Elevated free fatty acids in obesity and hypoxia [55] induce inhibitor of kappa B (IκB) kinase β (IKKβ), which phosphorylates serine residues of IRS-1 and interrupts IRS1/PI3k/Akt-dependent eNOS activity that causes NO depletion and impairment of insulin signaling [123]. This evidence concerns the gene IRS1 and obesity due to melanocortin 4 receptor deficiency.