Therefore, these findings consistently support the notion that the selective increase in FGF21 sensitivity in adipose and cardiac tissues is an important mechanism mediating the cardiometabolic benefits of FGF21 (Fig. 2), and also suggest that FGF21-based pharmacotherapy for obesity-related cardiometabolic diseases should be implemented in conjunction with exercise intervention to increase its sensitivity. The gene discussed is FGF21; the disease is obesity due to melanocortin 4 receptor deficiency.