Insulin resistance by tumor necrosis factor- in myocytes and brown adipocytes

¹ Departamento de Bioquimica y Biologia Molecular II, Facultad de Farmacia, Universidad Complutense, 28040-Madrid, Spain

^* To whom correspondence should be addressed. E-mail: mlorenzo{at}farm.ucm.es.

	Abstract

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, 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 for developing insulin resistance. The direct exposure to TNF- 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 insulin receptor substrate (IRS) proteins. In this regard, the Ser³⁰⁷ residue in IRS-1 has been identified as a site for TNF--inhibitory effects in myotubes, with p38 mitogen-activated protein kinase (MAPK) and inhibitor kB kinase being involved in the phosphorylation of this residue. Conversely, serine phosphorylation of IRS-2 mediated by TNF- activation of MAPK was the mechanism found in brown adipocytes. Protein-tyrosine 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 on PTP1B are protected against insulin resistance induced by this cytokine. Furthermore, down-regulation of PTP1B activity is also possible by the use of pharmacological agonists of nuclear receptors that restored insulin sensitivity in the presence of TNF-. In conclusion, the lack of PTP1B in muscle and brown adipocytes increase insulin sensitivity and glucose uptake and could confer protection against insulin resistance induced by adipokines.

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

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