Lipid-induced insulin resistance mediated by the proinflammatory receptor TLR4 requires saturated fatty acid–induced ceramide biosynthesis in mice
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Obesity is associated with an enhanced inflammatory response that exacerbates insulin resistance and contributes to diabetes, atherosclerosis, and cardiovascular disease. One mechanism accounting for the increased inflammation associated with obesity is activation of the innate immune signaling pathway triggered by TLR4 recognition of saturated fatty acids, an event that is essential for lipid-induced insulin resistance. Using in vitro and in vivo systems to model lipid induction of TLR4-dependent inflammatory events in rodents, we show here that TLR4 is an upstream signaling component required for saturated fatty acid-induced ceramide biosynthesis. This increase in ceramide production was associated with the upregulation of genes driving ceramide biosynthesis, an event dependent of the activity of the proinflammatory kinase IKKβ. Importantly, increased ceramide production was not required for TLR4-dependent induction of inflammatory cytokines, but it was essential for TLR4-dependent insulin resistance. These findings suggest that sphingolipids such as ceramide might be key components of the signaling networks that link lipid-induced inflammatory pathways to the antagonism of insulin action that contributes to diabetes.
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“Ectopic lipid deposition has also been linked to cellular stress responses and apoptosis via increased lipid metabolism.[ 48 ]”
From Pathogenesis of sarcopenia and the relationship with fat mass: descriptive review (2022) · cites this paper as [48]
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- Authors
- Holland, W. L., Bikman, B. T., Wang, L.-P., Yuguang, G., Sargent, K. M., Bulchand, S., Knotts, T. A., Shui, G., Clegg, D. J., Wenk, M. R., Pagliassotti, M. J., Scherer, P. E., & Summers, S. A.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- National University of Singapore (SG)
- Duke University (US)
- University of Utah (US)
- United States Department of Agriculture (US)
- Agricultural Research Service (US)
- Colorado State University (US)
- Corresponding author
- Summers, Scott A.
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2011-05-02
- Volume
- 121
- Issue
- 5
- Pages
- 1858-1870
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC3083776
- OpenAlex
- W2133966719
- Cited by
- 705
- References
- 70
- Citations by year
- 2026: 22 · 2025: 28 · 2024: 39 · 2023: 44 · 2022: 50 · 2021: 43 · 2020: 48 · 2019: 46 · 2018: 48 · 2017: 54 · 2016: 50 · 2015: 51 · 2014: 44 · 2013: 60 · 2012: 67
- FWCI
- 23.48
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- National University of Singapore (submittedVersion)
- Funders
- Duke-NUS Medical School
- Agency for Science, Technology and Research
- National University of Singapore
- Ministry of Education, India
- National Institutes of Health (1tl1dk081181-01)
- Medical Research Council
- National Medical Research Council
- National Institute of Diabetes and Digestive and Kidney Diseases (TL1-DK081181, R01DK055758, R01DK081456, P01DK088761, F32DK083866)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- insulin resistance, TLR4, saturated fatty acids, ceramide biosynthesis, sphingolipids, obesity, inflammation, IKKβ, innate immune signaling, inflammatory cytokines, diabetes mellitus, lipid signaling
- MeSH terms
- Animals, Ceramides, Diabetes Mellitus, Experimental, Fatty Acids, Glucose, Hyperlipidemias, Inflammation, Insulin Resistance, Lipids, Male, Mice, Inbred BALB C, Mice, Inbred C57BL, Obesity, Glycine max, Sphingolipids, Cytokines, Rats, Sprague-Dawley, I-kappa B Proteins, Toll-Like Receptor 4, Mice, Rats
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