FGF21 preferentially binds and activates the FGFR1 that is predominantly expressed in adipose tissue and adipocytes.[35] The notion of “FGF21 resistance” is the widely proposed explanation for increases in circulating FGF21 levels in metabolic diseases.[36] In this model, the increase in FGF21 is caused by a downregulation of expression of its receptors (or desensitization) mainly in white adipose tissue, resulting in compensatory FGF21 production. The gene discussed is FGF21; the disease is metabolic disease.