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This Article Full Text Full Text (PDF) All Versions of this Article: jas.2007-0462v1 86/14_suppl/E94    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lorenzo, M. Articles by Nieto-Vazquez, I. Search for Related Content PubMed PubMed Citation Articles by Lorenzo, M. Articles by Nieto-Vazquez, I.

Insulin resistance induced by tumor necrosis factor- in myocytes and brown adipocytes^1,2

Departamento de Bioquimica y Biologia Molecular II, Facultad de Farmacia, Universidad Complutense, 28040-Madrid, Spain

³ Corresponding author: mlorenzo{at}farm.ucm.es

Insulin resistance is an important contributor to the pathogenesis of type 2 diabetes, and obesity is a risk factor for its development, in part because adipose tissue secretes proteins, called adipokines, that may influence insulin sensitivity. Among these molecules, tumor necrosis factor (TNF)- has been proposed as a link between obesity and insulin resistance because TNF- is overexpressed in adipose tissues of obese animals and humans, and obese mice lacking either TNF- or its receptor show protection against developing insulin resistance. Direct exposure to TNF- induces a state of insulin resistance in terms of glucose uptake in myocytes and brown adipocytes because of the activation of proinflammatory pathways that impair insulin signaling at the level of the insulin receptor substrate (IRS) proteins. In this regard, the Ser³⁰⁷ residue in IRS-1 has been identified as a site for the inhibitory effects of TNF- in myotubes, with p38 mitogen-activated protein kinase and inhibitor kB kinase being involved in the phosphorylation of this residue. Conversely, Ser phosphorylation of IRS-2 mediated by TNF- activation of mitogen-activated protein kinase was the mechanism found in brown adipocytes. Protein-Tyr phosphatase (PTP)1B 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- Accordingly, myocytes and primary brown adipocytes deficient in PTP1B are protected against insulin resistance induced by this cytokine. Furthermore, down-regulation of PTP1B activity is possible by the use of pharmacological agonists of nuclear receptors that restore insulin sensitivity in the presence of TNF-. 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.

Key Words: glucose uptake • liver X receptor • protein-tyr phosphatase 1B • obesity • p38 mitogen-activated protein kinase • rosiglitazone

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