FGF21/analogue suppresses high-fat diet induced islet cell dysfunction and cell apoptosis in mice
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摘要Background and aims: Lipotoxicity in the pancreas is a lipid metabolism disorder, which is due to the excessive accumulation of lipid intermediates in islets, finally leading to islet dysfunction and β-cell apoptosis, as seen in obesity-related type 2 diabetes mellitus (T2DM). Fibroblast growth factor 21 (FGF21) is a potent regulator of lipid homeostasis that has been reported to be beneficial for islet cell health. However, the protective mechanism(s) whereby FGF21 regulates islet fatty acid (FA) metabolism, thereby protecting islet failure under lipotoxic conditions remain elusive. We, therefore, sought to explore the protective effects of FGF21/analogue on islet lipid metabolism in lipototoxicity-induced animal and cell models.
Materials and methods: For in vivo models, C57/BL6J mice and global FGF21 knockout (KO) were fed with a 60% high-fat diet (HFD) and standard diet for 12-20 weeks; the HFD-treated mice were given with a long-acting mimetic of FGF21 (CVX-343/PF-0523102, a gift from Pfizer) for 6 weeks. For in vitro and ex vivo models, rat β-cell line INS-1E and islets isolated from normal C57/BL6J mice were cultured and exposed to palmitic acid (PA normal: 0mM; high: 0.7mM) with/without FGF21 (100nM), mimicking lipotoxic conditions for different time course studies. Real-time quantitative PCR, RNA-seq and Western blot analyses were performed for the expression levels of the genes and proteins of interest.
Results: In animal experiment-treated with the FGF21 analogue (CVX-343), there were significant reductions in the HFD-induced body-weight gain (44.18 ± 1.13 vs 35.13 ± 0.71 g, n=15, p<0.0001), the levels of fasting blood glucose (12.77 ± 0.48 vs 9.47 ± 0.48 mM, n=15, p<0.0001) and triglyceride accumulation (0.144 ± 0.003 vs 0.080 ± 0.004 ug/mg protein, n=15, p<0.0001); meanwhile, the levels of glucose tolerance (2722 ± 134.5 vs 1942 ± 96.4, n=15, p<0.0001) and insulin sensitivity (987.3 ± 118.3 vs 575.5 ± 57.1, n=15, p<0.01) were markedly improved, in relation to the HFD-fed control mice. Moreover, FGF21 KO mice fed with HFD exhibited decreases in insulin sensitivity (1292 ± 12 vs 1946 ± 137, n=5, p<0.05) and glucose tolerance (2984 ± 280 vs 3703 ± 132, n=5, p<0.05), in relation to HFD-fed control mice. Exogenous application of FGF21 in isolated islets from wildtype mice displayed higher expression of lipid oxidation-related genes, including carnitine palmitoyltransferase-1 (CPT1, 6.04 ± 0.33 vs 7.58 ± 0.34, n=4, p<0.05) and acyl-CoA oxidase (ACO, 2.50 ± 0.06 vs 3.11 ± 0.10, n=4, p<0.01), in relation to the PA-treated islets; these observed effects were due, in part, to the activation of the PPARα/RXR signaling, as demonstrated by RNA-seq. In INS-1E cell studies, FGF21 treatment ameliorated the PA-induced FA levels (16.84 ± 0.97 vs 9.66 ± 0.47 mEq/g protein, n=4, p<0.001) and triglyceride accumulation (1.32 ± 0.06 vs 0.90 ± 0.04 ug/mg protein, n=4, p<0.01); meanwhile, FGF21 reversed high PA-induced cell apoptosis (197.5 ± 10.1 vs 170.3 ± 5.7 %, n=4, p<0.001) and improved cell proliferation (62.0 ± 1.2 vs 71.8 ± 2.6 %, n=5, p<0.05), as well as enhanced glucose stimulated insulin secretion (1.95 ± 0.16 vs 2.62 ± 0.13, n=4, p<0.05).
Conclusion: Our study findings indicate that FGF21 is protective against lipotoxicity-induced islet cell dysfunction and cell demise, probably via the mediation of lipid homeostasis, in HFD-treated mice; these data lend furher support for FGF21 analogue as a therapeutic target for obesity and T2DM.
著者Ting XIE, Po Sing LEUNG
會議名稱53rd Annual Meeting of the European Association for the Study of Diabetes
關鍵詞GROUP 2: Islets, Transplantation, Immunology type 1 diabetes

上次更新時間 2018-23-01 於 02:47