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. Here, IRS2 is linked to obesity due to melanocortin 4 receptor deficiency.