EGFR Tyrosine Kinase Inhibitor (PD153035) Improves Glucose Tolerance and Insulin Action in High-Fat Diet–Fed Mice

Diabetes, Dec 2009

OBJECTIVE In obesity, an increased macrophage infiltration in adipose tissue occurs, contributing to low-grade inflammation and insulin resistance. Epidermal growth factor receptor (EGFR) mediates both chemotaxis and proliferation in monocytes and macrophages. However, the role of EGFR inhibitors in this subclinical inflammation has not yet been investigated. We investigated, herein, in vivo efficacy and associated molecular mechanisms by which PD153035, an EGFR tyrosine kinase inhibitor, improved diabetes control and insulin action. RESEARCH DESIGN AND METHODS The effect of PD153035 was investigated on insulin sensitivity, insulin signaling, and c-Jun NH2-terminal kinase (JNK) and nuclear factor (NF)-κB activity in tissues of high-fat diet (HFD)-fed mice and also on infiltration and the activation state of adipose tissue macrophages (ATMs) in these mice. RESULTS PD153035 treatment for 1 day decreased the protein expression of inducible nitric oxide synthase, tumor necrosis factor (TNF)-α, and interleukin (IL)-6 in the stroma vascular fraction, suggesting that this drug reduces the M1 proinflammatory state in ATMs, as an initial effect, in turn reducing the circulating levels of TNF-α and IL-6, and initiating an improvement in insulin signaling and sensitivity. After 14 days of drug administration, there was a marked improvement in glucose tolerance; a reduction in insulin resistance; a reduction in macrophage infiltration in adipose tissue and in TNF-α, IL-6, and free fatty acids; accompanied by an improvement in insulin signaling in liver, muscle, and adipose tissue; and also a decrease in insulin receptor substrate-1 Ser307 phosphorylation in JNK and inhibitor of NF-κB kinase (IKKβ) activation in these tissues. CONCLUSIONS Treatment with PD153035 improves glucose tolerance, insulin sensitivity, and signaling and reduces subclinical inflammation in HFD-fed mice.

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EGFR Tyrosine Kinase Inhibitor (PD153035) Improves Glucose Tolerance and Insulin Action in High-Fat Diet–Fed Mice

Patricia O. Prada Eduardo R. Ropelle Rosa H. Mour ao Claudio T. de Souza Jose R. Pauli Dennys E. Cintra Andre Schenka Silvana A. Rocco Roberto Rittner Kleber G. Franchini Jose Vassallo Lcio A. Velloso Jose B. Carvalheira Mario J.A. Saad OBJECTIVE-In obesity, an increased macrophage infiltration in adipose tissue occurs, contributing to low-grade inflammation and insulin resistance. Epidermal growth factor receptor (EGFR) mediates both chemotaxis and proliferation in monocytes and macrophages. However, the role of EGFR inhibitors in this subclinical inflammation has not yet been investigated. We investigated, herein, in vivo efficacy and associated molecular mechanisms by which PD153035, an EGFR tyrosine kinase inhibitor, improved diabetes control and insulin action. RESEARCH DESIGN AND METHODS-The effect of PD153035 was investigated on insulin sensitivity, insulin signaling, and c-Jun NH2-terminal kinase (JNK) and nuclear factor (NF)-B activity in tissues of high-fat diet (HFD)-fed mice and also on infiltration and the activation state of adipose tissue macrophages (ATMs) in these mice. RESULTS-PD153035 treatment for 1 day decreased the protein expression of inducible nitric oxide synthase, tumor necrosis factor (TNF)-, and interleukin (IL)-6 in the stroma vascular fraction, suggesting that this drug reduces the M1 proinflammatory state in ATMs, as an initial effect, in turn reducing the circulating levels of TNF- and IL-6, and initiating an improvement in insulin signaling and sensitivity. After 14 days of drug administration, there was a marked improvement in glucose tolerance; a reduction in insulin resistance; a reduction in macrophage infiltration in adipose tissue and in TNF-, IL-6, and free fatty acids; accompanied by an improvement in insulin signaling in liver, muscle, and adipose tissue; and also a decrease in insulin receptor substrate-1 Ser307 phosphorylation in JNK and inhibitor of NF-B kinase (IKK) activation in these tissues. CONCLUSIONS-Treatment with PD153035 improves glucose tolerance, insulin sensitivity, and signaling and reduces subclinical inflammation in HFD-fed mice. Diabetes 58:2910-2919, 2009 - Erosine kinase inhibitors are used in the clinic to pidermal growth factor receptor (EGFR) tytreat malignancies (1). It has recently been observed that a modest number of patients, suffering from both malignancies and type 2 diabetes, were successfully treated not only for their malignancies but also for diabetes when given some tyrosine kinase inhibitors (25). However, the molecular mechanisms that account for the effect of these drugs on insulin action and glucose metabolism are unknown. Insulin stimulates a signaling network composed of a number of molecules, initiating the activation of insulin receptor tyrosine kinase and phosphorylation of insulin receptor substrates, including insulin receptor substrate (IRS)-1 and IRS-2 (6 8). Following tyrosine phosphorylation, IRS-1/IRS-2 bind and activate the enzyme phosphatidylinositol 3-kinase (PI3-K). The activation of PI3-K increases serine phosphorylation of Akt, which is responsible for most of the metabolic actions of insulin, such as glucose transport, lipogenesis, and glycogen synthesis (7,8). In the most prevalent forms of insulin resistance, dietinduced obesity, and type 2 diabetes, there is a downregulation in this signaling pathway in insulin-sensitive tissues, parallel to a state of chronic low-grade inflammation (6). Several serine/threonine kinases are activated by inflammatory or stressful stimuli and contribute to inhibition of insulin signaling, including c-Jun NH2-terminal kinase (JNK) (9 13) and inhibitor of nuclear factor (NF)-B kinase (IKK) (12,14). In obesity, an increased macrophage infiltration in adipose tissue occurs, contributing to this low-grade inflammation (1517), which has an important role in the increased tissue production of proinflammatory molecules and acute-phase proteins associated with obesity (13,14). EGFR has been described in monocytes and in macrophages and mediates both chemotaxis and proliferation in macrophages (18 20). However, the role of EGFR inhibitors on this subclinical inflammation of obesity was not yet investigated. PD153035 has been shown to possess highly potent and selectively inhibitory activity against EGFR tyrosine kinase and rapidly suppresses autophosphorylation of EGFR at low nanomolar concentrations in fibroblasts and human epidermoid carcinoma cells, as well as selectively blocking EGF-mediated cellular processes, including mitogenesis and early gene expression (2123). In addition, PD153035 has been shown to reduce JNK and IKK/IB/ NF-B pathways (24,25). Moreover, EGFR and other tyrosine kinase inhibitors have also been shown to inhibit the growth of monocyte/macrophages, suggesting possible mechanisms to improve insulin action (26 29). Herein, we investigated the in vivo efficacy and associated molecular mechanisms by which PD153035, an EGFR tyrosine kinase inhibitor, imp (...truncated)


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Patricia O. Prada, Eduardo R. Ropelle, Rosa H. Mourão, Claudio T. de Souza, Jose R. Pauli, Dennys E. Cintra, André Schenka, Silvana A. Rocco, Roberto Rittner, Kleber G. Franchini, José Vassallo, Lício A. Velloso, José B. Carvalheira, Mario J.A. Saad. EGFR Tyrosine Kinase Inhibitor (PD153035) Improves Glucose Tolerance and Insulin Action in High-Fat Diet–Fed Mice, Diabetes, 2009, pp. 2910-2919, 58/12, DOI: 10.2337/db08-0506