Given the pleiotropic activities of FGF19 and FGF21 on multiple receptors (i.e., FGFR1c, 2c, and 3c), further exploration into altering receptor specificity of FGF19 or FGF21 to achieve specific activation of a particular FGFR may provide a safer and more predictable approach to exploit endocrine FGF pathways and provide new therapeutic options for the epidemic of obesity associated-disorders such as type 2 diabetes, nonalcoholic fatty liver disease and other manifestations of insulin resistance and the metabolic syndrome. Here, FGF21 is linked to Insulin resistance.