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Hematopoietic Cell-Specific Deletion of Toll-like Receptor 4 Ameliorates Hepatic and Adipose Tissue Insulin Resistance in High-Fat-Fed Mice
Open accessAbstract
Chronic low-grade inflammation, particularly in adipose tissue, is an important modulator of obesity-induced insulin resistance. The Toll-like receptor 4 (Tlr4) is a key initiator of inflammatory responses in macrophages. We performed bone marrow transplantation (BMT) of Tlr4lps-del or control C57Bl/10J donor cells into irradiated wild-type C57Bl6 recipient mice to generate hematopoietic cell-specific Tlr4 deletion mutant (BMT-Tlr4(-/-)) and control (BMT-WT) mice. After 16 weeks of a high-fat diet (HFD), BMT-WT mice developed obesity, hyperinsulinemia, glucose intolerance, and insulin resistance. In contrast, BMT-Tlr4(-/-) mice became obese but did not develop fasting hyperinsulinemia and had improved hepatic and adipose insulin sensitivity during euglycemic clamp studies, compared to HFD BMT-WT controls. HFD BMT-Tlr4(-/-) mice also showed markedly reduced adipose tissue inflammatory markers and macrophage content. In summary, our results indicate that Tlr4 signaling in hematopoietic-derived cells is important for the development of hepatic and adipose tissue insulin resistance in obese mice.
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“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 [77]
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MethodA RAPID METHOD OF TOTAL LIPID EXTRACTION AND PURIFICATION
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MethodObesity is associated with macrophage accumulation in adipose tissue
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BackgroundInfluentialDefective LPS Signaling in C3H/HeJ and C57BL/10ScCr Mice: Mutations in Tlr4 Gene
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BackgroundInfluentialTLR4 links innate immunity and fatty acid-induced insulin resistance
Shi, H., Kokoeva, M. V., Inouye, K., Tzameli, I., Yin, H., & Flier, J. S. (2006) · Journal of Clinical Investigation · doi:10.1172/jci28898 · Cited by 3,690 · cited 13×
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MethodInfluentialDevelopment of T H 1 CD4 + T Cells Through IL-12 Produced by Listeria -Induced Macrophages
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Kim, J. J., & Sears, D. D. (2010) · Gastroenterology Research and Practice · doi:10.1155/2010/212563 · Cited by 260
“TLR4 is expressed on Kupffer cells and other liver cell components and modulates liver pro-inflammatory activity induced by high-fat diet- and fructose-induced hepatic steatosis and insulin resistance in mouse models [26, 44, 54, 93], although a direct role for liver tissue TLR4 in these processes is unclear.”
BackgroundGut microbiota and non-alcoholic fatty liver disease: new insights
Aron‐Wisnewsky, J., Gaborit, B., Dutour, A., & Clément, K. (2013) · Clinical Microbiology and Infection · doi:10.1111/1469-0691.12140 · Cited by 257
“Since then, other studies in TLR-4 null mice (–/–) have confirmed that TLR-4 is essential for hepatic fat deposition and NASH development [96–98].”
BackgroundBolton, J. L., Smith, S. H., Huff, N. C., Gilmour, M. I., Foster, W. M., Auten, R. L., & Bilbo, S. D. (2012) · The FASEB Journal · doi:10.1096/fj.12-210989 · Cited by 248
“Moreover, toll-like-receptor 4 (TLR4), the innate immune system’s pattern recognition receptor present on all innate immune cells, including microglia, has been implicated as critical in the crosstalk that occurs between inflammatory and metabolic signals (17, 18).”
BackgroundImplication of inflammatory signaling pathways in obesity-induced insulin resistance
Tanti, J., Ceppo, F., Jager, J., & Berthou, F. (2013) · Frontiers in Endocrinology · doi:10.3389/fendo.2012.00181 · Cited by 255
“In one study, mice developed obesity but with less inflammation and insulin resistance in adipose tissue and liver and no change in muscles (Saberi et al., 2009).”
BackgroundA decade of progress in adipose tissue macrophage biology
Hill, A. A., Bolus, W. R., & Hasty, A. H. (2014) · Immunological Reviews · doi:10.1111/imr.12216 · Cited by 227
“(88) showed that when TLR4 is exclusively removed from hematopoietic cells, mice become resistant to HFD-induced AT inflammation and systemic insulin resistance.”
BackgroundBuckman, L. B., Hasty, A. H., Flaherty, D. K., Buckman, C. T., Thompson, M. M., Matlock, B. K., Weller, K., & Ellacott, K. L. J. (2014) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2013.06.007 · Cited by 216
“…of obesity (Coenen et al., 2009; De Taeye et al., 2007; Furuhashi et al., 2008; Kowalski et al., 2011; Nicholls et al., 2011; Orr et al., 2012; Saberi et al., 2009; Xu et al., 2012), including one of the ini- Please cite this article in press as: Buckman, L.B., et al. Obesity induced by a hi…”
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Singer-Englar, T., Barlow, G. M., & Mathur, R. (2018) · Expert Review of Gastroenterology & Hepatology · doi:10.1080/17474124.2019.1543023 · Cited by 224
Intestinal Barrier and Permeability in Health, Obesity and NAFLD
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Recent advances in obesity-induced inflammation and insulin resistance
Tateya, S., Kim, F., & Tamori, Y. (2013) · Frontiers in Endocrinology · doi:10.3389/fendo.2013.00093 · Cited by 211
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Central Resistin Overexposure Induces Insulin Resistance Through Toll-Like Receptor 4
Benomar, Y., Gertler, A., De Lacy, P., Crépin, D., Ould Hamouda, H., Riffault, L., & Taouis, M. (2013) · Diabetes · doi:10.2337/db12-0237 · Cited by 177
“Conversely, TLR4 loss-of-function mutation or pharmacological inhibition of this receptor prevents saturated fatty acid-induced inflammation and insulin resistance (30,31,33).”
BackgroundSirt1 enhances skeletal muscle insulin sensitivity in mice during caloric restriction
Schenk, S., McCurdy, C. E., Philp, A., Chen, M. Z., Holliday, M. J., Bandyopadhyay, G. K., Osborn, O., Baar, K., & Olefsky, J. M. (2011) · Journal of Clinical Investigation · doi:10.1172/jci58554 · Cited by 197
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Jin, C., & Flavell, R. A. (2013) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2013.06.022 · Cited by 197
The Gut Microbiota and Liver Disease
Llorente, C., & Schnabl, B. (2015) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2015.04.003 · Cited by 195
Obesity, fatty liver disease and intestinal microbiota
Arslan, N. (2014) · World Journal of Gastroenterology · doi:10.3748/wjg.v20.i44.16452 · Cited by 200
Inflammatory cause of metabolic syndrome via brain stress and NF-κB
Cai, D., & Liu, T. (2012) · Aging · doi:10.18632/aging.100431 · Cited by 192
“In the context of metabolic dysregulations, overnutrition constitutes an environmental stimulus that can activate TLR pathways to mediate the development of metabolic syndrome related disorders such as obesity, insulin resistance, T2D, and atherosclerotic CVDs in rodents [146-157].”
BackgroundInnate Immune Receptors: Key Regulators of Metabolic Disease Progression
Jin, C., Henao‐Mejia, J., & Flavell, R. A. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.05.011 · Cited by 195
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“…due to their long duration, given rodent lifespans (Robertson et al., 2011), and difficulties in the interpretation of conventional knockout and cell depletion experiments (Clementi et al., 2009; Feng et al., 2011; Jin and Flavell, 2013; Orr et al., 2012; Saberi et al., 2009; Tanti et al., 2012).”
BackgroundInfluentialEpicardial Adipose Tissue: Clinical Biomarker of Cardio-Metabolic Risk
Fricke, A. C. V., & Iacobellis, G. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20235989 · Cited by 194
“Specifically, increased secretion of TNF-alpha leads to increased aggregation of activated macrophages from bone marrow and infiltration of macrophages into adipose tissue [21,22].”
BackgroundConnecting Type 1 and Type 2 Diabetes through Innate ImmunityPreprint
Odegaard, J. I., & Chawla, A. (2012) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a007724 · Cited by 188
“Indeed, infusion of saturated fatty acids alone is sufficient to induce acute insulin resistance in the absence of obesity (Shi et al. 2006), whereas genetic deletion of TLR4 in experimental animals protects against diet-induced insulin resistance (Saberi et al. 2009).”
BackgroundMetaflammation in obesity and its therapeutic targeting
Schleh, M. W., Caslin, H. L., Garcia, J. N., Mashayekhi, M., Srivastava, G., Bradley, A. B., & Hasty, A. H. (2023) · Science Translational Medicine · doi:10.1126/scitranslmed.adf9382 · Cited by 200
“The canonical model for TLR activation has been important for understanding signals responsible for inducing a pro-inflammatory environment in obesity and AT insulin resistance ( 45 ).”
BackgroundThe adipocyte microenvironment and cancer
Mukherjee, A., Bilecz, A. J., & Lengyel, E. R. (2022) · Cancer and Metastasis Reviews · doi:10.1007/s10555-022-10059-x · Cited by 179
Metabolic adaptations of tissue-resident immune cells
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“TLR4 confers protection against insulin resistance in skeletal muscle [96], adipose tissue, and liver [26, 97].”
BackgroundToll-like Receptor 4 Deficiency Promotes the Alternative Activation of Adipose Tissue Macrophages
Orr, J. S., Puglisi, M. J., Ellacott, K. L. J., Lumeng, C. N.-K., Wasserman, D. H., & Hasty, A. H. (2012) · Diabetes · doi:10.2337/db11-1595 · Cited by 173
“Olefsky and colleagues (32) recently reported that hematopoietic cell TLR4 deficiency, as well as lentiviral mediated knockdown of TLR4 in hematopoietic cells, attenuates IR after HF feeding.”
BackgroundThe Metabolically Benign and Malignant Fatty Liver
Stefan, N., & Häring, H. (2011) · Diabetes · doi:10.2337/db11-0231 · Cited by 177
“In contrast, hematopoietic JNK1 (41), inhibitor of kB kinase (IKK-b) (42), and TLR4 (43) deletion in mice in other studies was associated with prevention of hepatic and adipose tissue insulin resistance.”
BackgroundBadeanlou, L., Furlan-Freguia, C., Yang, G., Ruf, W., & Samad, F. (2011) · Nature Medicine · doi:10.1038/nm.2461 · Cited by 172
“2f,g ), consistent with other models in which lower myeloid cell inflammation is associated with lower steatosis, modestly higher muscle triglyceride concentrations and greater insulin sensitivit”
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Pathophysiology of NASH: perspectives for a targeted treatment
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Vila, I. K., Badin, P.-M., Marques, M.-A., Monbrun, L., Lefort, C., Mir, L., Louche, K., Bourlier, V., Roussel, B., Gui, P., et al. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.03.062 · Cited by 165
“Of note, irradiated WTmice transplanted with bone marrow of TLR4 null mice show markedly reduced monocyte infiltration in AT (Saberi et al., 2009).”
Background
Metadata
- Authors
- Saberi, M., Woods, N.-B., de Luca, C., Schenk, S., Lu, J. C., Bandyopadhyay, G., Verma, I. M., & Olefsky, J. M.
- Affiliations
- University of California San Diego (US)
- Salk Institute for Biological Studies (US)
- Corresponding author
- Olefsky, Jerrold M.
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2009-11
- Volume
- 10
- Issue
- 5
- Pages
- 419-429
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC2790319
- OpenAlex
- W2010911569
- Cited by
- 456
- References
- 26
- Citations by year
- 2026: 14 · 2025: 17 · 2024: 15 · 2023: 11 · 2022: 17 · 2021: 20 · 2020: 27 · 2019: 21 · 2018: 35 · 2017: 24 · 2016: 28 · 2015: 35 · 2014: 34 · 2013: 60 · 2012: 46
- FWCI
- 22.03
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Funders
- Lustgarten Foundation
- National Institutes of Health (DK033651, T32 DK 007494, DK074868, U54 HD 012303-25)
- Ellison Medical Foundation
- Fondation Leducq
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- TLR4, insulin resistance, obesity, high-fat diet, bone marrow transplantation, hepatic insulin sensitivity, adipose tissue inflammation, macrophages, low-grade inflammation, hyperinsulinemia, impaired glucose tolerance
- MeSH terms
- Adipose Tissue, Animals, Dietary Fats, Hematopoietic Stem Cells, Insulin Resistance, Liver, Macrophages, Mice, Obese, Obesity, Organ Specificity, Glucose Clamp Technique, Signal Transduction, Glucose Intolerance, Toll-Like Receptor 4, Mice, Gene Knockout Techniques
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