Deletion of GFRAL blunts weight lowering effects of FGF21 in female mice.

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 wildtype mice, which lost 12% body weight relative to 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 glycaemic 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. Lastly, 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, the further examination of the interconnectedness between GDF15 and FGF21 endocrine axes in male rodents imply 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 signalling in regulating compensatory food intake induced by FGF21 pharmacology.