs (i.e., FGF21 and FGF19) and a single paracrine FGF (FGF1) have been shown to exert multiple beneficial effects in obesity and T2D, including potent glucose-lowering activity, improved lipid profiles, and enhanced energy expenditure[3,4,5]. We surmised that ligand identity may not matter, and that other cognate paracrine FGFs of FGFR1c might possess anti-hyperglycemic activity in vivo If so, these could be repurposed for treating T2D and related metabolic disorders. By testing the glucose-lowering activity of representative members from the five paracrine FGF subfamilies in T2D mice, we identified FGF4 as a new antihyperglycemic molecule We show that both paracrine FGF4 and FGF1 elicit more potent and durable anti-hyperglycemic effects than endocrine FGF21. We further show that paracrine FGFs exert their glycemic control by activating the AMPK signaling pathway in an insulin-independent manner
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