FGF21 Coordinates Adiponectin to Mediate the Beneficial Effects of Low-Protein Diet on Primordial Follicle Reserve

Abstract

Global per capita consumption of protein is rising, while infertility is becoming prevailing. Here we found that mouse primordial follicle activation, the first step of folliculogenesis, 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 fibroblast growth factor 21 (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. Collectively, dietary protein consumption controlled ovarian primordial follicle reserve and fertility, which required coordination between FGF21 and adiponectin. Funding Statement: This study was funded in part by National Natural Science Foundation of China (Grant 31772616). Declaration of Interests: None of the authors have a conflict of interests to declare. Ethics Approval Statement: All animal procedures in this study were handled in accordance with Guide for the Care and Use of Laboratory Animals (National Research Council, Bethesda, MD, USA), and the Institutional Animal Care and Research Committee of Sichuan Agricultural University (SICAU-2015-034).