Consistent with previous studies (32, 41–43), male mice fed HFD for 16 weeks presented with obesity, hyperglycemia, glucose intolerance, insulin resistance, defective glucose-stimulated insulin release (GSIS), and changes in islet gene expression such as Ins1, Ins2 and Gck (Figure S1B–H), as expected. Here, INS is linked to obesity due to melanocortin 4 receptor deficiency.