It is well known that Irs2 expression is suppressed by insulin signaling itself at the transcriptional level through the insulin response element via inactivated FoxO or activated SREBP proteins [159,160,161,162,163], suggesting that hyperinsulinemia, which is common in obesity, metabolic syndrome, T2DM, and NAFLD, could cause hepatic insulin resistance by downregulation of Irs2. The gene discussed is INS; the disease is obesity due to melanocortin 4 receptor deficiency.