Buch-Rasmussen Alberte Silke, Andersen Helle, Stage Christina, Hansen Ann Maria Kruse, Paulsen Sarah J, Gillum Matthew Paul, Andersen Birgitte, Secher Anna, Latta Markus, Clemmensen Christoffer, Jørgensen Sebastian Beck
J Endocrinol. 2025 Apr 15;265(2). doi: 10.1530/JOE-25-0017. Print 2025 May 1.
The role of the GDF15 receptor, GDNF family receptor alpha-like (GFRAL), in the metabolic effects of FGF21 was investigated by treating female GFRAL knockout mice with recombinant human FGF21. In contrast to FGF21-treated wild-type mice, which lost 12% body weight relative to the vehicle, the absence of GFRAL coincided with a greater compensatory increase in food intake, and accordingly, the weight-lowering effect of FGF21 treatment was blunted. Interestingly, the glycemic benefits of FGF21 persisted in the absence of GFRAL. Potential crosstalk between FGF21 and GDF15 was further investigated acutely in obese male rats, in which a single dose of FGF21 did not increase endogenous circulating GDF15 levels and vice versa. Finally, overexpression of GDF15 or FGF21 with hydrodynamic gene delivery in obese male mice did not alter the expression of the other's receptor complex in regions of the hypothalamus and hindbrain. Collectively, we demonstrate an impaired weight-lowering effect of exogenous FGF21 in female GFRAL, knockout mice. Yet, further examination of the interconnectedness between the GDF15 and FGF21 endocrine axes in male rodents implies that they largely operate in parallel and are not extensively intertwined. In future studies, it will be important to investigate the influence of sex, particularly on the role of GDF15-GFRAL signaling in regulating compensatory food intake induced by FGF21 pharmacology.
通过用重组人FGF21处理雌性GFRAL基因敲除小鼠，研究了生长分化因子15（GDF15）受体——胶质细胞源性神经营养因子家族受体α样蛋白（GFRAL）在FGF21代谢效应中的作用。与接受FGF21处理的野生型小鼠（相对于载体组体重减轻了12%）不同，GFRAL的缺失伴随着食物摄入量更大的代偿性增加，因此，FGF21处理的体重降低效应减弱。有趣的是，在没有GFRAL的情况下，FGF21的降糖益处仍然存在。在肥胖雄性大鼠中对FGF21和GDF15之间的潜在相互作用进行了进一步的急性研究，在这些大鼠中，单剂量的FGF21不会增加内源性循环GDF15水平，反之亦然。最后，在肥胖雄性小鼠中通过流体动力学基因递送过表达GDF15或FGF21，并没有改变下丘脑和后脑区域中另一个受体复合物的表达。总体而言，我们证明了外源性FGF21在雌性GFRAL基因敲除小鼠中的体重降低效应受损。然而，对雄性啮齿动物中GDF15和FGF21内分泌轴之间相互联系的进一步研究表明，它们在很大程度上是并行运作的，并没有广泛地相互交织。在未来的研究中，研究性别影响，特别是GDF15 - GFRAL信号在调节FGF21药理学诱导的代偿性食物摄入中的作用将是很重要的。
