In these studies, the ability of FGF21 to lower blood glucose levels and improve insulin sensitivity in diet-induced obesity (DIO) mice was dependent on adiponectin secretion (96) since an adipose-specific deficiency of Klb or adiponectin in these mice eliminated the FGF21-mediated metabolic improvements (84, 95–97). Here, INS is linked to obesity due to melanocortin 4 receptor deficiency.