Simultaneously, excess adiposity, particularly visceral adipose tissue, generates inflammatory cytokines including tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) that impair insulin signaling through serine phosphorylation of insulin receptor substrate-1, as extensively documented by Hotamisligil in his landmark Nature review on inflammation and metabolic disorders [28]. Here, IRS1 is linked to metabolic disease.