Introduction

Energy homeostasis is critical for life; therefore diverse hormonal mechanisms have evolved to regulate cellular energy utilization as well as inter-tissue communication to coordinate metabolic pathways. Although regulation of cellular metabolism by major controllers such as insulin and glucagon is well-established, a new distinct subgroup of fibroblast growth factors consisting of FGF19, FGF21 and FGF23, has been recently identified to play critical roles in the metabolic network. Within FGF superfamily, these three factors share the highest level of homology with one another and propagate their effects via FGFRs, although each of them displays a diverse mechanism of receptor activation. In contrast to classical FGFs that require heparin for efficient FGFR engagement, FGF19, FGF21 and FGF23 lack conventional heparin-binding domains. This property allows these factors to elude body’s vast depot of extracellular heparan sulphate proteoglycans and be readily present in the circulation, thus putatively function in an endocrine-like manner [1,2]. Despite the absence of heparin-binding domains, FGF19, FGF21 and FGF23 still require cofactors, type 1 transmembrane proteins Klotho [3] or βKlotho [4], for efficient FGFR activation [5–۷]. In contrast to ubiquitously expressed FGFRs, patterns of Klotho and βKlotho expression in the body are fairly restricted. Thus, Klotho and βKlotho, not FGFRs, define tissue selectivity of action for the hormone-like FGFs and determine the distinct physiological roles of these factors: FGF19 regulates cholesterol/bile acid (BA) synthesis, FGF21 controls glucose and lipid metabolism, and FGF23 modulates phosphate/vitamin D metabolism [8–۱۰].