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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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Tsukumo, D. M. L., Carvalho-Filho, M. A., Carvalheira, J. B. C., Prada, P. O., Hirabara, S. M., Schenka, A. A., Araújo, E. P., Vassallo, J., Curi, R., Velloso, L. A., et al. (2007) · Diabetes · doi:10.2337/db06-1595 · Cited by 826 · cited 12×
“These findings are comparable to the results of Tsukomo et al. (2007).”
BackgroundInfluentialRetractedA SIMPLE METHOD FOR THE ISOLATION AND PURIFICATION OF TOTAL LIPIDES FROM ANIMAL TISSUES
Folch, J., Lees, M., & Stanley, G. H. S. (1957) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)64849-5 · Cited by 65,189 · cited 1×
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MethodA RAPID METHOD OF TOTAL LIPID EXTRACTION AND PURIFICATION
Bligh, E. G., & Dyer, W. J. (1959) · Canadian Journal of Biochemistry and Physiology · doi:10.1139/o59-099 · Cited by 54,751 · cited 1×
“The triacylglycerol (TAG) and diacyglycerol (DAG) levels in liver and muscle cell lysates were determined using 50–100 mg of tissue, subjected to lipid extraction by organic solvents as previously described by Bligh and Dyer (1959) and Folch et al. (1957).”
MethodObesity 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 · cited 5×
“It is likely that the reduced expression of TNF-a is directly related to the reduced macrophage infiltration, as macrophages are the primary source of TNF-a in obese adipose tissue (Weisberg et al., 2003; Xu et al., 2003).”
BackgroundInfluentialDefective LPS Signaling in C3H/HeJ and C57BL/10ScCr Mice: Mutations in Tlr4 Gene
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“Hematopoietic Deletion of Tlr4 Does Affect Peripheral Lineage Distributions To generate mice with a complete knockout of Tlr4 in macrophages and other immune cells, we transplanted irradiated wild-type (WT) C57BL6 mice with bone marrow from Tlr4 (Poltorak et al., 1998) or WT C57BL/10J mice.”
BackgroundMethodXu, 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 · cited 5×
“It is likely that the reduced expression of TNF-a is directly related to the reduced macrophage infiltration, as macrophages are the primary source of TNF-a in obese adipose tissue (Weisberg et al., 2003; Xu et al., 2003).”
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×
“In addition, obesity due to high-fat diet (HFD) feeding and insulin resistance caused by a lipid-plus-heparin infusion were etabolism 10, 419–429, November 4, 2009 ª2009 Elsevier Inc. 419 attenuated in Tlr4 knockout mice, in parallel with decreased inflammation in both liver and adipose tissue (Shi et al., 2006; Tsuku…”
BackgroundResultInfluentialA Third-Generation Lentivirus Vector with a Conditional Packaging System
Dull, T., Zufferey, R., Kelly, M., Mandel, R. J., Nguyen, M., Trono, D., & Naldini, L. (1998) · Journal of Virology · doi:10.1128/jvi.72.11.8463-8471.1998 · Cited by 3,341 · cited 6×
“To ensure high-level transduction efficiency in the bone marrow cells, we included the marker gene GFP in both vectors.”
MethodInfluentialDevelopment of T H 1 CD4 + T Cells Through IL-12 Produced by Listeria -Induced Macrophages
Hsieh, C.-S., Macatonia, S. E., Tripp, C. S., Wolf, S. F., O'Garra, A., & Murphy, K. M. (1993) · Science · doi:10.1126/science.8097338 · Cited by 3,134 · cited 1×
“It is notable that IL-12 p70 was reduced in our mice because IL-12 is important for the transition of naive T cells into Th1 cells (Hsieh et al., 1993).”
BackgroundToll-like receptors in the induction of the innate immune response
Aderem, A. A., & Ulevitch, R. J. (2000) · Nature · doi:10.1038/35021228 · Cited by 3,082 · cited 1×
“The ‘‘sensors’’ that potentially link obesity to inflammation are the Toll-like family of receptors (Tlrs); Tlrs are pattern recognition receptors that play critical roles in innate immunity (Aderem and Ulevitch, 2000; Wolowczuk et al., 2008).”
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The immune system's involvement in obesity-driven type 2 diabetes
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“TLR4 Hematopoietic cell specific TLR4 deletion (128) ↓ IR, ↓adipose and liver inflammation”
BackgroundAdipose tissue recruitment of leukocytes
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“Those mice also showed markedly reduced adipose tissue inflammation and macrophage infiltration (Saberi et al., 2009).”
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Kobyliak, N. M., Virchenko, O., & Falalyeyeva, T. M. (2015) · Nutrition Journal · doi:10.1186/s12937-016-0166-9 · Cited by 156
“Furthermore, a stimulation of TLR4 by fatty acids can lead to the recruitment of pro-inflammatory macrophages to adipose tissue [57, 58] and cross-talk between macrophages and adipocytes in adipose tissue, which involves activation of NF-κB and JNK by TLR signaling and mediates insulin resistance by phosphorylation of…”
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Hypothalamic dysfunction in obesity
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“encoding IKKb and TLR4 in myeloid cells, which give rise to macrophages and neutrophils, protects mice from high-fat diet-induced insulin insensitivity in the muscle, fat and liver((79,85)).”
BackgroundBeaven, S. W., Matveyenko, A. V., Wroblewski, K., Chao, L. C., Wilpitz, D. C., Hsu, T. W., Lentz, J., Drew, B. G., Hevener, A. L., & Tontonoz, P. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.04.021 · Cited by 145
“Inflammatory signaling is postulated to be an important determinant of insulin sensitivity, with increased inflammation associated with insulin resistance (Arkan et al., 2005; Cai et al., 2005; Saberi et al., 2009).”
Macrophages, Meta-Inflammation, and Immuno-Metabolism
Shapiro, H., Lutaty, A., & Ariel, A. (2011) · The Scientific World JOURNAL · doi:10.1100/2011/397971 · Cited by 153
“The confirmation that FSatFAs drive M1skewing in obese AT was provided by demonstrating that Tlr4 knockdown confined to hematopoietic cells attenuates the increase in AT M1 versus M2 markers [113] and the detection of a subpopulation of ATinfiltrating macrophages that are classically activated by FSatFAs in obesity [1…”
BackgroundModulation of obesity-induced inflammation by dietary fats: mechanisms and clinical evidence
Teng, K., Chang, C.-Y., Chang, L. F., & Nesaretnam, K. (2014) · Nutrition Journal · doi:10.1186/1475-2891-13-12 · Cited by 151
“The absence of TLR in studies on mice demonstrated the diminished effect of insulin resistance modulated by pro-inflammatory pathways [32,33].”
BackgroundInnate immune activation in obesity
Lumeng, C. N.-K. (2012) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2012.10.002 · Cited by 147
“TLR4 deficiency specifically in hematopoietic cells was shown to be sufficient to protect mice from insulin resistance without weight loss (Saberi et al., 2009).”
BackgroundInflammaging: The ground for sarcopenia?
Liang, Z., Zhang, T., Liu, H., Li, Z., Peng, L., Wang, C., & Wang, T. (2022) · Experimental Gerontology · doi:10.1016/j.exger.2022.111931 · Cited by 156
Mechanistic links between gut microbial community dynamics, microbial functions and metabolic health
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Inflammatory Concepts of Obesity
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“TLR4 deficiency improves insulin sensitivity in high-fat dietinduced obese mice [145, 146].”
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Oxygenation of adipose tissue: A human perspective
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Inflammasomes and Metabolic Disease
Henao‐Mejia, J., Elinav, E., Thaiss, C. A., & Flavell, R. A. (2013) · Annual Review of Physiology · doi:10.1146/annurev-physiol-021113-170324 · Cited by 176
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“Studies on TLR-4 null mice have confirmed that TLR-4 is essential for hepatic fat deposition and NASH development (Poggi et al., 2007, Saberi et al., 2009, Henao-Mejia et al., 2012).”
BackgroundJNK regulation of hepatic manifestations of the metabolic syndrome
Czaja, M. J. (2010) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2010.08.010 · Cited by 131
Brain Insulin Dysregulation: Implication for Neurological and Neuropsychiatric Disorders
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The Interplay between Obesity and Inflammation
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“Most M1-like polarized ATMs derive from circulating monocytes and the transition is regulated by dietary or hydrolyzed bisaturated fatty acids via a TLR4-dependent mechanism [22,157– 160].”
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“Several laboratories have demonstrated that saturated fatty acids act as ligands for toll-like receptor 4 (TLR4)4 in macrophages and adipocytes (3–6).”
BackgroundInfluentialRole and function of macrophages in the metabolic syndrome
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Ding, Y., Subramanian, S., Montes, V. N., Goodspeed, L., Wang, S., Han, C.-Y., Teresa, A. S., Kim, J. K., O’Brien, K. D., & Chait, A. (2012) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.112.249847 · Cited by 116
Knockdown of ANT2 reduces adipocyte hypoxia and improves insulin resistance in obesity
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Self-citationThe impact of maternal high-fat diet on offspring neurodevelopment
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BackgroundThe Gut Microbiome and Individual-Specific Responses to Diet
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CD14 Modulates Inflammation-Driven Insulin Resistance
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“The grafting of mice with bone marrow stem cells has been used to evaluate the influence of these cells on wholebody insulin sensitivity (8).”
BackgroundMethodInfluentialPierre, N., Deldicque, L., Barbé, C., Naslain, D., Cani, P. D., & Francaux, M. (2013) · PLoS ONE · doi:10.1371/journal.pone.0065061 · Cited by 109
“also a protection against obesity [16,17,50], probably because of a more favorable energy balance.”
BackgroundNew therapeutic approaches for the treatment of obesity
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Insulin Resistance in the Defense against Obesity
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“Consistently, haematopoietic deletion of TLR-4 (in irradiated mice that received TLR-4-/- bone marrow cells) prevented mice from AT inflammation and insulin resistance in the course of diet-induced obesity (33).”
BackgroundAdipose tissue inflammation in glucose metabolism
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“…of obesity, bacterial LPS and peptidoglycans, as pro-inflammatory agents, activate pathogen recognition receptors (PRRs) on macrophages and neutrophils, and as part of the non-specific immune response (Burcelin 2012) are responsible for hyperinsulinaemia and insulin resistance (Saberi et al. 2009).”
BackgroundXu, H., Li, H., Woo, S., Kim, S.-M., Shende, V. R., Neuendorff, N., Guo, X., Guo, T., Qi, T., Pei, Y., et al. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.539601 · Cited by 98
“Briefly, male wild-type C57BL/6J recipient mice at 5– 6 weeks of age were lethally irradiated and subjected to BMT to generate chimeric mice using the established method (24, 26).”
MethodEtienne‐Mesmin, L., Vijay–Kumar, M., Gewirtz, A. T., & Chassaing, B. (2016) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2016.04.007 · Cited by 102
An update on immune dysregulation in obesity‐related insulin resistance
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“It has been shown that HFD in TLR2 or TLR4 mice causes less macrophage recruitment and AT inflammation that improves insulin sensitivity.(81,82) In lean animals, adipocyte‐derived IL‐4 and IL‐13 induce the expression of PPAR‐γ/δ by ATMs, which facilitates their polarization towards M2‐like macrophages.”
BackgroundThe NLRP3 inflammasome: Role in metabolic disorders and regulation by metabolic pathways
Jiang, D., Chen, S., Sun, R., Zhang, X., & Wang, D. (2018) · Cancer Letters · doi:10.1016/j.canlet.2018.01.034 · Cited by 95
Toll-like receptors and metabolic (dysfunction)-associated fatty liver disease
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Renal Protective Effects of Toll-like Receptor 4 Signaling Blockade in Type 2 Diabetic Mice
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“(47) emphasized the importance of TLR4 signaling inmacrophages for thedevelopmentofhepaticand adipose tissue insulin resistance using a hematopoietic cellspecific TLR4 deletion achieved via bone marrow transplantation.”
BackgroundNutrition Regulates Innate Immunity in Health and Disease
Nobs, S. P., Zmora, N., & Elinav, E. (2020) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-120919-094440 · Cited by 93
“Hence, mice deficient in TLR4 were protected against high-fat-diet (HFD)-mediated insulin resistance (159, 165).”
BackgroundFilippov, S. I., Pinkosky, S. L., Lister, R. J., Pawloski, C., Hanselman, J. C., Cramer, C. T., Srivastava, R. A. K., Hurley, T. R., Bradshaw, C. D., Spahr, M. A., et al. (2013) · Journal of Lipid Research · doi:10.1194/jlr.m035212 · Cited by 89
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“First, TLR4 expression is increased in adipose tissue inflammatory macrophages in obesity [46,47]; Second, TLR4 knockout (KO) mice or mice with a loss-of-function mutation in the TLR4 gene are protected from obesity-induced insulin resistance [46,48]; Third, hematopoietic cell-specific deletion of TLR4 ameliorates HFD…”
BackgroundGriffin, C. A., Eter, L., Lanzetta, N., Abrishami, S., Varghese, M., McKernan, K. E., Muir, L. A., Lane, J., Lumeng, C. N.-K., & Singer, K. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.ra117.001526 · Cited by 88
“Some investigators have reported a metabolic and inflammatory role for TLR4 (17, 18), whereas others have reported that TLR4 knockout does not improve metabolic function (19).”
BackgroundHMGB1, an innate alarmin, plays a critical role in chronic inflammation of adipose tissue in obesity
Zhang, J., Zhang, L., Zhang, S., Yu, Q., Xiong, F., Huang, K., Wang, C., & Yang, P. C. (2017) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2017.06.012 · Cited by 91
“…of Tlr4 reduces HFD-induced hepatic steatosis and inflammation along with improved hepatic insulin sensitivity (Orr et al. 2012; Poggi et al. 2007; Saberi et al. 2009; Tsukumo et al. 2016), and blockade of TLR4 signaling confers protection against lipid-induced insulin resistance in skeletal…”
Mast Cells in Allergic and Inflammatory Diseases
Sismanopoulos, N., Delivanis, D.-A., Alysandratos, K.-D., Angelidou, A., Therianou, A., Kalogeromitros, D., & C. Theoharides, T. (2012) · Current Pharmaceutical Design · doi:10.2174/138161212800165997 · Cited by 87
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Impact of Divergent Effects of Astaxanthin on Insulin Signaling in L6 Cells
Ishiki, M., Nishida, Y., Ishibashi, H., Wada, T., Fujisaka, S., Takikawa, A., Urakaze, M., Sasaoka, T., Usui, I., & Tobe, K. (2013) · Endocrinology · doi:10.1210/en.2012-2198 · Cited by 86
Changes in Adipose Tissue Macrophages and T Cells During Aging
Garg, S. K., Delaney, C. E., Shi, H., & Yung, R. L. (2013) · Critical Reviews in Immunology · doi:10.1615/critrevimmunol.2013006833 · Cited by 82
miR-150 regulates obesity-associated insulin resistance by controlling B cell functions
Ying, W., Tseng, A. M., Chang, R. C.-A., Wang, H., Lin, Y., Kanameni, S., Brehm, T. J., Morin, A., Jones, B. T., Splawn, T. G., et al. (2016) · Scientific Reports · doi:10.1038/srep20176 · Cited by 81
Bile acid receptors and nonalcoholic fatty liver disease
Yuan, L. (2015) · World Journal of Hepatology · doi:10.4254/wjh.v7.i28.2811 · Cited by 82
Sachithanandan, N., Graham, K. L., Galic, S., Honeyman, J. E., Fynch, S. L., Hewitt, K. A., Steinberg, G. R., & Kay, T. W. (2011) · Diabetes · doi:10.2337/db11-0259 · Cited by 81
“Mice with hematopoietic deletion of TLR4 have reduced obesity-related inflammation and insulin resistance (37).”
Multi-tissue, selective PPARγ modulation of insulin sensitivity and metabolic pathways in obese rats
Hsiao, G., Chapman, J., Ofrecio, J. M., Wilkes, J. J., Resnik, J. L., Thapar, D., Subramaniam, S., & Sears, D. D. (2010) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00219.2010 · Cited by 82
“These findings assert that suppressing the inflammatory state is central for reversing insulin resistance and are supported by published studies showing that disruption of inflammatory signaling in immune cells prevents high-fat diet-induced insulin resistance (1, 37, 42).”
ResultLashinger, L. M., Rossi, E. L., & Hursting, S. D. (2014) · Clinical Pharmacology & Therapeutics · doi:10.1038/clpt.2014.136 · Cited by 80
Nucleic Acid-Targeting Pathways Promote Inflammation in Obesity-Related Insulin Resistance
Revelo, X. S., Ghazarian, M., Chng, M. H. Y., Luck, H., Kim, J. H., Zeng, K., Shi, S. Y., Tsai, S. J., Lei, H., Kenkel, J. A., et al. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.06.024 · Cited by 83
“Most notably, TLR4 has been proposed to be a critical link between the consumption of dietary fats, changes in gut microbiota, and metabolic inflammation, (Davis et al., 2008; Saberi et al., 2009; Shi et al., 2006).”
Insights into the role of macrophage migration inhibitory factor in obesity and insulin resistance
Finucane, O. M., Reynolds, C. M., McGillicuddy, F. C., & Roche, H. M. (2012) · Proceedings of The Nutrition Society · doi:10.1017/s0029665112000730 · Cited by 81
“Furthermore, haematopoietic cell specific deletion of TLR ameliorated HFD-induced hyperinsulinemia, hepatic and adipose tissue IR, concomitant with impaired ATM content((48)).”
Grant, L., Shearer, K. D., Czopek, A., Lees, E. K., Owen, C., Agouni, A., Workman, J., Martin-Granados, C., Forrester, J. V., Wilson, H. M., et al. (2014) · Diabetes · doi:10.2337/db13-0885 · Cited by 76
“Mice with myeloid-TLR-4 deletion are protected against high-fat diet (HFD)induced inflammation, adipose macrophage infiltration, and insulin resistance (14).”
BackgroundFetuin-A: the missing link in lipid-induced inflammation
Heinrichsdorff, J., & Olefsky, J. M. (2012) · Nature Medicine · doi:10.1038/nm.2869 · Cited by 76
Self-citationDalby, M. J., Aviello, G., Ross, A., Walker, A. W., Barrett, P., & Morgan, P. J. (2018) · Scientific Reports · doi:10.1038/s41598-018-33928-4 · Cited by 75
Immunometabolism of AMPK in insulin resistance and atherosclerosis
Fullerton, M. D., Steinberg, G. R., & Schertzer, J. D. (2012) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2012.02.004 · Cited by 73
Wiedemann, M. S. F., Wueest, S., Item, F., Schoenle, E. J., & Konrad, D. (2013) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00179.2013 · Cited by 74
“Consistently impinging on adipose tissue inflammation improves obesity-associated insulin resistance (19, 20, 22, 25).”
BackgroundThe Complex Interplay between Lipids, Immune System and Interleukins in Cardio-Metabolic Diseases
Bernardi, S., Marcuzzi, A., Piscianz, E., Tommasini, A., & Fabris, B. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19124058 · Cited by 71
Macrophage Function in the Pathogenesis of Non-alcoholic Fatty Liver Disease: The Mac Attack
Oates, J. R., McKell, M. C., Moreno‐Fernandez, M. E., Damen, M. S. M. A., Deepe, G. S., Qualls, J. E., & Divanovic, S. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.02893 · Cited by 78
Secondary muscle pathology and metabolic dysregulation in adults with cerebral palsy
Peterson, M. D., Gordon, P. M., Hurvitz, E. A., & Burant, C. (2012) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00338.2012 · Cited by 74
Zadjali, F., Santana‐Farré, R., Vesterlund, M., Carow, B., de Mirecki-Garrido, M., Hernández, I., Flodström‐Tullberg, M., Parini, P., Rottenberg, M. E., Norstedt, G., et al. (2012) · The FASEB Journal · doi:10.1096/fj.12-205583 · Cited by 74
“Toll-like receptor-driven macrophage activation in liver and adipose tissues by high-fat feeding leads to the production of inflammatory cytokines, a process that is required for diet-induced hepatic insulin resistance (3).”
BackgroundCoope, A., Torsoni, A. S., & Velloso, L. A. (2016) · European Journal of Endocrinology · doi:10.1530/eje-15-1065 · Cited by 73
Macrophages: The Potent Immunoregulatory Innate Immune Cells
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Role of TLR4 in the induction of inflammatory changes in adipocytes and macrophages
McKernan, K. E., Varghese, M., Patel, R. R., & Singer, K. (2020) · Adipocyte · doi:10.1080/21623945.2020.1760674 · Cited by 70
“Previous studies have also indicated a role for TLR4 in the development of adipose tissue fibrosis and insulin resistance in obesity [30,31].”
BackgroundInfluentialObesity-induced inflammation: The impact of the hematopoietic stem cell niche
Bowers, E., & Singer, K. (2021) · JCI Insight · doi:10.1172/jci.insight.145295 · Cited by 72
“tivity (35, 38), decreased activation of proinflammatory ATMs (36, 38), and decreased AT fibrosis (37).”
BackgroundKrause, M. D. S., Bock, P. M., Takahashi, H., de Bittencourt, P. I. H., & Newsholme, P. (2015) · Clinical Science · doi:10.1042/cs20140695 · Cited by 71
Human microflora, probiotics and wound healing
Tsiouris, C. G., & Tsiouri, M. G. (2017) · Wound Medicine · doi:10.1016/j.wndm.2017.09.006 · Cited by 70
Inflammasome biology in fibrogenesis
Ouyang, X., Ghani, A., & Mehal, W. Z. (2013) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2013.03.020 · Cited by 70
Toll-like receptor 2/4 links to free fatty acid-induced inflammation and β-cell dysfunction
Yin, J., Peng, Y., Wu, J., Wang, Y., & Yao, L. (2013) · Journal of Leukocyte Biology · doi:10.1189/jlb.0313143 · Cited by 69
“tected against diet-induced insulin resistance [39].”
Li, F., Li, H., Jin, X., Zhang, Y., Kang, X., Zhang, Z., Xu, M., Qian, Z., Ma, Z., Gao, X. Y., et al. (2019) · Cell Cycle · doi:10.1080/15384101.2019.1638694 · Cited by 66
“Recent findings demonstrated that TLR4 played a crucial role in the development of insulin resistance which was closely related to exosomes [20,38,39].”
BackgroundTLR4 inhibitor TAK-242 attenuates the adverse neural effects of diet-induced obesity
Moser, V. A., Uchoa, M. F., & Pike, C. J. (2018) · Journal of Neuroinflammation · doi:10.1186/s12974-018-1340-0 · Cited by 65
“First, our observations in adipose tissue of partial reductions in both markers of macrophage activation (CD68, F4/80, MHCII) and pro-inflammatory cytokines (IL-6, TNFα) in HFD-fed mice treated with TAK-242 is consistent with previous findings [42, 44, 46, 48, 53].”
BackgroundResultEstrada, J. A., & Contreras, I. (2019) · Nutrients · doi:10.3390/nu11051076 · Cited by 65
“Importantly, high-fat dietary regimes increase the amount of LPS-producing intestinal bacteria, as well as plasma LPS concentrations, in both animals and humans [139].”
BackgroundThe serine protease prostasin regulates hepatic insulin sensitivity by modulating TLR4 signalling
Uchimura, K., Hayata, M., Mizumoto, T., Miyasato, Y., Kakizoe, Y., Morinaga, J., Onoue, T., Yamazoe, R., Ueda, M. U., Adachi, M., et al. (2014) · Nature Communications · doi:10.1038/ncomms4428 · Cited by 59
Metabolic syndrome and hidradenitis suppurativa: epidemiological, molecular, and therapeutic aspects
Mintoff, D., Benhadou, F., Pace, N. P., & Frew, J. W. (2021) · International Journal of Dermatology · doi:10.1111/ijd.15910 · Cited by 61
Galvão, K. N., Felippe, M. J. B., Brittin, S. B., Sper, R. B., Fraga, M., Galvão, J. S., Caixeta, L. S., Guard, C. L., Ricci, A. L., & Gilbert, R. O. (2011) · Theriogenology · doi:10.1016/j.theriogenology.2011.08.008 · Cited by 59
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“adipose tissue. The degree of obesity (~40 g body weight on high-fat diet) and white adipose tissue inflammation (Tnf-α, iNos, F4/80, Cd11c gene induction) in this study was remarkably similar to that seen in other studies using BMT mice, even under conditions of longer-term high-fatdiet feeding (16–20 weeks) using th…”
ResultMcCurdy, C. E., Schenk, S., Holliday, M., Philp, A., Houck, J. A., Patsouris, D., MacLean, P. S., Majka, S. M., Klemm, D. J., & Friedman, J. E. (2012) · Diabetes · doi:10.2337/db11-1433 · Cited by 60
Self-citationWang, X., Rao, H., Liu, F., Wei, L., Li, H., & Wu, C. (2021) · Cells · doi:10.3390/cells10123300 · Cited by 66
Roth, S. W., Bitterman, M. D., Birnbaum, M. J., & Bland, M. L. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.02.033 · Cited by 58
“Deletion of Tlr4 in macrophages and other bone marrow-derived cells or in hepatocytes or adipocytes reduces insulin resistance in high-fat diet-fed mice (Jia et al., 2014; Saberi et al., 2009; Tao et al., 2017), indicating that TLR4 expression is required in immune and metabolic tissues for diet-induced insulin resist…”
Immune Cells Link Obesity-associated Type 2 Diabetes and Periodontitis
Zhu, M., & Nikolajczyk, B. S. (2014) · Journal of Dental Research · doi:10.1177/0022034513518943 · Cited by 57
“Saturated free fatty acids and/or hyperglycemia activates macrophages, thus triggering a cytokine-driven inflammatory cascade and insulin resistance, primarily via TNF-α, IL-6, and IL-1β, among others (Saberi et al., 2009; Chawla et al., 2011).”
BackgroundMima, A., Qi, W., Hiraoka‐Yamamoto, J., Park, K., Matsumoto, M., Kitada, M., Li, Q., Mizutani, K., Yu, E., Shimada, T., et al. (2012) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.12-10207 · Cited by 55
Kim, J., Jang, H.-J., & Hwang, D. H. (2015) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00369.2015 · Cited by 57
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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