The proinflammatory cytokine tumor necrosis factor alpha (TNFa) has also been proposed as a link between adiposity and the development of insulin resistance.47 TNFa initiates an inflammatory response by stimulating IkB kinase-^ (IkK-P). Serine phosphorylation of inhibitor protein of kB (IkB) triggers ubiquitination and degradation of IkB, and, eventually, activation of the nuclear factor kB (NF-kB), a transcription factor involved in immune and inflammatory responses.
TNFa is highly expressed in adipose tissue, and infusion of TNFa into rats caused insulin resistance, while neutralization of the cytokine with antibodies to TNFa reversed insulin resistance in obese rats. The insulin resistance induced by TNFa can be prevented by treatment with the salicylate, which is known to inhibit IkK^. Treatment of adipocytes and skeletal muscle with TNFa causes insulin resistance by decreasing insulin-induced IRS-1 tyrosine phoshorylation and activation of IRS-1-associated PI 3-kinase. This is likely caused by phosphorylation of serine 307 of the IRS-1 protein. The serine kinase that is directly responsible for the phosphorylation of IRS-1 has not been determined with certainty, but candidates include c-Jun N-terminal kinase (JNK),47 PKC,61 and IkK^.26
The insulin resistance induced by muscle lipids may also be mediated through inflammatory pathways.79 Kim et al.61 found that infusion of fatty acids into rats caused insulin resistance and decreased insulin signaling in skeletal muscle. Lipid-induced insulin resistance could be prevented by pretreating the rats with salicylate, a known inhibitor of IkK-0. Likewise, fatty-acid infusion in an IkKP knock-out mouse did not produce insulin resistance as it did in wild-type controls.
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