The endocrine Fibroblast Growth Factor family: Possible insulin-sensitizing therapeutics

Abstract

This thesis focuses on the endocrine members of the Fibroblast Growth Factor (FGF) family. The 23 FGFs, polypeptides that perform different actions in an organism, can be divided into seven subfamilies, functioning intracrine, paracrine or endocrine. The endocrine family consists of FGF19, the human ortholog of FGF15, FGF21 and FGF23. To function in the body, endocrine FGFs signal through FGF receptors (FGFR) with the use of co-receptor Klotho. Tissue specific expression of FGFR and Klotho determines in which tissue endocrine FGF functions. FGF23 regulates phosphate and calcium plasma levels. Via active vitamin D (AVD) FGF23 lowers insulin sensitivity. FGF15/19 and FGF21 are regulated by food intake. FGF15/19 expression is regulated by bile acid (BA) uptake in the ileum after feeding. FGF15/19 inhibits bile acid synthesis, increases energy expenditure and improves metabolic parameters. FGF21 increases in a lower energy state. FGF21 also increases energy expenditure, improves metabolic parameters and improves insulin-sensitivity. FGF23 has a huge impact on phosphate en calcium serum levels which makes it unsuitable as insulin sensitizer. Besides improving metabolic parameters, FGF15/19 regulates BA synthesis and induces liver tumors. FGF21 improves metabolic parameters, increases insulin sensitivity, and most likely does this without big negative side effects. Furthermore, FGF21 is suggested to be safe for healthy organisms and in total shows to be the most promising target as future therapeutic for diabetes mellitus type 2 and obesity.