One working theory is that obesity-associated increases in FGF21 reflect an FGF21-resistant state due to observed downregulation of FGFR1c and KLB in the liver and WAT, as well as reduced efficacy of recombinant FGF21 (rFGF21) in mice and humans (33, 34). This evidence concerns the gene KLB and obesity due to melanocortin 4 receptor deficiency.