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.
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FFA activates TLR4 signaling, and mice lacking TLR4 are partially protected against high fat diet-induced insulin resistance.
“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]
The section on high-fat diets and the Figure 8 caption report partial protection against insulin resistance in female TLR4-knockout mice; the Discussion reports no corresponding insulin-sensitivity difference in males. The paper also reports that FFAs activate TLR4 signaling. The claim omits the female-specific qualification and thus implies a broader finding than the paper supports. (LLM, conf=0.88)
Experimental — accuracy not yet measuredActivation of TLR4 via LPS leads to release of pro-inflammatory cytokines such as TNF and IL-6, and similar effects are observed if free fatty acids bind TLR4.
“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]
Free fatty acid products from necrotic adipocytes cause pro-inflammatory activation of macrophages through TLR-2 and TLR-4 signaling.
“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]
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 [74]
Probiotics intake may improve markers of insulin metabolism and lipid profiles by reducing cytokines and suppressing NF-κB pathway and gut microbiota-SCFA-hormone axis.
“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
Weight loss induced by gastric bypass reduces circulating visfatin and TNF-a.
“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]
TLR2 and TLR4 pattern recognition receptors are important in fatty-acid-induced macrophage activation.
“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]
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 [116]
Adipose tissue macrophages sit in a lipid-rich environment, and fatty acids can broadly activate their inflammatory program.
“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]
Macrophages and adipocytes lacking Tlr2, Tlr4, or both do not activate inflammation.
“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]
Dietary-derived saturated fatty acids and erythrocyte content of saturated fatty acids positively correlate with circulating measures of CRP and can contribute to inflammation by favoring TLR4 signaling in macrophages.
“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]
FFAs can serve as ligands for the TLR4 complex, thereby activating the classical inflammatory response in the context of increased local extracellular lipid concentrations, which ultimately drives adipose tissue macrophage accumulation.
“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]
Either high rates of lipolysis or an influx of saturated FFAs into adipocytes do cause temporary inflammation within adipose tissue.
“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]
TLR4 specifically mediates inflammatory responses to free fatty acids, which are elevated in obesity and are associated with insulin resistance.
“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]
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- 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 › 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, 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
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