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Hematopoietic Cell-Specific Deletion of Toll-like Receptor 4 Ameliorates Hepatic and Adipose Tissue Insulin Resistance in High-Fat-Fed Mice
Open accessAbstract
Chronic low-grade inflammation, particularly in adipose tissue, is an important modulator of obesity-induced insulin resistance. The Toll-like receptor 4 (Tlr4) is a key initiator of inflammatory responses in macrophages. We performed bone marrow transplantation (BMT) of Tlr4lps-del or control C57Bl/10J donor cells into irradiated wild-type C57Bl6 recipient mice to generate hematopoietic cell-specific Tlr4 deletion mutant (BMT-Tlr4(-/-)) and control (BMT-WT) mice. After 16 weeks of a high-fat diet (HFD), BMT-WT mice developed obesity, hyperinsulinemia, glucose intolerance, and insulin resistance. In contrast, BMT-Tlr4(-/-) mice became obese but did not develop fasting hyperinsulinemia and had improved hepatic and adipose insulin sensitivity during euglycemic clamp studies, compared to HFD BMT-WT controls. HFD BMT-Tlr4(-/-) mice also showed markedly reduced adipose tissue inflammatory markers and macrophage content. In summary, our results indicate that Tlr4 signaling in hematopoietic-derived cells is important for the development of hepatic and adipose tissue insulin resistance in obese mice.
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“A number of studies have shown that TLR-4 deficient mice are not protected from diet-induced obesity, but are protected from obesity-induced insulin resistance [74,76,77].”
From Macrophage polarization: an opportunity for improved outcomes in biomaterials and regenerative medicine (2012) · cites this paper as [77]
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Tsukumo, D. M. L., Carvalho-Filho, M. A., Carvalheira, J. B. C., Prada, P. O., Hirabara, S. M., Schenka, A. A., Araújo, E. P., Vassallo, J., Curi, R., Velloso, L. A., et al. (2007) · Diabetes · doi:10.2337/db06-1595 · Cited by 826 · cited 12×
“These findings are comparable to the results of Tsukomo et al. (2007).”
BackgroundInfluentialRetractedA SIMPLE METHOD FOR THE ISOLATION AND PURIFICATION OF TOTAL LIPIDES FROM ANIMAL TISSUES
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MethodA RAPID METHOD OF TOTAL LIPID EXTRACTION AND PURIFICATION
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MethodObesity is associated with macrophage accumulation in adipose tissue
Weisberg, S. P., McCann, D., Desai, M., Rosenbaum, M., Leibel, R. L., & Ferrante, A. W. (2003) · Journal of Clinical Investigation · doi:10.1172/jci200319246 · Cited by 10,041 · cited 5×
“It is likely that the reduced expression of TNF-a is directly related to the reduced macrophage infiltration, as macrophages are the primary source of TNF-a in obese adipose tissue (Weisberg et al., 2003; Xu et al., 2003).”
BackgroundInfluentialDefective LPS Signaling in C3H/HeJ and C57BL/10ScCr Mice: Mutations in Tlr4 Gene
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“Hematopoietic Deletion of Tlr4 Does Affect Peripheral Lineage Distributions To generate mice with a complete knockout of Tlr4 in macrophages and other immune cells, we transplanted irradiated wild-type (WT) C57BL6 mice with bone marrow from Tlr4 (Poltorak et al., 1998) or WT C57BL/10J mice.”
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BackgroundInfluentialTLR4 links innate immunity and fatty acid-induced insulin resistance
Shi, H., Kokoeva, M. V., Inouye, K., Tzameli, I., Yin, H., & Flier, J. S. (2006) · Journal of Clinical Investigation · doi:10.1172/jci28898 · Cited by 3,690 · cited 13×
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“This possibility is consistent with findings from recent studies, which have shown that deletion of toll-like receptor 4 (Tlr4) in hematopoietic cells abrogates HF dietassociated inflammation in liver and adipose tissue [29], and that liver damage due to adoptive transfer of immature myeloid cells (CD11bLy6CLy6G(2)) f…”
ResultMacrophage deletion of Noc4l triggers endosomal TLR4/TRIF signal and leads to insulin resistance
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“Results indicated that TLR4 signalling in hematopoietic derived cells is important for the development of hepatic and adipose tissue insulin resistance in obese mice (Saberi et al. 2009).”
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“Second, previous studies demonstrating TLR4-specific activation of inflammation by HF diets used mice lacking TLR4 globally (7) or in bone marrow cells (8), leaving open the possibility that cells other than macrophages could have contributed to the exacerbated inflammation and systemic insulin resistance.”
BackgroundInfluentialTargeting Regulation of Macrophage to Treat Metabolic Disease: Role of Phytochemicals
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“이와 같은 결과는 조혈세포의 TLR4 신호전달이 비만 마우스에서 인슐린 저항 성 발현에 중요하다는 점을 제시해 준다.(122) 한편 TLR4 유전”
Obesity and Insulin Resistance Are the Central Issues in Prevention of and Care for Comorbidities
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BackgroundDietary Fat Inflames CD4 + T Cell Memory in Obesity
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“Saberi et al.10 reported that deletion of the TLR-4 gene protects mice from development of insulin resistance secondary to high-fat feeding and obesity, with a concomitant reduction in macrophage infiltration into adipose tissue.”
BackgroundInfluentialObesity, Insulin Resistance, and Inflammaging
Itariu, B. K., & Stulnig, T. M. (2013) · Elsevier eBooks · doi:10.1016/b978-0-12-397803-5.00013-7 · Cited by 5
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Uncoupling Obesity from Cancer: Bromodomain Co-regulators That Control Inflammatory Networks
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Role of the Immune System in Obesity-Associated Inflammation and Insulin Resistance
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CCL26 and CXCL12 preserve insulin-sensitizing macrophages in subcutaneous adipose tissue in obesity
Jeelani, I., da Cunha, F. F., Rohm, T. V., Nasamran, C. A., Wang, L., Moon, J.-S., Prakash, S., Oswari, J., Isaac, R., Murphy, C., et al. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.116450 · Cited by 3
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Toll-like Receptor 4 Contributes to PCOS-like Metabolic and Reproductive PathogenesisPreprint
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“Prior research has established TLR4 contributes to high-fat diet-induced metabolic dysfunction through endogenous lipid activation, adipose tissue inflammation, obesity, and insulin resistance( 42 – 46 ).”
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Adipose Tissue and Immuno-Metabolic Regulation
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Expression of adipocyte/macrophage fatty acid binding protein promotes tumor growth and metastasis.
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Metadata
- Authors
- Saberi, M., Woods, N.-B., de Luca, C., Schenk, S., Lu, J. C., Bandyopadhyay, G., Verma, I. M., & Olefsky, J. M.
- Affiliations
- University of California San Diego (US)
- Salk Institute for Biological Studies (US)
- Corresponding author
- Olefsky, Jerrold M.
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2009-11
- Volume
- 10
- Issue
- 5
- Pages
- 419-429
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC2790319
- OpenAlex
- W2010911569
- Cited by
- 456
- References
- 26
- Citations by year
- 2026: 14 · 2025: 17 · 2024: 15 · 2023: 11 · 2022: 17 · 2021: 20 · 2020: 27 · 2019: 21 · 2018: 35 · 2017: 24 · 2016: 28 · 2015: 35 · 2014: 34 · 2013: 60 · 2012: 46
- FWCI
- 22.03
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Funders
- Lustgarten Foundation
- National Institutes of Health (DK033651, T32 DK 007494, DK074868, U54 HD 012303-25)
- Ellison Medical Foundation
- Fondation Leducq
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- TLR4, insulin resistance, obesity, high-fat diet, bone marrow transplantation, hepatic insulin sensitivity, adipose tissue inflammation, macrophages, low-grade inflammation, hyperinsulinemia, impaired glucose tolerance
- MeSH terms
- Adipose Tissue, Animals, Dietary Fats, Hematopoietic Stem Cells, Insulin Resistance, Liver, Macrophages, Mice, Obese, Obesity, Organ Specificity, Glucose Clamp Technique, Signal Transduction, Glucose Intolerance, Toll-Like Receptor 4, Mice, Gene Knockout Techniques
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