Hepatocyte Toll-like receptor 4 regulates obesity-induced inflammation and insulin resistance
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Chronic low-grade inflammation is a hallmark of obesity and thought to contribute to the development of obesity-related insulin resistance. Toll-like receptor 4 (Tlr4) is a key mediator of pro-inflammatory responses. Mice lacking Tlr4s are protected from diet-induced insulin resistance and inflammation; however, which Tlr4-expressing cells mediate this effect is unknown. Here we show that mice deficient in hepatocyte Tlr4 (Tlr4LKO) exhibit improved glucose tolerance, enhanced insulin sensitivity and ameliorated hepatic steatosis despite the development of obesity after a high-fat diet (HFD) challenge. Furthermore, Tlr4LKO mice have reduced macrophage content in white adipose tissue, as well as decreased tissue and circulating inflammatory markers. In contrast, the loss of Tlr4 activity in myeloid cells has little effect on insulin sensitivity. Collectively, these data indicate that the activation of Tlr4 on hepatocytes contributes to obesity-associated inflammation and insulin resistance, and suggest that targeting hepatocyte Tlr4 might be a useful therapeutic strategy for the treatment of type 2 diabetes.
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Microbiota-associated molecular patterns such as bacterial lipopolysaccharide accumulate in the portal vein and act as ligands for TLR2 and TLR4, activating pro-inflammatory pathways that lead to secretion of cytokines and chemokines from various liver cell types including endothelia, myofibroblasts and hepatocytes.
“Microbiota-associated molecular patterns such as bacterial lipopolysaccharide accumulate in the portal vein and have been shown to act as ligands for TLR2 and TLR4. These activate pro-inflammatory pathways leading to secretion of cytokines and chemokines from various cell types in the liver, including endothelia, myofibroblasts and hepatocytes.125,149,150”
From Understanding the cellular interactome of non-alcoholic fatty liver disease (2022) · cites this paper as [149]
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- Authors
- Jia, L., Vianna, C. R., Fukuda, M., Berglund, E. D., Liu, C., Tao, C., Sun, K., Liu, T., Harper, M. J., Lee, C. E., Lee, S., Scherer, P. E., & Elmquist, J. K.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Scherer, Philipp E.
- Elmquist, Joel K.
- ORCID
- Venue
- Nature Communications
- Published
- 2014-05-12
- Volume
- 5
- Issue
- 1
- Pages
- 3878-3878
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC4080408
- OpenAlex
- W2025772141
- Cited by
- 294
- References
- 45
- Citations by year
- 2026: 12 · 2025: 20 · 2024: 13 · 2023: 20 · 2022: 22 · 2021: 40 · 2020: 31 · 2019: 30 · 2018: 39 · 2017: 28 · 2016: 20 · 2015: 13 · 2014: 6
- FWCI
- 16.88
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Nature Communications (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- University of Texas Southwestern Medical Center
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (P01DK088761, RL9DK081180)
- Topics
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diet, Metabolism, and Disease
- Keywords
- TLR4, hepatocytes, obesity, insulin resistance, low-grade inflammation, hepatic steatosis, glucose tolerance, high-fat diet, type 2 diabetes, myeloid cells, tissue-specific knockout mice
- MeSH terms
- Animals, Cells, Cultured, Diabetes Mellitus, Type 2, Enzyme Activation, Fatty Liver, Glucose Tolerance Test, Inflammation, Insulin Resistance, Liver, Macrophages, Mice, Inbred C57BL, Obesity, Mice, Knockout, Hepatocytes, Toll-Like Receptor 4, Mice, Adipose Tissue, White, Diet, High-Fat
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