Although FGF21 plays a beneficial role in metabolism, circulating FGF21 levels have been reported to paradoxically increase in obesity and in T2DM patients and animal models, and they are positively correlated with the severity of glucose intolerance and insulin resistance, indicating an FGF21-resistant state (Chavez et al., 2009; Fisher et al., 2010; So et al., 2013; Roesch et al., 2015; Hu et al., 2016; So and Leung, 2016). Here, FGF21 is linked to obesity due to melanocortin 4 receptor deficiency.