Cbl-b is a critical regulator of macrophage activation associated with obesity-induced insulin resistance in mice.
Cbl-b is a critical regulator of macrophage activation associated with obesity-induced insulin resistance in mice.
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作者：
Abe T;Hirasaka K;Kagawa S;Kohno S;Ochi A;Utsunomiya K;Sakai A;Ohno A;Teshima-Kondo S;Okumura Y;Oarada M;Maekawa Y;Terao J;Mills EM;Nikawa T
我们之前报道了casitas b细胞淋巴瘤-b （Cbl-b）在衰老相关小鼠胰岛素抵抗中的潜在参与。由于肥胖也诱导巨噬细胞募集到脂肪组织，我们在这里阐明了Cbl-b在肥胖相关胰岛素抵抗中的作用。给Cbl-b+/+和Cbl-b - / -小鼠喂食高脂肪饮食（HFD），然后检测与肥胖相关的胰岛素信号变化。与Cbl-b+/+小鼠相比，HFD引起巨噬细胞向脂肪组织募集，并增加了Cbl-b−/−小鼠的炎症反应。采用Cbl-b - / -小鼠腹腔巨噬细胞和过表达Cbl-b的RAW264.7巨噬细胞，研究饱和脂肪酸（FAs）对巨噬细胞活化的直接影响。在巨噬细胞中，Cbl-b通过泛素化和TLR4降解抑制饱和fa诱导的toll样受体4 （TLR4）信号传导。通过骨髓移植和一种TLR4拮抗剂Eritoran，研究了Cbl-b在体内的生理作用。造血细胞特异性的Cbl-b基因缺失导致胰岛素和葡萄糖耐量试验反应紊乱。itoran阻断TLR4信号通路可降低肥胖Cbl-b - / -小鼠的空腹血糖和血清白介素-6水平。这些结果表明，Cbl-b缺乏可通过饱和fa介导的巨噬细胞活化，加重hfd诱导的胰岛素抵抗。因此，抑制TLR4信号是治疗肥胖相关胰岛素抵抗的一种有吸引力的治疗策略。
We previously reported the potential involvement of casitas B-cell lymphoma-b (Cbl-b) in aging-related murine insulin resistance. Because obesity also induces macrophage recruitment into adipose tissue, we elucidated here the role of Cbl-b in obesity-related insulin resistance. Cbl-b+/+ and Cbl-b−/− mice were fed a high-fat diet (HFD) and then examined for obesity-related changes in insulin signaling. The HFD caused recruitment of macrophages into adipose tissue and increased inflammatory reaction in Cbl-b−/− compared with Cbl-b+/+ mice. Peritoneal macrophages from Cbl-b−/− mice and Cbl-b–overexpressing RAW264.7 macrophages were used to examine the direct effect of saturated fatty acids (FAs) on macrophage activation. In macrophages, Cbl-b suppressed saturated FA-induced Toll-like receptor 4 (TLR4) signaling by ubiquitination and degradation of TLR4. The physiological role of Cbl-b in vivo was also examined by bone marrow transplantation and Eritoran, a TLR4 antagonist. Hematopoietic cell-specific depletion of the Cbl-b gene induced disturbed responses on insulin and glucose tolerance tests. Blockade of TLR4 signaling by Eritoran reduced fasting blood glucose and serum interleukin-6 levels in obese Cbl-b−/− mice. These results suggest that Cbl-b deficiency could exaggerate HFD-induced insulin resistance through saturated FA-mediated macrophage activation. Therefore, inhibition of TLR4 signaling is an attractive therapeutic strategy for treatment of obesity-related insulin resistance.
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影响因子：
4.8
作者：
Medvedev, Andrei E.;Piao, Wenji;Vogel, Stefanie N.
通讯作者：
Vogel, Stefanie N.
影响因子：
7.7
作者：
Lee YS;Li P;Huh JY;Hwang IJ;Lu M;Kim JI;Ham M;Talukdar S;Chen A;Lu WJ;Bandyopadhyay GK;Schwendener R;Olefsky J;Kim JB
通讯作者：
Kim JB
DOI：
10.1016/j.bbamcr.2004.09.013
发表时间：
2005-03-22
影响因子：
5.1
作者：
Hirasaka, K;Nikawa, T;Kishi, K
通讯作者：
Kishi, K
影响因子：
4.4
作者：
Gustin, Sonja E.;Thien, Christine B. F.;Langdon, Wallace Y.
通讯作者：
Langdon, Wallace Y.
肿瘤坏死因子-α的脂肪表达--在与肥胖相关的胰岛素抵抗中的直接作用
影响因子：
56.9
作者：
HOTAMISLIGIL, GS;SHARGILL, NS;SPIEGELMAN, BM
通讯作者：
SPIEGELMAN, BM