Contribution of TNF-á to Obesity-Associated Insulin Resistance

Zusammenfassung

Insulin resistance is an important contributor to the pathogenesis of type 2 diabetes, and obesity is a risk factor for its development, due in part to the fact that adipose tissue secretes proteins called adipokines, that may influence insulin sensitivity. Among these molecules, TNF-á has been proposed as a link between obesity and insulin resistance because TNF-á is overexpressed in adipose tissues of obese animals and humans, and obese mice lacking either TNF-á or its receptor show protection for developing insulin resistance. The direct exposure to TNF-á induced a state of insulin resistance on glucose uptake in myocytes and brown adipocytes, due to the activation of pro-inflammatory pathways that impair insulin- signaling at the level of the IRS proteins. In this regard the residue Ser307 in IRS-1 has been identified as a site for TNF-á-inhibitory effects in myotubes, with p38MAPK and IKK being involved in the phosphorylation of this residue. Conversely, serine phosphorylation of IRS-2 mediated by TNF-á activation of MAPKs was the mechanism found in brown adipocytes. The phosphatase PTP1B acts as a physiological negative regulator of insulin signaling by dephosphorylating the phosphotyrosine residues of the insulin receptor and IRS-1, and PTP1B expression is increased in muscle and white adipose tissue of obese and diabetic humans and rodents. Moreover, up-regulation of PTP1B expression was recently found in cells treated with TNF-á. Accordingly, myocytes and primary brown adipocytes deficient on PTP1B are protected against insulin resistance by this cytokine. Furthermore, down-regulation of PTP1B activity is also possible by the use of pharmacological agonists of nuclear receptors that restore insulin sensitivity in the presence of TNF-á. In conclusion, the lack of PTP1B in muscle and brown adipocytes increases insulin sensitivity and glucose uptake and could confer protection against insulin resistance induced by adipokines.