In this regard, our research data suggest that that obesity and over-nutrition enhanced the mammalian target of rapamycin (mTOR)/ribosomal S6 kinase 1 (S6K1) signaling pathway that induces vascular insulin resistance through the increased serine phosphorylation of the critical insulin-signaling/docking molecule insulin receptor substrate 1 (IRS-1) [46]. Here, IRS1 is linked to obesity due to melanocortin 4 receptor deficiency.