The DOI matches its Crossref record; 48 of the 48 references it cites were found in a registry or an index.
TLR4 links innate immunity and fatty acid-induced insulin resistance
Open accessAbstract
TLR4 is the receptor for LPS and plays a critical role in innate immunity. Stimulation of TLR4 activates proinflammatory pathways and induces cytokine expression in a variety of cell types. Inflammatory pathways are activated in tissues of obese animals and humans and play an important role in obesity-associated insulin resistance. Here we show that nutritional fatty acids, whose circulating levels are often increased in obesity, activate TLR4 signaling in adipocytes and macrophages and that the capacity of fatty acids to induce inflammatory signaling in adipose cells or tissue and macrophages is blunted in the absence of TLR4. Moreover, mice lacking TLR4 are substantially protected from the ability of systemic lipid infusion to (a) suppress insulin signaling in muscle and (b) reduce insulin-mediated changes in systemic glucose metabolism. Finally, female C57BL/6 mice lacking TLR4 have increased obesity but are partially protected against high fat diet-induced insulin resistance, possibly due to reduced inflammatory gene expression in liver and fat. Taken together, these data suggest that TLR4 is a molecular link among nutrition, lipids, and inflammation and that the innate immune system participates in the regulation of energy balance and insulin resistance in response to changes in the nutritional environment.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Activation of inflammation is prevented in macrophages and adipocytes that are deficient in Tlr2, Tlr4, or Tlr2/Tlr4 (105, 114-116).”
From Insulin sensitivity: Modulation by nutrients and inflammation (2008) · cites this paper as [116]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Shi et al. showed that FFA activates TLR4 signaling and that mice lacking TLR4 are partially protected against high fat diet-induced insulin resistance (306).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [306]
Experimental — accuracy not yet measuredIn the citing paper
“For instance, activation of TLR4 via LPS leads to the release of pro-inflammatory cytokines (e.g., TNF, interleukin [IL]-6), but similar effects are also observed if free fatty acids bind to TLR4.63”
From An integrated view of anti-inflammatory and antifibrotic targets for the treatment of NASH (2023) · cites this paper as [63]
In the citing paper
“A number of free fatty acid products released from necrotic adipocytes have been shown to cause pro-inflammatory activation of macrophages through TLR-2 and TLR-4 signaling pathways, suggesting a potential mechanism by which obesity-induced inflammation may occur [73,74].”
From Macrophage polarization: an opportunity for improved outcomes in biomaterials and regenerative medicine (2012) · cites this paper as [74]
In the citing paper
“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 [74]
In the citing paper
“Probiotics intake may improve markers of insulin metabolism and lipid profiles by reducing cytokines and suppressing the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway (Shi et al., 2006) and gut microbiota-short chain fatty acids (SCFA)-hormone axis (Yadav et al., 2013).”
From Effect of Probiotic Supplementation on Cognitive Function and Metabolic Status in Alzheimer's Disease: A Randomized, Double-Blind and Controlled Trial (2016) · cites this paper as Shi et al., 2006
In the citing paper
“Weight loss induced by gastric bypass reduced the circulating concentrations of visfatin (123) and TNF-a (124,125) .”
From Dietary factors and low-grade inflammation in relation to overweight and obesity (2011) · cites this paper as [125]
In the citing paper
“An important component of these fatty acid-induced activation events are the pattern recognition receptors TLR2 and TLR4 (105, 114-116).”
From Insulin sensitivity: Modulation by nutrients and inflammation (2008) · cites this paper as [116]
In the citing paper
“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 [116]
In the citing paper
“Clearly, ATMs exist in a lipid-rich environment and fatty acids can broadly activate the macrophage inflammatory program (105, 114-116).”
From Insulin sensitivity: Modulation by nutrients and inflammation (2008) · cites this paper as [116]
In the citing paper
“Dietary-derived saturated fatty acids [26] and erythrocyte content of saturated fatty acids (indicator of long-term consumption) [27], positively correlate with circulating measures of CRP and can contribute to inflammation by favoring TLR4 signaling in macrophages [67].”
From The menace of obesity to depression and anxiety prevalence (2022) · cites this paper as [67]
In the citing paper
“However, FFAs can also serve as ligands for the TLR4 complex (33), thereby activating the classical inflammatory response in the context of increased local extracellular lipid concentrations, which ultimately drives ATMΦ accumulation (34,35).”
From Adipose tissue remodeling and obesity (2011) · cites this paper as [33]
In the citing paper
“Even though we do not consider AT as a conventional tissue suffering from lipotoxic side effects, either high rates of lipolysis or an influx of saturated FFAs into adipocytes do cause temporary inflammation within the tissue (33).”
From Adipose tissue remodeling and obesity (2011) · cites this paper as [33]
In the citing paper
“TLR4, specifically, has been shown to mediate inflammatory responses to free fatty acids, which are elevated in obesity and are associated with insulin resistance38.”
From Sterile inflammation: sensing and reacting to damage (2010) · cites this paper as [38]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Obesity 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
Xu, H., Barnes, G. T., Yang, Q., Tan, G., Yang, D., Chou, C. J., Sole, J., Nichols, A., Ross, J. S., Tartaglia, L. A., et al. (2003) · Journal of Clinical Investigation · doi:10.1172/jci200319451 · Cited by 6,760
Yamauchi, T., Kamon, J., Waki, H., Terauchi, Y., Kubota, N., Hara, K., Mori, Y., Ide, T., Murakami, K., Tsuboyama-Kasaoka, N., et al. (2001) · Nature Medicine · doi:10.1038/90984 · Cited by 4,915
The hormone resistin links obesity to diabetes
Steppan, C. M., Bailey, S. T., Bhat, S., Brown, E. J., Banerjee, R. R., Wright, C. M., Patel, H. R., Ahima, R. S., & Lazar, M. A. (2001) · Nature · doi:10.1038/35053000 · Cited by 4,755
Toll-like receptors and innate immunity
Medzhitov, R. (2001) · Nature Reviews Immunology · doi:10.1038/35100529 · Cited by 4,308
Inflammation, stress, and diabetes
Wellen, K. E., & Hotamisligil, G. S. (2005) · Journal of Clinical Investigation · doi:10.1172/jci25102 · Cited by 4,143
Mutation of the mouse klotho gene leads to a syndrome resembling ageing
Kuro-o, M., Matsumura, Y., Aizawa, H., Kawaguchi, H., Suga, T., Utsugi, T., Ohyama, Y., Kurabayashi, M., Kaname, T., Kume, E., et al. (1997) · Nature · doi:10.1038/36285 · Cited by 3,837
Hoshino, K., Takeuchi, O., Kawai, T., Sanjo, H., Ogawa, T., Takeda, Y., Takeda, K., & Akira, S. (1999) · The Journal of Immunology · doi:10.4049/jimmunol.162.7.3749 · Cited by 3,374
A central role for JNK in obesity and insulin resistance
Hirosumi, J., Tuncman, G., Chang, L., Görgün, C. Z., Uysal, K. T., Maeda, K., Karin, M., & Hotamisligil, G. S. (2002) · Nature · doi:10.1038/nature01137 · Cited by 3,359
Obesity and insulin resistance
Kahn, B. B., & Flier, J. S. (2000) · Journal of Clinical Investigation · doi:10.1172/jci10842 · Cited by 3,345
Self-citation
Research works printed but not linked: 1
- 10.1172/JCI200525102 · DOI · Paper page
Cited by
Sorted by citations
Items 1,001–1,030 of 1,030
Strekalova, T. V., Evans, M. C., Costa-Nunes, J. P., Бачурин, С. О., Yeritsyan, N., Couch, Y., Steinbusch, H. W. M., Köhler, E., Lesch, K., & Anthony, D. C. (2015) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2015.02.015 · Cited by 82
Intestinal microflora and metabolic diseases
Serino, M., Luche, E., Chabo, C., Amar, J., & Burcelin, R. (2009) · Diabetes & Metabolism · doi:10.1016/j.diabet.2009.03.003 · Cited by 77
The microbiome-gut-brain axis: implications for schizophrenia and antipsychotic induced weight gain
Kanji, S., Fonseka, T. M., Marshe, V. S., Sriretnakumar, V., Hahn, M. K., & Müller, D. J. (2018) · European Archives of Psychiatry and Clinical Neuroscience · doi:10.1007/s00406-017-0820-z · Cited by 79
Green, C. J., Macrae, K., Fogarty, S., Hardie, D. G., Sakamoto, K., & Hundal, H. S. (2011) · Biochemical Journal · doi:10.1042/bj20101517 · Cited by 78
Dietary Oleic Acid Increases M2 Macrophages in the Mesenteric Adipose Tissue
Camell, C., & Smith, C. W. (2013) · PLoS ONE · doi:10.1371/journal.pone.0075147 · Cited by 76
Ding, Y., Li, J., Liu, S., Zhang, L., Xiao, H., Li, J., Chen, H., Petersen, R. B., Huang, K., & Zheng, L. (2014) · International Journal of Obesity · doi:10.1038/ijo.2013.98 · Cited by 76
Van de Velde, L.-A., Subramanian, C., Smith, A. M., Barron, L., Qualls, J. E., Neale, G., Alfonso-Pecchio, A., Jackowski, S., Rock, C. O., Wynn, T. A., et al. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.766238 · Cited by 75
NAFLD and HBV interplay - related mechanisms underlying liver disease progression
Tourkochristou, E., Assimakopoulos, S. F., Thomopoulos, K., Marangos, M., & Triantos, C. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.965548 · Cited by 70
Yin, X., Zheng, F., Pan, Q., Zhang, S., Yu, D., Xu, Z., & Li, H. (2015) · Journal of Molecular Endocrinology · doi:10.1530/jme-15-0101 · Cited by 67
Zhang, Z., Tanaka, I., Pan, Z., Ernst, P. B., Kiyono, H., & Kurashima, Y. (2022) · European Journal of Immunology · doi:10.1002/eji.202149532 · Cited by 69
Luteolin Inhibits Inflammatory Response and Improves Insulin Sensitivity in the Endothelium
Deqiu, Z., Kang, L., Jiali, Y., Baolin, L., & Gaolin, L. (2011) · Biochimie · doi:10.1016/j.biochi.2010.11.002 · Cited by 65
A Balance of Lipid-Sensing Mechanisms in the Brain and Liver
Caspi, L., Wang, P. Y. T., & Lam, T. K. T. (2007) · Cell Metabolism · doi:10.1016/j.cmet.2007.07.005 · Cited by 58
A New Hypothesis for Alzheimer’s Disease: The Lipid Invasion Model
Rudge, J. D. (2022) · Journal of Alzheimer's Disease Reports · doi:10.3233/adr-210299 · Cited by 58
Chen, Q., Lai, S. M., Xu, S., Tan, Y., Leong, K., Liu, D., Tan, J. C., Naik, R. R., Barron, A. M., Adav, S. S., et al. (2021) · The EMBO Reports · doi:10.15252/embr.202152835 · Cited by 56
Tang, L., Okamoto, S., Shiuchi, T., Toda, C., Takagi, K., Sato, T., Saito, K., Yokota, S., & Minokoshi, Y. (2015) · Endocrinology · doi:10.1210/en.2015-1096 · Cited by 55
Role of exercise-induced hepatokines in metabolic disorders
Ennequin, G., Sirvent, P., & Whitham, M. (2019) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00433.2018 · Cited by 54
Pillon, N. J., Arane, K., Bilan, P. J., Chiu, T. T., & Klip, A. (2012) · Cell Communication and Signaling · doi:10.1186/1478-811x-10-30 · Cited by 53
Weight loss prior to lung transplantation is associated with improved survival
Chandrashekaran, S., Keller, C. A., Kremers, W. K., Peters, S. G., Hathcock, M. A., & Kennedy, C. C. (2015) · The Journal of Heart and Lung Transplantation · doi:10.1016/j.healun.2014.11.018 · Cited by 50
Abu Bakar, M. H., Azmi, M. N., Shariff, K. A., & Tan, J. S. (2019) · Applied Biochemistry and Biotechnology · doi:10.1007/s12010-018-2920-2 · Cited by 47
Macrae, K., Stretton, C., Lipina, C., Blachnio-Zabielska, A., Baranowski, M., Gorski, J., Marley, A., & Hundal, H. S. (2013) · Journal of Lipid Research · doi:10.1194/jlr.m036996 · Cited by 46
Tschritter, O., Preissl, H., Hennige, A. M., Sartorius, T., Grichisch, Y., Stefan, N., Guthoff, M., Düsing, S., Machann, J., Schleicher, E., et al. (2009) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2009-0469 · Cited by 42
Rapid linkage of innate immunological signals to adaptive immunity by the brain-fat axis
Kim, M. S., Yan, J., Wu, W., Zhang, G., Zhang, Y., & Cai, D. (2015) · Nature Immunology · doi:10.1038/ni.3133 · Cited by 40
McGillicuddy, F. C., Reynolds, C. M., Finucane, O., Coleman, E., Harford, K. A., Grant, C., Sergi, D., Williams, L. M., Mills, K. H. G., & Roche, H. M. (2013) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00297.2013 · Cited by 36
Innate Immune Pathway Links Obesity to Insulin Resistance
Shah, P. K. (2007) · Circulation Research · doi:10.1161/circresaha.107.101104 · Cited by 31
Beals, J. W., Mackenzie, R. W. A., van Vliet, S., Skinner, S. K., Pagni, B. A., Niemiro, G. M., Ulanov, A. V., Li, Z., Dilger, A. C., Paluska, S. A., et al. (2017) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2017-00360 · Cited by 28
A polyphenol rescues lipid induced insulin resistance in skeletal muscle cells and adipocytes
Gogoi, B., Chatterjee, P., Mukherjee, S., Buragohain, A. K., Bhattacharya, S., & Dasgupta, S. (2014) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2014.08.079 · Cited by 28
Kwon, O. S., Nelson, D. S., Barrows, K. M., O'Connell, R. M., & Drummond, M. J. (2016) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00253.2016 · Cited by 24
Capturing the multifaceted function of adipose tissue macrophages
Matz, A. J., Qu, L., Karlinsey, K., Vella, A. T., & Zhou, B. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1148188 · Cited by 16
Zbinden-Foncea, H., van Loon, L. J. C., Raymackers, J.-M., Francaux, M., & Deldicque, L. (2013) · International Journal of Sport Nutrition and Exercise Metabolism · doi:10.1123/ijsnem.23.3.201 · Cited by 12
Liu, J., Wu, H., Zhou, L., Jin, Q., Ji, H., Hu, B., Wu, H., Chen, T., Wang, X., Hong, J., et al. (2026) · Metabolism · doi:10.1016/j.metabol.2025.156453 · Cited by 7
Metadata
- Authors
- Shi, H., Kokoeva, M. V., Inouye, K., Tzameli, I., Yin, H., & Flier, J. S.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- Corresponding author
- Flier, Jeffrey S.
- Venue
- Journal of Clinical Investigation
- Published
- 2006-11-01
- Volume
- 116
- Issue
- 11
- Pages
- 3015-3025
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC1616196
- OpenAlex
- W2156280702
- Cited by
- 3,690
- References
- 47
- Citations by year
- 2026: 126 · 2025: 131 · 2024: 135 · 2023: 140 · 2022: 167 · 2021: 176 · 2020: 209 · 2019: 180 · 2018: 206 · 2017: 243 · 2016: 220 · 2015: 259 · 2014: 222 · 2013: 274 · 2012: 252
- FWCI
- 86.79
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-R37-28082, R37DK028082)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Keywords
- TLR4, lipopolysaccharide receptor, innate immunity, obesity, adipocytes, macrophages, inflammation, insulin signaling, glucose metabolism, high-fat diet, energy balance, TLR4-deficient mice
- MeSH terms
- Adipose Tissue, Animals, Cell Line, Fats, Fatty Acids, Female, Glucose, Humans, Immunity, Innate, Insulin Resistance, Macrophages, Muscles, Signal Transduction, Cytokines, NF-kappa B, Adipocytes, Genes, Reporter, Mice, Knockout, Toll-Like Receptor 4, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
