Introduction : Fibroblast growth factor 21 (FGF21) is a key metabolic regulator, which has been shown to be beneficial for islet function and glucose homeostasis. However, its protective effects against lipotoxicity-induced islet dysfunction and T2DM have yet to be determined. Therefore, this study aimed to uncover the regulatory pathways of FGF21 involved in islet lipid metabolism with lipotoxicity-induced animal and cell models.

Methods : C57/BL6J mice and global FGF21 knockout (KO) were fed with a 60% high-fat diet (HFD) for 12-20 weeks; the HFD-treated mice were given with a memetic of FGF21, namely CVX-343 (PF-05231023, Pfizer) for 6 weeks. Meanwhile INS-1E and isolated islets from control mice were exposed to palmitic acid (PA), mimicking lipotoxic conditions for different time course studies.

Results : Results showed that exogenous FGF21 ameliorated the PA-induced fatty acid and triglyceride accumulation as well as reversed high PA-induced cell apoptosis and enhanced glucose stimulated insulin secretion, impaired by high PA in vitro and ex vivo conditions. Mechanically, FGF21 exerted its effect via its acute stimulation of the AMPK-ACC (acetyl-CoA carboxylase) pathway, inhibiting the ACC activity and activating the PPARδ signaling, as evidenced by RNA-seq analysis. In vivo studies with HFD-fed normal mice treated with the CVX-343 and FGF21 KO mice further confirmed the demonstrated effects of FGF21-mediated on insulin sensitivity and glucose tolerance.

Conclusions : Our study indicate that FGF21 is protective against lipotoxicity-induced islet cell dysfunction via the mediation of lipid homeostasis, in HFD-treated mice; these data provide further support for FGF21 and/or its analogues as a therapeutic target for obesity and T2DM.