However, its promotion of hepatocyte proliferation and carcinogenic potential challenges the development of FGF19 for chronic use. With the identification of FGFR4 as the receptor mediating the induction of hepatocyte proliferation but not the improvement in glucose tolerance, it was predicted that FGF19-like molecules with reduced FGFR4 activity should provide metabolic benefits without causing unwanted side effects. Indeed, we have identified a chimeric FGF19v protein that fits these criteria; it ameliorates hyperglycemia and hyperinsulinemia without a detectable increase in hepatic AFP expression in ob/ob mice. When lean and tumorprone FVB mice were challenged with a supra-therapeutic dose by combination of continuous infusion and daily injection, FGF19v induced only a two-fold increase in hepatic BrdU incorporation compared with vehicle-treated mice, whereas FGF19 induced on average.9 fold increase. While it is not clear how significant this residual level of FGFR4 activity of FGF19v molecule would be in the therapeutic setting, in Masitinib particular considering humans have endogenous FGF19 protein, further fine mapping of amino acid residues that are important for FGFR4 interaction should help to identify FGF19 variants without residual FGFR4 activity, thus with no proliferative actions. Such proteins would have therapeutic potential for the treatment of insulin resistance, type 2 diabetes, and the broader metabolic syndrome. Each FGF family protein consists of the structurally conserved central globular domain, and the flanking N-terminal and Cterminal segments that are structurally flexible and are divergent in primary sequence. In X-ray crystal structures of multiple FGF/ FGFR complexes, the N-terminal segment of the FGF molecule makes specific contact with the FGFR and is believed to play an important role determining the specificity of the FGF-FGFR interaction. Through our efforts to identify specific regions within FGF19 that are important for FGFR4 activation, we found that changing the entire N-terminal segment of FGF19 to that of FGF21 substantially removes FGFR4 activations without impairing its ability to activate FGFR1. Conversely, changing N-terminal 34 amino acid of FGF21 to the corresponding sequence of FGF19 confers activation of FGFR4. Thus, determinants of receptor specificity reside within the flexible N-terminal segments of FGF19, although other regions within FGF19 are essential for maximum activation of FGFR4. While this manuscript was in preparation, Wu et al. reported an identification of a FGF19 variant with a dramatically reduced ability to activate FGFR4, but that was only modestly compromised for FGFR1c activation and retained the ability to acutely reduce blood glucose levels in ob/ob mice. In this variant called FGF19-4, five amino acids in the N-terminal segment and 8 amino acids at the N-terminal end of the globular domain.