Furthermore, in a hyperinsulinemic-euglycemic clamp experiment, shRNA-mediated depletion of 85% of liver P300 (remaining P300 protein levels are similar to that of liver P300 in mice fed a regular diet) in mice fed an HFD improved liver insulin sensitivity, suggesting that HFD-induced P300 is an important pathological factor leading to the development of liver insulin resistance in obesity. This evidence concerns the gene INS and obesity due to melanocortin 4 receptor deficiency.