IRS1 and obesity due to melanocortin 4 receptor deficiency: Pro-inflammatory cytokines including IL-6 and TNF-α are produced from AT during obesity. TNF-α promotes serine phosphorylation of ISR1 and IRS2 and is closely associated with insulin resistance [26]. TNFα plays an active role in insulin resistance because of its ability to bind IRS1 and IRS2 thereby phosphorylates serine residue and inhibits insulin stimulated tyrosine phosphorylation [84]. Tyrosine phosphorylation at specific sites on receptor substrates are very important for glucose uptake, lipogenesis, and glycogen and protein synthesis, as well as for stimulation of cell growth [85].