While the IR and, Irs1 mRNA and protein levels remained unaffected in both zones, the mRNA and protein levels of Irs2, which is known to be suppressed at the transcriptional level by hyperinsulinemia associated with HF diet-induced obesity-linked insulin resistance4, 6, 7, were markedly downregulated in both the zones (Fig. 4d–f; Supplementary Fig. 5). This evidence concerns the gene IRS1 and obesity due to melanocortin 4 receptor deficiency.