Paracrine FGFs target skeletal muscle to exert potent anti-hyperglycemic effects

Fibroblast growth factors are involved in systemic glucose homeostasis and of interest for developing therapies for type 2 diabetes and associated metabolic diseases. Here the authors identify paracrine FGF4 as an anti-hyperglycemic FGF, which targets skeletal muscle to upregulate the glucose transporter GLUT4 cell surface abundance. 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 beta-klotho (KLB), an obligatory FGF21 co-receptor. Mechanistically, both FGF4 and FGF1 upregulate GLUT4 cell surface abundance in skeletal muscle in an AMPK alpha-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.

Automated summary

This study identifies paracrine FGF4 as an anti-hyperglycemic FGF that targets skeletal muscle to increase the abundance of the glucose transporter GLUT4 on the cell surface. Compared to endocrine FGF21, the paracrine FGF4 shows superior glycemic control in diabetic mice and has anti-inflammatory properties, suggesting its potential for treating type 2 diabetes and related metabolic disorders.