FGF21 preserves the pancreatic islet from lipotoxicity-induced cell dysfunction through regulation of AMPK/PPAR signaling pathways
Refereed conference paper presented and published in conference proceedings



摘要Fibroblast growth factor 21 (FGF21), a potent regulator of lipid metabolism, has been shown to be positive for ameliorating islet function and proliferation. However, its protective effects against lipotoxicity-induced islet dysfunction and T2DM yet remain elusive. Therefore, this study aimed to illustrate the regulatory pathways of FGF21 involved in islet lipid metabolism with lipotoxicity-induced animal and cell models.
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 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 PPARγ/δ signaling, as evidenced by RNA-seq analysis and further experiments. 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.
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.
著者Ting XIE, Po Sing LEUNG
會議名稱Epigenomics of Diabetes and Other Metabolic Diseases, Gordon Research Conference 2018
會議地點Hong Kong

上次更新時間 2018-27-11 於 10:47