The FGF family consists of over 20 small (~17-26 kDa) secreted peptides, originally recognized for their ability to stimulate fibroblast proliferation. This mitogenic activity was found to be mediated through FGF receptors (FGFRs) 1, 2, or 3. A fourth related tyrosine kinase receptor, FGFR4, displayed binding affinity for FGFs but did not elicit a mitogenic response.
FGFs exert their cellular effects through at least five distinct subfamilies of high-affinity FGFRs: FGFR-1, -2, -3, and -4, all possessing intrinsic tyrosine kinase activity (with multiple splice isoforms except for FGFR-4), and FGFR-5, which lacks an intracellular kinase domain. Emerging evidence suggests the importance of FGFRs in regulating glucose and lipid homeostasis. Overexpression of a dominant-negative FGFR-1 in pancreatic beta cells has been linked to diabetes in mice, implying a crucial role for FGF signaling in normal beta cell function and blood sugar regulation. FGFR-2 appears vital during pancreatic development. Furthermore, FGFR-4 has been implicated in cholesterol metabolism and bile acid synthesis.
Studies indicate that FGF-19 promotes resistance to diet-induced obesity, improves glucose tolerance, and enhances lipid profiles in diabetic rodents. Given that these effects are partly mediated through observed changes in metabolic rates, FGF-19 can be regarded as a regulator of energy expenditure.
While FGF-21 exhibits preferential expression in the liver, a comprehensive understanding of its bioactivity and mechanism of action has been limited. Notably, FGF-21 acts as a potent activator of glucose uptake in adipocytes, offering protection against diet-induced obesity when overexpressed in transgenic mice. Moreover, therapeutic administration of FGF-21 to diabetic rodents has been shown to reduce blood glucose and triglyceride levels.
FGF-21 signals through FGF receptor 1c and 4, using β-Klotho as a cofactor, to activate the PI3K and MAPK pathways . The expression of FGF-21 is regulated by tissue-specific peroxisome proliferator-activated receptors (PPARs). For instance, PPAR-α stimulation leads to FGF-21 production in the liver, while PPAR-γ activation results in its production in adipose tissue .
FGF-21 has several important biological functions: