Cbl-b is a critical regulator of macrophage activation associated with obesity-induced insulin resistance in mice.
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.
Department of Nutritional Physiology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
Tomoki
T
Abe
Katsuya
K
Hirasaka
Sachiko
S
Kagawa
Shohei
S
Kohno
Arisa
A
Ochi
Kenro
K
Utsunomiya
Atsuko
A
Sakai
Ayako
A
Ohno
Shigetada
S
Teshima-Kondo
Yuushi
Y
Okumura
Motoko
M
Oarada
Yoichi
Y
Maekawa
Junji
J
Terao
Edward M
EM
Mills
Takeshi
T
Nikawa
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology; D008262:Macrophage Activation / Q000235:genetics / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D009765:Obesity / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology*; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction
D048868:Adaptor Proteins, Signal Transducing; C118387:Cblb protein, mouse; D016328:NF-kappa B; D050721:Proto-Oncogene Proteins c-cbl