Consistent with improved systemic glucose tolerance and insulin sensitivity in L-Ago2 KO mice, HFD-induced pancreatic β-cell proliferation and islet hypertrophy were attenuated compared to L-Ago2 WT mice (Supplementary Fig. 4c–g), supporting that hepatic Ago2-deficiency improves insulin sensitivity in the pathogenesis of obesity. Here, AGO2 is linked to obesity due to melanocortin 4 receptor deficiency.