Increased systemic TNF-α in obesity leads to increased activity of IKK, p38 MAPK, JNK, and PKC proteins, which modify IRS protein serine residues and hinder tyrosine phosphorylation, causing insulin resistance in adipose tissues, muscles, and the liver [47,163]. The gene discussed is IARS1; the disease is obesity due to melanocortin 4 receptor deficiency.