EGFR tyrosine kinase inhibitor (PD153035) improves glucose tolerance and insulin action in high-fat diet-fed mice.
EGFR tyrosine kinase inhibitor (PD153035) improves glucose tolerance and insulin action in high-fat diet-fed mice.
复制标题
作者：
Prada PO;Ropelle ER;Mourão RH;de Souza CT;Pauli JR;Cintra DE;Schenka A;Rocco SA;Rittner R;Franchini KG;Vassallo J;Velloso LA;Carvalheira JB;Saad MJ
在肥胖症中，脂肪组织中的巨噬细胞浸润增加，导致低度炎症和胰岛素抵抗。表皮生长因子受体（EGFR）介导单核细胞和巨噬细胞的趋化性和增殖。然而，EGFR抑制剂在这种亚临床炎症中的作用尚未研究。我们在此研究了EGFR酪氨酸激酶抑制剂PD 153035改善糖尿病控制和胰岛素作用的体内疗效和相关分子机制。研究了PD 153035对高脂饮食（HFD）喂养小鼠组织中胰岛素敏感性、胰岛素信号传导和c-Jun NH 2-末端激酶（JNK）和核因子（NF）-κB活性的影响，以及对这些小鼠脂肪组织巨噬细胞（ATM）浸润和活化状态的影响。PD 153035治疗1天可降低基质血管部分中诱导型一氧化氮合酶、肿瘤坏死因子（TNF）-α和白细胞介素（IL）-6的蛋白表达，表明该药物可降低ATM中的M1促炎状态，作为初始效应，进而降低TNF-α和IL-6的循环水平，并开始改善胰岛素信号传导和敏感性。给药14天后，葡萄糖耐量显著改善;胰岛素抵抗减轻;脂肪组织中巨噬细胞浸润以及TNF-α、IL-6和游离脂肪酸减少;同时肝脏、肌肉和脂肪组织中胰岛素信号传导改善;并降低JNK和NF-κB激酶抑制剂（IKKβ）的胰岛素受体底物1 Ser 307磷酸化。PD 153035治疗改善了HFD喂养小鼠的葡萄糖耐量、胰岛素敏感性和信号传导，并减少了亚临床炎症。
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. 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. 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. Treatment with PD153035 improves glucose tolerance, insulin sensitivity, and signaling and reduces subclinical inflammation in HFD-fed mice.
登录
查看更多内容
影响因子：
7.7
作者：
Carvalho, MA;Ueno, M;Saad, MJA
通讯作者：
Saad, MJA
影响因子：
3.9
作者：
Normanno, N;De Luca, A;Pinto, A
通讯作者：
Pinto, A
影响因子：
7.7
作者：
Jiao, Ping;Chen, Qiu;Shah, Suketu;Du, Jing;Tao, Bo;Tzameli, Iphigenia;Yan, Weiqun;Xu, Haiyan
通讯作者：
Xu, Haiyan
影响因子：
56.9
作者：
FRY, DW;KRAKER, AJ;BRIDGES, AJ
通讯作者：
BRIDGES, AJ
影响因子：
12.8
作者：
Cheon, HyeonJoo;Woo, Young-Seok;Sohn, Jeongwon
通讯作者：
Sohn, Jeongwon