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ID 106157
Title Alternative
Cbl-bは、マウスにおいて肥満によるインスリン抵抗性を引き起こすマクロファージ活性化の重要な調節因子である
Cbl-b DEFICIENCY AND MACROPHAGE ACTIVATION
Author
Abe, Tomoki The University of Tokushima KAKEN Search Researchers
Hirasaka, Katsuya The University of Tokushima KAKEN Search Researchers
Kagawa, Sachiko The University of Tokushima
Kohno, Shohei The University of Tokushima
Ochi, Arisa The University of Tokushima
Utsunomiya, Kenro The University of Tokushima
Sakai, Atsuko The University of Tokushima
Ohno, Ayako The University of Tokushima KAKEN Search Researchers
Okumura, Yuushi The University of Tokushima KAKEN Search Researchers
Oarada, Motoko The University of Chiba
Maekawa, Yoichi The University of Tokushima
Mills, Edward M. University of Texas at Austin
Content Type
Thesis or Dissertation
Description
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.
Journal Title
Diabetes
ISSN
00121797
1939327X
NCID
AA00628057
AA12037590
Publisher
American Diabetes Association
Volume
62
Issue
6
Start Page
1957
End Page
1969
Published Date
2013-06-01
Remark
内容要旨・審査要旨・論文本文の公開:
内容要旨・審査要旨 : LID201405161003.pdf
論文本文 : k2676_fulltext.pdf
著者の申請により要約(2014-07-24公開)に替えて論文全文を公開(2020-03-13)
本論文は, 著者Tomoki Abeの学位論文として提出され, 学位審査・授与の対象となっている。
Rights
© 2013 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
EDB ID
DOI (Published Version)
URL ( Publisher's Version )
FullText File
language
eng
TextVersion
ETD
MEXT report number
甲第2676号
Diploma Number
甲栄第210号
Granted Date
2014-03-24
Degree Name
Doctor of Nutritional Science
Grantor
Tokushima University
departments
Medical Sciences