Fibroblast growth factor 21 coordinates adiponectin to mediate the beneficial effects of low-protein diet on primordial follicle reserve

BACKGROUND: Global consumption of protein per capita is rising, while rates of infertility are increasing. However, a clear relationship between protein intake and reproductive health has not been demonstrated. The activation of the quiescent primordial follicles is the first step of folliculogenesis, and their activation must be tightly controlled to prevent premature exhaustion of the ovarian follicular reserve. METHODS: The primordial follicle reserve of wild-type or liver-specific ablation of fibroblast growth factor 21 (FGF21) in mice, subjected to limited or excessive protein diets or oral gavage test, were detected in vivo. Mouse ovary organ cultures were used to examine the direct role of metabolites or metabolic hormones on primordial follicle activation. FINDINGS: Mouse primordial follicle activation, was reduced by restricted protein intake and was accelerated by excessive protein intake, in an ovarian mTORC1 signaling-dependent manner. Furthermore, restricted or excessive protein intake resulted in an augmentation or decline of oocyte number and fertility at older age, respectively. Liver-specific ablation of FGF21, which resulted in a reduction of 87% in circulating FGF21, abrogated the preserving effect of low-protein intake on primordial follicle pool. Interestingly, FGF21 had no direct effect on the activation of primordial follicles, but instead required an adipokine adiponectin. Moreover, AdipoRon, an oral adiponectin receptor agonist, prevented the over-activation effect of excessive protein intake on primordial follicle activation. INTERPRETATION: Dietary protein consumption controlled ovarian primordial follicle reserve and fertility, which required coordination between FGF21 and adiponectin. FUND: Natural Science Foundation of China (Grant 31772616).