Diabetes Research, Novo Nordisk A/S, DK-2760, Måløv, Denmark.
Obesity Research, Novo Nordisk A/S, Seattle, WA, 98109, USA.
Int J Obes (Lond). 2018 Jun;42(6):1151-1160. doi: 10.1038/s41366-018-0080-7. Epub 2018 Jun 11.
Administration of FGF21 and FGF21 analogues reduce body weight; improve insulin sensitivity and dyslipidemia in animal models of obesity and in short term clinical trials. However potential adverse effects identified in mice have raised concerns for the development of FGF21 therapeutics. Therefore, this study was designed to address the actions of FGF21 on body weight, glucose and lipid metabolism and importantly its effects on bone mineral density (BMD), bone markers, and plasma cortisol in high-fat fed obese rhesus macaque monkeys.
Obese non-diabetic rhesus macaque monkeys (five males and five ovariectomized (OVX) females) were maintained on a high-fat diet and treated for 12 weeks with escalating doses of FGF21. Food intake was assessed daily and body weight weekly. Bone mineral content (BMC) and BMD were measured by DEXA scanning prior to the study and on several occasions throughout the treatment period as well as during washout. Plasma glucose, glucose tolerance, insulin, lipids, cortisol, and bone markers were likewise measured throughout the study.
On average, FGF21 decreased body weight by 17.6 ± 1.6% after 12 weeks of treatment. No significant effect on food intake was observed. No change in BMC or BMD was observed, while a 2-fold increase in CTX-1, a marker of bone resorption, was seen. Overall glucose tolerance was improved with a small but significant decrease in HbA. Furthermore, FGF21 reduced concentrations of plasma triglycerides and very low density lipoprotein cholesterol. No adverse changes in clinical chemistry markers were demonstrated, and no alterations in plasma cortisol were observed during the study.
In conclusion, FGF21 reduced body weight in obese rhesus macaque monkeys without reducing food intake. Furthermore, FGF21 had beneficial effects on body composition, insulin sensitivity, and plasma triglycerides. No adverse effects on bone density or plasma cortisol were observed after 12 weeks of treatment.
成纤维细胞生长因子 21（FGF21）及其类似物的给药可降低肥胖动物模型和短期临床试验中的体重；改善胰岛素敏感性和血脂异常。然而，在小鼠中发现的潜在不良反应引起了人们对 FGF21 治疗药物开发的担忧。因此，本研究旨在研究 FGF21 对体重、葡萄糖和脂质代谢的作用，以及其对高脂肪喂养肥胖恒河猴骨密度（BMD）、骨标志物和血浆皮质醇的重要影响。
肥胖非糖尿病恒河猴（五雄五雌）维持高脂肪饮食，并用 FGF21 进行 12 周的递增剂量治疗。每天评估食物摄入量，每周测量体重。在研究前和治疗期间的多个时间点以及洗脱期测量骨矿物质含量（BMC）和 BMD。同样在整个研究过程中测量血浆葡萄糖、葡萄糖耐量、胰岛素、脂质、皮质醇和骨标志物。
平均而言，FGF21 在治疗 12 周后使体重降低了 17.6±1.6%。未观察到食物摄入量有显著变化。BMC 或 BMD 无变化，而骨吸收标志物 CTX-1 增加了 2 倍。总体葡萄糖耐量改善，HbA 略有显著降低。此外，FGF21 降低了血浆甘油三酯和极低密度脂蛋白胆固醇的浓度。研究过程中未显示临床化学标志物的不良变化，也未观察到血浆皮质醇的变化。
总之，FGF21 可降低肥胖恒河猴的体重，而不减少食物摄入。此外，FGF21 对身体成分、胰岛素敏感性和血浆甘油三酯有有益作用。在 12 周的治疗后，未观察到骨密度或血浆皮质醇的不良反应。
