Du Pei, Wang Ting, Wang Rong, Liu Shang, Wang Hang, Yin Hongping
School of Life Science and Technology, China Pharmaceutical University, 639 Long Mian Avenue, Nanjing 211198, China.
Glycomics and Glycan Bioengineering Research Center (GGBRC), College of Food Science and Technology, Nanjing Agricultural University, 1 Weigang, Nanjing 210095, China.
Int J Mol Sci. 2025 Mar 16;26(6):2672. doi: 10.3390/ijms26062672.
Fibroblast growth factor 21 (FGF21), a hormone-like protein, plays a crucial role in enhancing glucose and lipid metabolism, offering promising therapeutic avenues for conditions such as nonalcoholic steatohepatitis and severe hypertriglyceridemia. Despite its potential, this protein's limited stability and brief half-life pose significant challenges for its use in clinical settings. In this study, we created an FGF21 analog (named FGF21-164) that is a mutant of FGF21 and fused it with the tandem repeat sequence of human CD164. FGF21-164, characterized by extensive glycosylation and sialylation, exhibits enhanced pharmacokinetic properties, particularly in terms of its significantly longer half-life compared to its native form. The in vitro efficacy of FGF21-164 was evaluated using 3T3-L1-induced adipocytes. The protein demonstrated a dose-dependent increase in glucose uptake and effectively decreased lipid droplet accumulation surrounding the adipocytes. The in vivo activity of FGF21-164 was evaluated in (/) and diet-induced obesity (DIO) mice. A single subcutaneous dose of FGF21-164 led to a rapid decrease in blood glucose levels and sustained normal fasting glucose levels for up to 28 days. Additionally, repeated dosing of FGF21-164 significantly curbed weight gain and reduced hepatic fat accumulation in DIO mice.
成纤维细胞生长因子21（FGF21）是一种类似激素的蛋白质，在增强葡萄糖和脂质代谢方面发挥着关键作用，为非酒精性脂肪性肝炎和严重高甘油三酯血症等病症提供了有前景的治疗途径。尽管具有潜力，但这种蛋白质稳定性有限且半衰期短，在临床应用中面临重大挑战。在本研究中，我们创建了一种FGF21类似物（命名为FGF21 - 164），它是FGF21的突变体，并将其与人CD164的串联重复序列融合。FGF21 - 164具有广泛的糖基化和唾液酸化特征，表现出增强的药代动力学特性，特别是与天然形式相比，其半衰期显著延长。使用3T3 - L1诱导的脂肪细胞评估了FGF21 - 164的体外功效。该蛋白质显示出葡萄糖摄取的剂量依赖性增加，并有效减少了脂肪细胞周围的脂滴积累。在（/）和饮食诱导的肥胖（DIO）小鼠中评估了FGF21 - 164的体内活性。单次皮下注射FGF21 - 164导致血糖水平迅速下降，并使正常空腹血糖水平维持长达28天。此外，重复给药FGF21 - 164显著抑制了DIO小鼠的体重增加并减少了肝脏脂肪积累。
