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)-alpha has been proposed as a link between obesity and insulin resistance because TNF-alpha is overexpressed in adipose tissues of obese animals and humans, and obese mice lacking either TNF-alpha or its receptor show protection against developing insulin resistance. Direct exposure to TNF-alpha 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 Ser(307) residue in IRS-1 has been identified as a site for the inhibitory effects of TNF-alpha 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-alpha 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-alpha 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-alpha. 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.