TNF and obesity due to melanocortin 4 receptor deficiency: In diabetes and obesity, increased levels of pro-inflammatory cytokines, particularly tumor necrosis factor alpha (TNF-α) activates c-Jun terminal kinase (JNK), resulting in insulin receptor substrate 1 (IRS1) suppression by increasing the inhibitory phosphorylation of Ser312IRS1, Ser636IRS1, and decreasing activating phosphorylation of Tyr465IRS1 (Hotamisligil et al., 1993; Rui et al., 2001; Pedersen et al., 2003).