INS and obesity due to melanocortin 4 receptor deficiency: To this end, mice were first fed with HFD to induce obesity (8-week diet) and, after that, mice were assigned either to metformin treatment (HFD + Met), known to reduce body weight and improve insulin sensitivity (62), or switched to standard chow (HFD to Chow; Figure 4A and Supplementary Figures 7A–C).