In addition to the complexity of FGF21 expression kinetics in response to different dietary or environmental stressors, FGF21 levels are paradoxically elevated in individuals with obesity (3, 26–29), non-alcoholic steatohepatitis (NASH) (30), and non-alcoholic fatty liver disease (NAFLD) (31, 32). Here, FGF21 is linked to obesity due to melanocortin 4 receptor deficiency.