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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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 [77]
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“Adoptive transfer experiments suggest that the hematopoietic compartment is an important site of the diabetogenic action of TLR4 signaling (57).”
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Chronic tissue inflammation and metabolic diseasePreprint
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“These ATMs have a gene expression profile that resembles a classical or M1 activation state induced by LPS and IFN-g stimulation that may relate to the ability of free fatty acids to activate TLR4 (31, 32).”
BackgroundInvestigation of Macrophage Polarization Using Bone Marrow Derived Macrophages
Ying, W., Cheruku, P. S., Bazer, F. W., Safe, S. H., & Zhou, B. (2013) · Journal of Visualized Experiments · doi:10.3791/50323 · Cited by 337 · see citing works
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“The observation that LPS is required for macrophage accumulation but not for adiposity is in agreement with earlier studies in which mice lacking CD14 or with a haematopoietic cell-specific TLR4 deletion (and hence reduced LPS signalling) develop obesity on a high-fat diet but show markedly reduced adipose tissue macr…”
ResultTLR4 at the Crossroads of Nutrients, Gut Microbiota, and Metabolic Inflammation
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Hepatocyte Toll-like receptor 4 regulates obesity-induced inflammation and insulin resistance
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“Inhibiting several pathways that drive inflammatory Cell Repo This is an open access article under the CC BY-N signaling and/or production in macrophages improves insulin sensitivity during obesity (Han et al., 2013; Patsouris et al., 2008; Saberi et al., 2009; Wei et al., 2016).”
Role of AMP-activated protein kinase in adipose tissue metabolism and inflammation
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Macrophages in obesity and non-alcoholic fatty liver disease: crosstalk with metabolism
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“by activation of pattern recognition receptors, such as Toll-like receptors (TLRs), of which TLR4 is the most well-studied in this context.(24) Furthermore, adipose tissue expansion in obesity often exceeds the compensatory increase in oxygen delivery through angiogenesis, causing adipose tissue hypoxia and adipocyte…”
BackgroundRole of the Gut Microbiome in Obesity and Diabetes Mellitus
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FoxO1 regulates Tlr4 inflammatory pathway signalling in macrophages
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“For example, depletion of Tlr4 from macrophages by adaptive transfer of Tlr4 KO bone marrow into WT mice, preventing obesity-induced tissue inflammation leading to amelioration of hepatic steatosis and insulin resistance (Saberi et al, 2009).”
BackgroundSelf-citationProgramming of Host Metabolism by the Gut Microbiota
Bäckhed, F. (2011) · Annals of Nutrition and Metabolism · doi:10.1159/000328042 · Cited by 256 · see citing works
“]. Activation of Toll-like-receptor-4 in macrophages recruited to the adipose tissue promotes inflammation, which reduces insulin sensitivity [”
BackgroundCaesar, R., Fåk, F., & Bäckhed, F. (2010) · Journal of Internal Medicine · doi:10.1111/j.1365-2796.2010.02270.x · Cited by 253 · see citing works
Kim, J. J., & Sears, D. D. (2010) · Gastroenterology Research and Practice · doi:10.1155/2010/212563 · Cited by 249 · see citing works
“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 249 · see citing works
“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 243 · see citing works
“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 242 · see citing works
“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 220 · see citing works
“(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 · see citing works
“…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…”
BackgroundObesity, diabetes, and the gut microbiome: an updated review
Singer-Englar, T., Barlow, G. M., & Mathur, R. (2018) · Expert Review of Gastroenterology & Hepatology · doi:10.1080/17474124.2019.1543023 · Cited by 215 · see citing works
Intestinal Barrier and Permeability in Health, Obesity and NAFLD
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Recent advances in obesity-induced inflammation and insulin resistance
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Adipose tissue inflammation and ectopic lipid accumulation [Review]
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Central Resistin Overexposure Induces Insulin Resistance Through Toll-Like Receptor 4
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“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 · see citing works
Self-citationInnate sensors of pathogen and stress: Linking inflammation to obesity
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The Gut Microbiota and Liver Disease
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Obesity, fatty liver disease and intestinal microbiota
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Inflammatory cause of metabolic syndrome via brain stress and NF-κB
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“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
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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
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“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].”
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“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).”
BackgroundMetabolic Syndrome and Insulin Resistance: Underlying Causes and Modification by Exercise Training
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Metaflammation in obesity and its therapeutic targeting
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“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
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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
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“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
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“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.”
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“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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- 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 › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Physiology › 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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