Cbl-b Is a Critical Regulator of Macrophage Activation Associated With Obesity-Induced Insulin Resistance in Mice

被引：36

作者：

Abe, Tomoki ^{[1
]}

Hirasaka, Katsuya ^{[1
]}

Kagawa, Sachiko ^{[1
]}

Kohno, Shohei ^{[1
]}

Ochi, Arisa ^{[1
]}

Utsunomiya, Kenro ^{[1
]}

Sakai, Atsuko ^{[1
]}

Ohno, Ayako ^{[1
]}

Teshima-Kondo, Shigetada ^{[1
]}

Okumura, Yuushi ^{[1
]}

Oarada, Motoko ^{[2
]}

Maekawa, Yoichi ^{[3
]}

Terao, Junji ^{[4
]}

Mills, Edward M. ^{[5
]}

Nikawa, Takeshi ^{[1
]}

机构：

[1] Univ Tokushima, Dept Nutr Physiol, Inst Hlth Biosci, Grad Sch, Tokushima 770, Japan

[2] Chiba Univ, Med Mycol Res Ctr, Chiba, Japan

[3] Univ Tokushima, Dept Immunol & Parasitol, Inst Hlth Biosci, Grad Sch, Tokushima 770, Japan

[4] Univ Tokushima, Dept Food Sci, Inst Hlth Biosci, Grad Sch, Tokushima 770, Japan

[5] Univ Texas Austin, Coll Pharm, Austin, TX 78712 USA

来源：

DIABETES | 2013年 / 62卷 / 06期

关键词：

E3 UBIQUITIN LIGASE; NF-KAPPA-B; ADIPOSE-TISSUE; INFLAMMATORY CHANGES; NEGATIVE REGULATOR; EXPRESSION; DEGRADATION; ADIPOCYTES; RESPONSES; MYD88;

D O I：

10.2337/db12-0677

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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 Cb1-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 ubiquitinadon 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.

引用

页码：1957 / 1969

页数：13

共 41 条

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