The fibroblast growth factor(FGF)family is composed of 22 members, which can be divided into typical FGFs and hormone-like FGFs [1]. FGFs play an essential role in cell growth and differentiation, angiogenesis, embryonic development, and metabolic regulation [2]. FGF21 belongs to the FGF19 subfamily, which is mainly expressed in the liver and muscle and is a stress-inducible hormone with essential roles in glucose and lipid homeostasis [3]. The mRNA level of FGF21 was also detected in the ovaries of gilts in pre-puberty, in-puberty and post-puberty [4]. The family plays an essential role in the endocrine-based regulation of metabolism [3,5,6]. Studies have shown that there is a strong correlation between FGF21 and the occurrence of polycystic ovary syndrome (PCOS), a common ovarian disease [7,8]. FGF21 specifically binds to the complex consisting of fibroblast growth factor receptor-1 (FGFR1) and the coreceptor beta-klotho (KLB), and the terpolymer is essential to activate the downstream signaling cascades and regulate metabolic homeostasis [9].

Previous studies suggested that the overexpression of FGF21 significantly promotes non-small cell lung cancer growth and migration [10]. FGF21 inhibitor suppresses the proliferation and migration of human umbilical vein endothelial cells through the eNOS/PI3K/AKT pathway [11]. FGF21 acts on adipocytes and leading to the proliferation and commitment of adipocyte precursors into beige adipocytes [12]. These results suggest a critical role of FGF21 in cell growth and proliferation. In mammals, it is widely known that granulosa cells (GCs) proliferation plays a vital regulatory role in deciding the fate of follicles and follicular maturation [[13], [14], [15]]. GCs proliferate rapidly to support follicle growth and oocyte maturation in the growing follicle. Studies have shown that the proliferation of GCs is also regulated by cell cycle genes, including Cyclin B, Cyclin E, Cyclin D, CDKs, and p21 [16,17].

Estradiol (E2) produced in GCs are suggested to support the survival and proliferation of GCs and facilitate the maturation of follicles [18]. The rate–limiting step in steroid production is the StAR–mediated transport of cholesterol from the cytosol to the inner mitochondrial membrane, where cytochrome P450 enzymes catalyze cleavage of the cholesterol side chain. Here it is converted to pregnenolone by CYP11A1 [19]. This aromatase also transforms testosterone into E2 in ovarian GCs [19,20]. The development of mammalian follicles is a critical process in the ovary, and the proliferation and growth of GCs directly promote follicular development [21]. As proliferation and differentiation during follicular development, GCs can synthesize various hormones and growth factors and express their receptors [22,23]. These factors regulate follicular inner membrane cells and oocytes’ growth and maturation through gap junctions, regulating follicular development [24].

Studies have shown that the initiation of estrus was delayed in mice overexpressing FGF21 in the liver [25], but feeding high-fat diets restored fertility [26]. In addition, FGF21 indirectly regulates rodents ovarian mTORC1 signaling and primordial follicle activation by affecting the secretion of adiponectin [27]. The role of FGF21 in the direct regulation of mammal ovarian GCs is rarely reported. However, FGF21 and FGF21 receptors are expressed on GCs, so we speculate that it might affect female reproduction by regulating their physiological activities. Therefore, we used porcine ovaries to study the regulatory mechanism of FGF21 in ovarian GCs proliferation and hormone secretion. The results enriched our understanding of the role of FGF21 on ovarian physiology.