ArticleNature medicine2012
Fetuin-A acts as an endogenous ligand of TLR4 to promote lipid-induced insulin resistance.
Article in Nature medicine, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 465 papers, 6 of them syntheses that pooled it.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
465 citing papers in PubMed, 6 syntheses or guidelines pooled it, 897 citations in OpenAlex.
- Pooled it
- Alterations in the Plasma Protein Expression Pattern in Congenital Analbuminemia-A Systematic Review.Biomolecules · 2023Pooled it
- Relationship ofCanadian journal of gastroenterology & hepatology · 2023Pooled it
- Contribution of Liver and Pancreatic Islet Crosstalk to β-Cell Function/Dysfunction in the Presence of Fatty Liver.Frontiers in endocrinology · 2022Pooled it
- Personalized Dietary Recommendations Based on Lipid-Related Genetic Variants: A Systematic Review.Frontiers in nutrition · 2022Pooled it
- Saturated fatty acid biomarkers and risk of cardiometabolic diseases: A meta-analysis of prospective studies.Frontiers in nutrition · 2022Pooled it
- Evaluation of chemerin, fetuin-A, interleukin-34, and interleukin-13 levels following periodontal treatment in diabetes mellitus.Clinical oral investigations · 2025Trial
- Organokines and liver enzymes in adolescent girls with polycystic ovary syndrome during randomized treatments.Frontiers in endocrinology · 2024Trial
- Fetuin-B, a potential link of liver-adipose tissue cross talk during diet-induced weight loss-weight maintenance.Nutrition & diabetes · 2021Trial
- NDRG1-PTEN association modulates PTEN C-terminal tail phosphorylation in insulin-resistant neurons.Molecular and cellular biochemistry · 2026Article
- Key Hepatokines Linking MASLD and Type 2 Diabetes: From Pathophysiological Mechanisms to Therapeutic Modulation.International journal of molecular sciences · 2026Review
- Free Fatty Acids Carried by Lipoproteins: Revisiting the Overlooked Cargo.Acta physiologica (Oxford, England) · 2026Review
- Trained immunity: New insights into pathogenesis and therapeutic targets in diabetes and diabetic complications.Genes & diseases · 2026Review
- Biochemically Constrained Multi-Omics Integration Reveals Protein-Metabolite Dependencies Across Diseases.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- HFpEF and MASLD: converging mechanisms and clinical implications.Nature reviews. Cardiology · 2026Review
- Review
- When the Liver Flares: Inflammatory and Immunometabolic Mechanisms Driving the Transition from MASLD to MASH.Inflammation · 2026Review
- Iron overload in steatotic hepatocytes drives systemic metabolic dysfunction via alterations in hepatokine production.The Journal of clinical investigation · 2026Article
- Metabolic Dysfunction-Associated Steatotic Liver Disease as a Systemic Driver of Heart Failure With Preserved Ejection Fraction: Mechanistic Insights and Emerging Therapeutic Perspectives.Reviews in cardiovascular medicine · 2026Review
- Article
405 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
9 authors at 6 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Toll-like receptor 4 (TLR4) has a key role in innate immunity by activating an inflammatory signaling pathway. Free fatty acids (FFAs) stimulate adipose tissue inflammation through the TLR4 pathway, resulting in insulin resistance. However, current evidence suggests that FFAs do not directly bind to TLR4, but an endogenous ligand for TLR4 remains to be identified. Here we show that fetuin-A (FetA) could be this endogenous ligand and that it has a crucial role in regulating insulin sensitivity via Tlr4 signaling in mice. FetA (officially known as Ahsg) knockdown in mice with insulin resistance caused by a high-fat diet (HFD) resulted in downregulation of Tlr4-mediated inflammatory signaling in adipose tissue, whereas selective administration of FetA induced inflammatory signaling and insulin resistance. FFA-induced proinflammatory cytokine expression in adipocytes occurred only in the presence of both FetA and Tlr4; removing either of them prevented FFA-induced insulin resistance. We further found that FetA, through its terminal galactoside moiety, directly binds the residues of Leu100-Gly123 and Thr493-Thr516 in Tlr4. FFAs did not produce insulin resistance in adipocytes with mutated Tlr4 or galactoside-cleaved FetA. Taken together, our results suggest that FetA fulfills the requirement of an endogenous ligand for TLR4 through which lipids induce insulin resistance. This may position FetA as a new therapeutic target for managing insulin resistance and type 2 diabetes.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.