Role of Fibroblast Growth Factor 21 (FGF21) in the Regulation of Statural Growth

In this review, we discuss the evidence supporting the causative role of increased FGF21 expression in reduced GH action and impaired longitudinal bone growth. Fibroblast Growth Factor (FGF) 21 (FGF21) is a member of a subfamily of FGFs which lack the FGF heparin-binding domain. Thus, these FGFs can function as endocrine as well as paracrine factors. During fasting, increased expression of FGF21 induces gluconeogenesis, fatty acid oxidation, and ketogenesis: as a result, FGF21 is considered a key regulator of the metabolic adaptation to fasting. In addition, recent evidence indicates that FGF21 may regulate longitudinal bone growth. It has been shown that transgenic mice overexpressing FGF21 exhibit reduced bone growth and hepatic Growth Hormone (GH) insensitivity. FGF21 knock-out mice exposed to chronic food restriction experience greater body and tibial growth than their food-restricted wild-type littermates, suggesting that the increased FGF21 expression in wild-type mice during undernutrition leads to reduced skeletal growth. The FGF21-mediated attenuation of bone growth appears to be secondary to reduced GH sensitivity, both systemically and locally in the long bones' growth plate. The effects of FGF21 on GH action are direct, and may result from the reduced translocation of GH receptors from the cytoplasm to the cell membrane. Lastly, we discuss recent studies which have shown that FGF21 in infancy is inversely correlated with linear growth rate. In conclusion, all the evidence discussed in this review indicates that FGF21 may be an important negative regulator of mammalian growth.