Loss-of-Function Mutation in Toll-Like Receptor 4 Prevents Diet-Induced Obesity and Insulin Resistance
Open accessAbstract
Obesity is associated with insulin resistance and a state of abnormal inflammatory response. The Toll-like receptor (TLR)4 has an important role in inflammation and immunity, and its expression has been reported in most tissues of the body, including the insulin-sensitive ones. Because it is activated by lipopolysaccharide and saturated fatty acids, which are inducers of insulin resistance, TLR4 may be a candidate for participation in the cross-talk between inflammatory and metabolic signals. Here, we show that C3H/HeJ mice, which have a loss-of-function mutation in TLR4, are protected against the development of diet-induced obesity. In addition, these mice demonstrate decreased adiposity, increased oxygen consumption, a decreased respiratory exchange ratio, improved insulin sensitivity, and enhanced insulin-signaling capacity in adipose tissue, muscle, and liver compared with control mice during high-fat feeding. Moreover, in these tissues, control mice fed a high-fat diet show an increase in IκB kinase complex and c-Jun NH2-terminal kinase activity, which is prevented in C3H/HeJ mice. In isolated muscles from C3H/HeJ mice, protection from saturated fatty acid–induced insulin resistance is observed. Thus, TLR4 appears to be an important mediator of obesity and insulin resistance and a potential target for the therapy of these highly prevalent medical conditions.
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TLR-4 deficient mice are not protected from diet-induced obesity but are protected from obesity-induced insulin resistance.
“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 [76]
Tlr4-knockout mice are protected from lipid- and obesity-induced insulin resistance.
“In line with this, Tlr4-KO mice are protected against lipid-and obesity-induced insulin resistance (116, 117).”
From Insulin sensitivity: Modulation by nutrients and inflammation (2008) · cites this paper as [117]
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- Authors
- 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., & Saad, M. J. A.
- Affiliations
- Universidade Estadual de Campinas (UNICAMP) (BR)
- Department of Internal Medicine, State University of Campinas, Campinas, São Paulo, Brazil
- Universidade de São Paulo (BR)
- Department of Pathology, State University of Campinas, Campinas, São Paulo, Brazil
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2007-08-01
- Volume
- 56
- Issue
- 8
- Pages
- 1986-1998
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2137274603
- Cited by
- 826
- References
- 10
- Citations by year
- 2026: 6 · 2025: 5 · 2024: 9 · 2023: 13 · 2022: 12 · 2021: 25 · 2020: 17 · 2019: 29 · 2018: 22 · 2017: 35 · 2016: 61 · 2015: 82 · 2014: 74 · 2013: 89 · 2012: 94
- FWCI
- 39.77
- Type
- journal article
- Language
- en
- Status
- Retracted
- Open access
- bronze
- doi.org
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- TLR4, loss-of-function mutations, diet-induced obesity, insulin resistance, C3H/HeJ mice, high-fat diet, IκB kinase, c-Jun NH2-terminal kinase, saturated fatty acids, oxygen consumption, respiratory exchange ratio, adiposity
- MeSH terms
- Adipose Tissue, Animals, Animal Feed, Blood Glucose, Body Weight, Dietary Fats, Enzyme Activation, Fatty Acids, Insulin, Insulin Resistance, Liver, Male, Muscles, Mutation, Obesity, Phosphoproteins, Phosphoserine, Triglycerides, Signal Transduction, Microscopy, Electron, Transmission, JNK Mitogen-Activated Protein Kinases, Cell Shape, Toll-Like Receptor 4, Mice, I-kappa B Kinase, Insulin Receptor Substrate Proteins
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