Abstract

Objective: In obesity, an increased macrophage infiltration in adipose tissue occurs, contributing to the 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 on this subclinical inflammation was not yet 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.

Materials and Methods The effect of PD153035 was investigated on insulin sensitivity, insulin signaling and JNK and NF-κB activity in tissues of high-fat diet-fed mice, and also on infiltration and the activation state of adipose tissue macrophage (ATM) in these mice.

Results: PD153035 treatment for 1 day decreased the protein expression of iNOS, TNF-α and IL-6 in the stroma vascular fraction, suggesting that this drug reduces the M1 proinflammatory state in ATM, as an initial effect, in turn reducing the circulating levels of TNF-α and IL-6 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 FFAs, accompanied by an improvement in insulin signaling in liver, muscle and adipose tissue, and also a decrease in IRS-1 Ser³⁰⁷ phosphorylation, in JNK and IKKβ activation in these tissues

Conclusion: Treatment with PD153035 improves glucose tolerance, insulin sensitivity and signaling and reduces subclinical inflammation in HFD mice.