FGF21 binds fibroblast growth factor receptor (FGFR) tyrosine kinases complexed with the co-receptor β-klotho [10], [11] and activates MAPK preferentially via FGFR1c/β-klotho [12]. It is reported that the restricted gene expression profile of β-klotho in liver, WAT and pancreas confers tissue specificity for the metabolic activity of FGF21 [13], [14]. Indeed, FGF21 rapidly induces FGFR and MAPK activation in liver and WAT tissues [15], suggesting that both tissues are FGF21 target organs. FGF21 was initially identified as a stimulator of glucose uptake in mouse 3T3-L1 adipocytes [1] suggesting a prominent role in adipose tissue, and participation in regulation of glucose metabolism in this tissue. Additionally, FGF21 is involved in the regulation of adipocyte lipolysis [5], [16], [17]. The liver may also participate in the glucose- and lipid-lowering effect of FGF21 since FGF21 suppresses hepatic glucose output and inhibits hepatic lipogenesis and triglyceride formation [6], [15]. Although, both liver and adipose tissue may participate in the pharmacological action of FGF21, the degree and nature of their contributions may differ. FGF21 has a 10-fold higher affinity to induce ERK-phosphorylation in adipose tissue
