INS and obesity due to melanocortin 4 receptor deficiency: In contrast, during low-grade systemic inflammation characteristic of obesity, the produced cytokines TNF-α, IL-6, and IL-1β bind to their receptors on the cell membrane of adipocytes and insulin-sensitive tissues (liver, pancreas, and skeletal muscle), triggering an increase in the phosphorylation of serine and threonine residues in IRS-1/2 through the NF-κB/IKKβ and c-Jun N-terminal kinase pathways, which prevents appropriate activation of the insulin receptor signaling pathway and contributes thus to insulin resistance in insulin-sensitive tissues [83,84].