Our in vitro work with siRNA to knock down PRKD2 in Ins-1 cells and Hepa1-6 cells (Supplementary Fig. 8), as well as the quantifications of insulin levels and activities of the insulin signaling in 4-week- and 14-week-old PRKD2−/− mice (Fig. 4 and Supplementary Fig. 6) suggests a hyperinsulinemia-primary model that the development of obesity and IR following hyperinsulinemia. This evidence concerns the gene INS and obesity due to melanocortin 4 receptor deficiency.