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

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.

Severe iatrogenic hypoglycaemia modulates the fibroblast growth factor protein response

“…FGF4 has been shown on pancreatic beta cells and has been suggested to be involved in differentiated beta cells, 90 and has been suggested to exert potent antihyperglycaemic effects by targeting skeletal muscle. 91 There were no changes seen for FGF6 that has been reported to protect an animal model from diet-induced obesity and insulin resistance. 92 The FGF7 subfamily is composed of FGF3, FGF7, FGF10 and FGF22, although only FGF7 and FGF10 were available to be measured on the SomaScan panel.…”

“…For FGF4, there was a decrease at 2 h post‐hypoglycaemia relative to baseline in T2D, although not in controls, that reverted to baseline thereafter. FGF4 has been shown on pancreatic beta cells and has been suggested to be involved in differentiated beta cells, 90 and has been suggested to exert potent antihyperglycaemic effects by targeting skeletal muscle 91 . There were no changes seen for FGF6 that has been reported to protect an animal model from diet‐induced obesity and insulin resistance 92 …”

FGF4, A New Potential Regulator in Gestational Diabetes Mellitus

“…A cDNA fragment encoding human FGF4 (Ala67-Leu206) was expressed and purified according to the published protocols ( Bellosta et al, 2001 ; Ying et al, 2021 ). The pregnant GDM mice were divided into two groups and intraperitoneally injected with rFGF4 at 0.75 mg/kg at day E5.5, E7.5 and E9.5, E13.5 and E17.5 (E is the abbreviation of embryonic day) or 0.9% normal saline.…”

Identification of metabolic pathways underlying FGF1 and CHIR99021-mediated cardioprotection

“…Treatment with FGF1 increases insulin-dependent glucose uptake in skeletal muscle, inhibits glucose production in liver, and improves systemic insulin sensitization in diabetic mice ( Suh et al., 2014 ). FGF1 does so by upregulating GLUT4 expression and translocation to plasma membrane in skeletal muscle in an insulin-independent manner ( Ying et al., 2021 ). A recent report also suggests that FGF1-FGFR1 signaling pathway regulates blood glucose level by inhibiting lipolysis and hepatic glucose production ( Sancar et al., 2022 ).…”