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Ablation of CD11c-Positive Cells Normalizes Insulin Sensitivity in Obese Insulin Resistant Animals
Open accessAbstract
Obese adipose tissue is characterized by infiltration of macrophages. We and others recently showed that a specific subset of macrophages is recruited to obese adipose and muscle tissue. This subset expresses CD11c and produces high levels of proinflammatory cytokines that are linked to the development of obesity-associated insulin resistance. Here, we used a conditional cell ablation system, based on transgenic expression of the diphtheria toxin receptor under the control of the CD11c promoter, to study the effects of depletion of CD11c+ cells in obese mouse models. Our results show that CD11c+ cell depletion results in rapid normalization of insulin sensitivity. Furthermore, CD11c+ cell ablation leads to a marked decrease in inflammatory markers, both locally and systemically, as reflected by gene expression and protein levels. Together, these results indicate that these CD11c+ cells are a potential therapeutic target for treatment of obesity-related insulin resistance and type II diabetes.
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“Such conditional ablation resulted in a profound reduction of proinflammatory ATM accumulation, accompanied by rapid whole-body normalization of insulin sensitivity (43).”
From Adipose tissue remodeling and obesity (2011) · cites this paper as [43]
In the citing paper
“M1-like macrophages secrete inflammatory cytokines such as TNF-α and IL-6, and studies in M1-like macrophage knockout mice suggest they also promote insulin resistance.”
From The Vasculature in Prediabetes (2018) · cites this paper as [84]
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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 3×
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Monocyte and macrophage heterogeneity
Gordon, S., & Taylor, P. R. (2005) · Nature Reviews Immunology · doi:10.1038/nri1733 · Cited by 5,190 · cited 1×
“Resident tissue macrophages display tremendous heterogeneity in their activities and functions, primarily reflecting the local metabolic and immune microenvironment (Gordon and Taylor, 2005; Mantovani et al., 2004).”
Obesity induces a phenotypic switch in adipose tissue macrophage polarization
Lumeng, C. N., Bodzin, J. L., & Saltiel, A. R. (2007) · Journal of Clinical Investigation · doi:10.1172/jci29881 · Cited by 4,664 · cited 10×
“These results suggest that the source of the IL-10 in the DT treated CD11c-DTR BMT mice are the remaining CD11c ATMs (Cancello et al., 2005; Lumeng et al., 2007).”
InfluentialKim, H. J., Park, S. Y., Choi, Y. J., Han, S. J., Lee, K. W., & Kim, D. J. (2013) · Hormone Research in Paediatrics · doi:10.1159/000348848 · Cited by 3,061
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“…in ATMs is associated with a decrease in adipose tissue inflammation and a reduction in obesityinduced insulin resistance (Ellacott et al., 2007; Kanda et al., 2006; Lesniewski et al., 2007; Nara et al., 2007; Neels and Olefsky, 2006; Nomiyama et al., 2007; Weisberg et al., 2006), while an…”
InfluentialCinti, S., Mitchell, G., Barbatelli, G., Murano, I., Ceresi, E., Faloia, E., Wang, S., Fortier, M., Greenberg, A. S., & Obin, M. S. (2005) · Journal of Lipid Research · doi:10.1194/jlr.m500294-jlr200 · Cited by 2,529 · cited 2×
“Previously, ATMs were shown to cluster around dead adipocytes in so-called crown-like structures (CLS; (Cinti et al., 2005; Strissel et al., 2007), and CD11c+ cells are localized to these ATM clusters (Lumeng et al., 2007).”
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InfluentialObesity, Inflammation, and Insulin Resistance
Shoelson, S. E., Herrero, L., & Naaz, A. (2007) · Gastroenterology · doi:10.1053/j.gastro.2007.03.059 · Cited by 1,806 · cited 4×
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InfluentialIKK-β links inflammation to obesity-induced insulin resistance
Arkan, M. C., Hevener, A. L., Greten, F. R., Maeda, S., Li, Z.-W., Long, J. M., Wynshaw-Boris, A., Poli, G., Olefsky, J., & Karin, M. (2005) · Nature Medicine · doi:10.1038/nm1185 · Cited by 1,773
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Central and Peripheral Inflammation Link Metabolic Syndrome and Major Depressive Disorder
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“Notably, selectively depleting total or CD11c macrophages from adipose tissue or interfering with CCL2/CCR2 alleviates diet-induced insulin resistance (15, 37, 94, 129), demonstrating that macrophages contribute to whole-body glycemic dysregulation.”
BackgroundLocal proliferation of macrophages in adipose tissue during obesity-induced inflammation
Haase, J., Weyer, U., Immig, K., Klöting, N., Blüher, M., Eilers, J., Bechmann, I., & Gericke, M. T. (2013) · Diabetologia · doi:10.1007/s00125-013-3139-y · Cited by 246
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Singer, K., DelProposto, J. L., Morris, D. L., Zamarron, B. F., Mergian, T. A., Maley, N., Cho, K. W., Geletka, L. M., Subbaiah, P., Muir, L. A., et al. (2014) · Molecular Metabolism · doi:10.1016/j.molmet.2014.06.005 · Cited by 243
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“Collectively, these data demonstrated that the Fundc1 ablation facilitates M1 polarization of ATMs via a cell nonautonomous mechanism, which may depend on the macrophage microenvironment in WAT as obesity develops [45].”
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Stefanović-Račić, M., Yang, X., Turner, M. S., Mantell, B. S., Stolz, D. B., Sumpter, T. L., SIPULA, I. J., Dedousis, N. L., Scott, D. K., Morel, P. A., et al. (2012) · Diabetes · doi:10.2337/db11-1523 · Cited by 229
“Work also related to the current study demonstrated that targeted deletion of all CD11c cells in obese animals improves insulin resistance (41).”
Lipoxin A4 Attenuates Obesity-Induced Adipose Inflammation and Associated Liver and Kidney Disease
Börgeson, E., Johnson, A. M. F., Lee, Y. S., Till, A., Syed, G. H., Shah, S. T. A., Guiry, P. J., Dalli, J., Colas, R. A., Serhan, C. N., et al. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.05.003 · Cited by 225
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“mation and the induction of insulin resistance in response to HFD in the B6 mouse [12].”
BackgroundPatel, V. B., Shah, S., Verma, S., & Oudit, G. Y. (2017) · Heart Failure Reviews · doi:10.1007/s10741-017-9644-1 · Cited by 218
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
“Myeloid-specific deletion of CD11c in mice protected against HFD-induced accumulation of macrophages in adipose tissue and exhibited insulin sensitivity compared with the controls (57).”
BackgroundItoh, M., Kato, H., Suganami, T., Konuma, K., Marumoto, Y., Terai, S., Sakugawa, H., Kanai, S., Hamaguchi, M., Fukaishi, T., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0082163 · Cited by 211
“It is also known that ablation of CD11c-positive cells leads to a marked decrease in adipose tissue inflammation and normalizes insulin sensitivity without affecting body weight [43].”
BackgroundHwang, I., Park, Y. J., Kim, Y.-R., Kim, Y. N., Ka, S., Lee, H., Seong, J. K., Seok, Y., & Kim, J. B. (2015) · The FASEB Journal · doi:10.1096/fj.14-265983 · Cited by 206
“Treatment with Ex(9-39), a well-known GLP-1 receptor antagonist, led to aggravation of glucose intolerance inNH mice relative to the NHmice treated with vehicle (Fig.”
BackgroundMethodResultInfluentialRAGE Regulates the Metabolic and Inflammatory Response to High-Fat Feeding in Mice
Song, F., del Pozo, C. H., Rosario, R., Zou, Y. S., Ananthakrishnan, R., Xu, X., Patel, P. R., Benoit, V. M., Yan, S. F., Li, H., et al. (2014) · Diabetes · doi:10.2337/db13-1636 · Cited by 209
“The present finding that numbers of Cd11c-expressing cells were lower in PGAT when RAGE was deleted is consistent with previous work, because diphtheria toxin– mediated deletion of Cd11c resulted in significant protection against insulin resistance in HFD-fed mice, with enhanced M2 macrophage polarization, in the abse…”
ResultFink, L. N., Costford, S. R., Lee, Y. S., Jensen, T. E., Bilan, P. J., Oberbach, A., Blüher, M., Olefsky, J. M., Sams, A. G., & Klip, A. (2013) · Obesity · doi:10.1002/oby.20615 · Cited by 205
“7-13)% CD: 25 (19-31)% *** CD: 30 (28-33)% HFD1:13 (9-18)% HFD1:18 (13-27)% HFD1: 32 (31-33)% HFD10: 12 (9-14)% HFD10:13 (10-16)%* HFD10: 23 (17-32)%”
BackgroundInfluentialSelf-citationJiao, P., Ma, J., Feng, B., Zhang, H., Diehl, J. A., Eugene‐Chin, Y., Yan, W., & Xu, H. (2010) · Obesity · doi:10.1038/oby.2010.200 · Cited by 203
“Conditional depletion of CD11c+ macrophages by overexpressing the diphtheria toxin receptor under the control of CD11c promoter led to significant decrease of inflammatory molecules in adipose tissue and rapid normalization of insulin sensitivity (11).”
BackgroundThe Role of the Adipokine Leptin in Immune Cell Function in Health and Disease
Kiernan, K., & MacIver, N. J. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2020.622468 · Cited by 212
“Elimination of CD11c+ macrophages in a mouse model of obesity resulted in increased insulin sensitivity (89), and a less specific macrophage deletion strategy using chlodronate liposomes leading to apoptosis of phagocytic cells also resulted in increased insulin sensitivity and improved systemic glucose tolerance (90).”
BackgroundVieira‐Potter, V. J., Valentine, R. J., Wilund, K. R., Antao, N. N., Baynard, T., & Woods, J. A. (2009) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00054.2009 · Cited by 194
“These findings support other work showing WAT Mφ infiltration to be a causative factor in systemic inflammation and its metabolic consequences (22).”
BackgroundResultThe Role of the Immune System in Obesity and Insulin Resistance
Patel, P., Buras, E. D., & Balasubramanyam, A. (2013) · Journal of Obesity · doi:10.1155/2013/616193 · Cited by 201
“Remarkably, only 24–48 hours after diphtheria toxin administration, glucose tolerance tests completely normalized in these mice, associated with improved insulin sensitivity in both liver and skeletal muscle [26].”
BackgroundZhuge, F., Ni, Y., Nagashimada, M., Nagata, N., Xu, L., Mukaida, N., Kaneko, S., & Ota, T. (2016) · Diabetes · doi:10.2337/db16-0317 · Cited by 194
“Deletion of M1 macrophages normalizes sensitivity to insulin in obese mice (3,31), whereas reducing the number of M2 macrophages predisposes lean mice to insulin resistance (4).”
BackgroundMetabolic inflammation: Connecting obesity and insulin resistance
Dali‐Youcef, N., Mecili, M., Ricci, R., & Andrès, E. (2012) · Annals of Medicine · doi:10.3109/07853890.2012.705015 · Cited by 201
Macrophage polarization in metabolic disorders
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“ATMs have emerged as crucial contributors both local (tissue-specific) and systemic inflammation (9;19;39;40).”
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
“First, ablation of CD11cþ inflammatory macrophages using CD11c-DTR transgenic mice improves insulin sensitivity without altering adipose tissue mass in obese animals (Patsouris et al. 2008).”
BackgroundAdipose Tissue Fibrosis in Obesity: Etiology and Challenges
Marcelin, G., Gautier, E. L., & Clément, K. (2021) · Annual Review of Physiology · doi:10.1146/annurev-physiol-060721-092930 · Cited by 201
The immunomodulating role of exercise in metabolic disease
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“20 Patsouris, D. et al. (2008) Ablation of CD11c-positive cells normalizes”
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“24 h after co-culturing, macrophages and adipocytes were collected separately for various assays.”
MethodNagata, N., Xu, L., Kohno, S., Ushida, Y., Aoki, Y., Umeda, R., Fuke, N., Zhuge, F., Ni, Y., Nagashimada, M., et al. (2017) · Diabetes · doi:10.2337/db16-0662 · Cited by 177
“Moreover, the specific ablation of M1-like macrophages restores insulin sensitivity in diet-induced obese mice (44), while the deletion of Pparδ, which promotes M2 activation, predisposes lean mice to develop insulin resistance (45).”
BackgroundInflammation and macrophage modulation in adipose tissues
Vieira‐Potter, V. J. (2014) · Cellular Microbiology · doi:10.1111/cmi.12336 · Cited by 185
“, 2010), predict the development of IR (Nguyen et al., 2007; Patsouris et al., 2008), and tend to surround necrotic adipocytes forming what are now called ‘crown-like structures’ (Cinti et al.”
BackgroundInfluentialResistant starch can improve insulin sensitivity independently of the gut microbiota
Bindels, L. B., Muñoz, R. R. S., Neto, J. C. G., Mutemberezi, V., Martínez, I., Salazar, N., Cody, E. A., Quintero, M., Kittana, H., Reyes‐Gavilán, C. G. D. L., et al. (2017) · Microbiome · doi:10.1186/s40168-017-0230-5 · Cited by 181
“ATMs in the development of insulin resistance [4], and RS-mediated improvements in insulin sensitivity in rats have been associated with reduced CD11c expression in adipose tissue [70].”
BackgroundSystemic inflammation and insulin sensitivity in obese IFN-γ knockout mice
O’Rourke, R. W., White, A. E., Metcalf, M. D., Winters, B. R., Diggs, B. S., Zhu, X., & Marks, D. L. (2012) · Metabolism · doi:10.1016/j.metabol.2012.01.018 · Cited by 177
“Since CD11c+ has been shown to designate an obesity-specific M1 inflammatory ATM subpopulation [1,19-21], we used flow cytometry to determine if IFN-γ-KO had an effect on total macrophage and CD11c+ macrophage subpopulation frequencies in VAT, SAT, and spleen.”
MethodCho, K. W., Morris, D. L., DelProposto, J. L., Geletka, L. M., Zamarron, B. F., Martinez-Santibañez, G., Meyer, K. A., Singer, K., O’Rourke, R. W., & Lumeng, C. N.-K. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.09.004 · Cited by 180
“Similar to other reports, ablation of CD11c+ ATMs in obese animals reverses insulin resistance and adipose tissue inflammation (Patsouris et al., 2008).”
ResultTejido adiposo: heterogeneidad celular y diversidad funcional
Esteve, M. (2013) · Endocrinología y Nutrición · doi:10.1016/j.endonu.2013.03.011 · Cited by 192
Extracellular vesicles in obesity and diabetes mellitus
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Molecular pathways linking adipose innervation to insulin action in obesity and diabetes mellitus
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“Conditional macrophage ablation in combination with transgenic and gene deletion mouse models have demonstrated that CD11c macrophages, Nlrp3-inflammasome components and pro-inflammatory cytokines promote glucose intolerance and IR in both dietinduced obesity (DIO) and genetic mouse models of obesity [9,10,11,12,13,14…”
BackgroundMethodTributyrin attenuates obesity-associated inflammation and insulin resistance in high-fat-fed mice
Vinolo, M. A. R., Rodrigues, H. G., Festuccia, W. T., Crisma, A. R., Alves, V. S., Martins, A. R., do Amaral, C. L., Fiamoncini, J., Hirabara, S. M., Sato, F. T., et al. (2012) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00053.2012 · Cited by 173
Pathophysiology of NASH: perspectives for a targeted treatment
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“In keeping, ablation of Cd11c-positive adipose tissue macrophages is associated with reduction of steatosis and normalization of insulin sensitivity [55].”
Quercetin Protects against Obesity-Induced Skeletal Muscle Inflammation and Atrophy
Le, N. H., Kim, C.-S., Park, T., Park, J. H. Y., Sung, M.-K., Lee, D. G., Hong, S.-M., Choe, S.-Y., Goto, T., Kawada, T., et al. (2014) · Mediators of Inflammation · doi:10.1155/2014/834294 · Cited by 167
“Because both macrophages and free fatty acids increase in obese skeletal muscle [20, 21], we cocultured C2C12 skeletal muscle myotubes (Mb) with Raw264.”
BackgroundAdipose tissue: Cell heterogeneity and functional diversity
Esteve, M. (2014) · Endocrinología y Nutrición (English Edition) · doi:10.1016/j.endoen.2014.02.001 · Cited by 176
“insulin sensitivity normalized.(60) Thus, the presence of M1 macrophages and the inability to activate them by the alternative route play a significant role in the maintenance of inflammation and the occurrence of insulin resistance and obesity.”
BackgroundThe immune system's involvement in obesity-driven type 2 diabetes
Shu, C. J., Benoist, C. O., & Mathis, D. J. (2012) · Seminars in Immunology · doi:10.1016/j.smim.2012.12.001 · Cited by 170
“proinflammatory cytokine levels, and increased insulin sensitivity [25].”
Renin‐Angiotensin‐Aldosterone System in Diabetes and Hypertension
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Vasculature-associated fat macrophages readily adapt to inflammatory and metabolic challenges
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“Another notable study is when CD11c+ cells were depleted by using CD11c-DFTR mice (Patsouris et al., 2008).”
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Adipose Tissue Inflammation in the Pathogenesis of Type 2 Diabetes
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Adipose tissue macrophages as potential targets for obesity and metabolic diseases
Li, X., Ren, Y., Chang, K.-W., Wu, W., Griffiths, H. R., Lu, S., & Gao, D. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1153915 · Cited by 181
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Macdougall, C. E., Wood, E. G., Loschko, J., Scagliotti, V., Cassidy, F. C., Robinson, M. E., Feldhahn, N., Castellano, L., Voisin, M.-B., Marelli‐Berg, F. M., et al. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.02.007 · Cited by 163
“Depletion of all CD11c+ cells (including CD11c+ monocytes/macrophages) resulted in a rapid normalization of insulin sensitivity and decrease of pro-inflammatory cytokines in obese mice (Bertola et al., 2012; Patsouris et al., 2008; Stefanovic-Racic et al., (s).”
BackgroundRole of Epicardial Adipose Tissue in Health and Disease: A Matter of Fat?
Gaborit, B., Sengenès, C., Ancel, P., Jacquier, A., & Dutour, A. (2017) · Comprehensive physiology · doi:10.1002/cphy.c160034 · Cited by 183
“M1-like phenotype has been considered as a key event in the induction of obesity visceral adipose tissue inflammation (29, 37, 189, 246).”
Lê, K., Mahurkar‐Joshi, S., Alderete, T. L., Hasson, R. E., Adam, T. C., Kim, J. S., Beale, E., Xie, C., Greenberg, A. S., Allayee, H., et al. (2011) · Diabetes · doi:10.2337/db10-1263 · Cited by 150
“CD11c+ cells are a subclass of macrophages, called dendritic cells, which have been demonstrated to be proinflammatory and linked to systemic insulin resistance (10,16).”
BackgroundMing, X., Rajapakse, A. G., Yepuri, G., Xiong, Y., Carvas, J. M., Ruffieux, J., Scerri, I., Wu, Z., Popp, K., Li, J., et al. (2012) · Journal of the American Heart Association · doi:10.1161/jaha.112.000992 · Cited by 155
“(2) Silencing the Arg-II gene in human monocyte/macrophage cell lines decreases cell adhesion to endothelial cells and the production of proinflammatory mediators in response to oxLDL or LPS at both the mRNA and protein levels.”
BackgroundCho, K. W., Zamarron, B. F., Muir, L. A., Singer, K., Porsche, C. E., DelProposto, J. B., Geletka, L. M., Meyer, K. A., O’Rourke, R. W., & Lumeng, C. N.-K. (2016) · The Journal of Immunology · doi:10.4049/jimmunol.1600820 · Cited by 149
“Ablation of CD11c cells attenuates adipose tissue inflammation and improves glucose tolerance without changes in body weight (15, 16).”
BackgroundLeung, A. S., Gregory, N. S., Allen, L. H., & Sluka, K. A. (2015) · Pain · doi:10.1097/j.pain.0000000000000312 · Cited by 158
“Similar to this study, exercise increases the number of regulatory macrophages in adipose tissue from obese mice.(22,38) Because one function of regulatory macrophages is to secrete antiinflammatory cytokines, the increase of regulatory macrophages within physically active muscle suggests a concomitant increase in ant…”
ResultWu, C., McNeill, J. N., Goon, K. C., Little, D., Kimmerling, K. A., Huebner, J. L., Kraus, V. B., & Guilak, F. (2017) · Arthritis & Rheumatology · doi:10.1002/art.40161 · Cited by 147
“depleted CD11c + (another common marker for M1 macrophages) cells by administrating diphtheria toxin without inducing severe neutrophilia (47).”
Exercise Attenuates M1 Macrophages and CD8+ T Cells in the Adipose Tissue of Obese Mice
Kawanishi, N., Mizokami, T., Yano, H., & Suzuki, K. (2013) · Medicine & Science in Sports & Exercise · doi:10.1249/mss.0b013e31828ff9c6 · Cited by 146
Role of T Cells in Malnutrition and Obesity
Gerriets, V. A., & MacIver, N. J. (2014) · Frontiers in Immunology · doi:10.3389/fimmu.2014.00379 · Cited by 154
“Many studies have demonstrated the role for classically activated M1 macrophages in promoting insulin resistance, and numerous mouse models have confirmed that disabling the macrophage inflammatory response pathway in obesity is protective against the development of insulin resistance (25, 28).”
BackgroundCXCL12 secreted from adipose tissue recruits macrophages and induces insulin resistance in mice
Kim, D., Kim, J. J., Yoon, J. H., Ghim, J., Yea, K., Song, P., Park, S., Lee, A.-R., Hong, C. P., Jang, M. S., et al. (2014) · Diabetologia · doi:10.1007/s00125-014-3237-5 · Cited by 151
“Following reports that interference with ATM action normalises insulin sensitivity in diabetic mice [6–8], recruitment of macrophages into adipose tissue has been determined to be the critical event in adipose tissue inflammation and insulin resistance [5, 9].”
BackgroundMechanisms of Macrophage Polarization in Insulin Signaling and Sensitivity
Orliaguet, L., Dalmas, É., Drareni, K., Venteclef, N., & Alzaïd, F. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.00062 · Cited by 151
“In 2008, Patsouris and colleagues demonstrated that the ablation of CD11c cells during obesity restored insulin sensitivity by decreasing inflammatory markers (68).”
BackgroundLindhorst, A., Raulien, N., Wieghofer, P., Eilers, J., Rossi, F. M. V., Bechmann, I., & Gericke, M. T. (2021) · Cell Death and Disease · doi:10.1038/s41419-021-03872-9 · Cited by 163
Innate immune activation in obesity
Lumeng, C. N.-K. (2012) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2012.10.002 · Cited by 147
“In addition, ablation of inflammatory CD11c+ ATMs leads to a rapid decrease in adipose tissue inflammation and an improvement in insulin sensitivity (Patsouris et al., 2008).”
BackgroundHume, D. A. (2010) · Journal of Leukocyte Biology · doi:10.1189/jlb.0810472 · Cited by 144
“For example, in obesityassociated insulin resistance, such cells are seen in large numbers in adipose tissue, and their removal can permit normalization of insulin sensitivity [126, 127].”
BackgroundImmuno-microbiota cross and talk: The new paradigm of metabolic diseases
Burcelin, R., Garidou, L., & Pomié, C. (2012) · Seminars in Immunology · doi:10.1016/j.smim.2011.11.011 · Cited by 148
“Ablation of dendritic cells in high-fat diet-induced insulin-resistant mice, leads to a decrease in inflammatory markers and normalized insulin sensitivity [62].”
BackgroundOliver, E., McGillicuddy, F. C., Harford, K. A., Reynolds, C. M., Phillips, C. M., Ferguson, J. F., & Roche, H. M. (2011) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2011.06.014 · Cited by 139
“014 [3,10], with recent studies demonstrating protection of mice with genetic ablation of CD11c cells from high-fat diet (HFD)-induced IR [11].”
Feng, B., Jiao, P., Nie, Y., Kim, T., Jun, D., van Rooijen, N., Yang, Z., & Xu, H. (2011) · PLoS ONE · doi:10.1371/journal.pone.0024358 · Cited by 145
“Despite the fact that a genetic approach was used previously to deplete CD11c positive macrophages in adipose tissue and improved systemic insulin sensitivity was observed [22], this”
BackgroundCD11c Expression in Adipose Tissue and Blood and Its Role in Diet-Induced Obesity
Wu, H., Perrard, X. D., Wang, Q., Perrard, J. L., Polsani, V. R., Jones, P. H., Smith, C. W., & Ballantyne, C. M. (2009) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.109.198044 · Cited by 139
Püschel, G. P., Klauder, J., & Henkel, J. (2022) · Journal of Clinical Medicine · doi:10.3390/jcm11154358 · Cited by 156
The Vasculature in Prediabetes
Wasserman, D. H., Wang, T. J., & Brown, N. J. (2018) · Circulation Research · doi:10.1161/circresaha.118.311912 · Cited by 137
“studies in M1-like macrophage knockout mice suggest they also promote insulin resistance.(84) Although macrophages are”
BackgroundInflammatory Concepts of Obesity
Rocha, V. Z., & Folco, E. J. E. (2011) · International Journal of Inflammation · doi:10.4061/2011/529061 · Cited by 140
“Whereas deficiency or inhibition of CD11c-positive cells [162], CD8 T cells [18], mast cells [20] and NKT cells [21] improves metabolic parameters, an increase in the pool of CD4+ Foxp3+ T cells following CD3-specific antibody”
BackgroundZhou, Y., Yu, X., Chen, H., Sjöberg, S., Roux, J., Zhang, L., Ivoulsou, A.-H., Bensaid, F., Liu, C.-L., Liu, J., et al. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.09.013 · Cited by 136
“The stimulation of M2 cells using omega-3 fatty acids or thiazolidinediones during obesity improves metabolic function and mutes adipose tissue inflammation (Patsouris et al., 2008; Oh et al., 2010).”
Chrysin attenuates inflammation by regulating M1/M2 status via activating PPARγ
Feng, X., Qin, H., Shi, Q., Zhang, Y., Zhou, F., Wu, H., Ding, S., Niu, Z., Lü, Y., & Shen, P. (2014) · Biochemical Pharmacology · doi:10.1016/j.bcp.2014.03.016 · Cited by 138
“2 and 5), which is consistent with the previous reports that deletion of M1 marker genes such as TNF-a [53] and C-C motif chemokine receptor (CCR2) [46] or ablation of CD11c-positive cells resulted in normalizing insulin sensitivity in obese animals [54].”
ResultInnate Immune Cells in the Adipose Tissue in Health and Metabolic Disease
Michailidou, Z., Gomez-Salazar, M. A., & Alexaki, V. I. (2021) · Journal of Innate Immunity · doi:10.1159/000515117 · Cited by 143
Adipose tissue macrophage in obesity-associated metabolic diseases
Yao, J., Wu, D., & Qiu, Y. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.977485 · Cited by 151
Epidermal fatty acid binding protein promotes skin inflammation induced by high-fat diet
Zhang, Y., Li, Q., Rao, E., Sun, Y., Grossmann, M. E., Morris, R. J., Cleary, M. P., & Li, B. (2015) · Immunity · doi:10.1016/j.immuni.2015.04.016 · Cited by 137
“In line with our observations, the pathogenic role of CD11c+ macrophages in promoting insulin resistance as well as adipose tissue inflammation in obese mouse models has been confirmed by other studies (Patsouris et al., 2008; Lumeng et al., 2007; Wentworth et al., 2010).”
InfluentialRole of pro- and anti-inflammatory phenomena in the physiopathology of type 2 diabetes and obesity
Pirola, L., & Ferraz, J. C. (2017) · World Journal of Biological Chemistry · doi:10.4331/wjbc.v8.i2.120 · Cited by 139
Air Pollution as a Risk Factor for Type 2 Diabetes
Rao, X., Patel, P., Puett, R. C., & Rajagopalan, S. (2014) · Toxicological Sciences · doi:10.1093/toxsci/kfu250 · Cited by 136
“…trafficking by ablation of C-C chemokine receptor type 2 (CCR2) or depletion of M1 macrophages by CD11c knockout reduces obesity-induced by guest on January 13, 2016 http://toxsci.oxfordjournals.org/ D ow nloaded from adipose inflammation and IR (Patsouris et al., 2008; Weisberg et al., 2006).”
BackgroundRole of macrophage tissue infiltration in obesity and insulin resistance
Bourlier, V., & Bouloumié, A. (2009) · Diabetes & Metabolism · doi:10.1016/j.diabet.2009.05.001 · Cited by 141
“Although conflicting results have been reported [4,106], he presence of macrophages (CD11c+ cells) in skeletal muscle nd their accumulation in HFD-fed mice have been associted with increased expression of inflammatory factors [9,76], hereas ablation of myeloid CD11c+ cells reduced muscle acrophage content and decrease…”
BackgroundResultMeshkani, R., & Vakili, S. (2016) · Clinica Chimica Acta · doi:10.1016/j.cca.2016.08.015 · Cited by 136
“(CD11c + ) macrophages in skeletal muscle tissue in the context of obesity and insulin resistance [51, 91].”
BackgroundKillion, E. A., Reeves, A. R., ElAzzouny, M. A., Yan, Q.-W., Surujon, D., Griffin, J. D., Bowman, T. A., Wang, C., Matthan, N. R., Klett, E. L., et al. (2018) · Molecular Metabolism · doi:10.1016/j.molmet.2018.01.012 · Cited by 136
A Novel Function of Adipocytes in Lipid Antigen Presentation to iNKT Cells
Huh, J. Y., Kim, J. I., Park, Y. J., Hwang, I., Lee, Y. S., Sohn, J. H., Lee, S. K., Alfadda, A. A., Kim, S. S., Choi, S. H., et al. (2012) · Molecular and Cellular Biology · doi:10.1128/mcb.00552-12 · Cited by 137
Eguchi, J., Kong, X., Tenta, M., Wang, X., Kang, S., & Rosen, E. D. (2013) · Diabetes · doi:10.2337/db12-1327 · Cited by 134
Lanthier, N., Molendi‐Coste, O., Cani, P. D., van Rooijen, N., Horsmans, Y., & Leclercq, I. A. (2011) · The FASEB Journal · doi:10.1096/fj.11-189472 · Cited by 138
“We also show, in accordance with others (33, 34), that prolonged HFD feeding is needed to observe inflammatory and insulin sensitivity changes in skeletal muscle.”
ResultAdipocytes: Impact on tumor growth and potential sites for therapeutic intervention
Hefetz-Sela, S., & Scherer, P. E. (2013) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2013.01.008 · Cited by 136
Csóka, B., Koscsó, B., Törő, G., Kókai, E., Virág, L., Németh, Z. H., Pacher, P., Bai, P., & Haskó, G. (2013) · Diabetes · doi:10.2337/db13-0573 · Cited by 127
Dietary Regulation of Immunity
Lee, A. H., & Dixit, V. D. (2020) · Immunity · doi:10.1016/j.immuni.2020.08.013 · Cited by 127
“512 Immunity 53, September 15, 2020 CD11c ATMs during DIO reduces local and systemic pro-inflammatory cytokine amounts, reduces CLSs and infiltrating macrophages, and leads to rapid normalization of insulin sensitivity, thus highlighting the role of inflammatory ATMs in driving metabolic disease (Patsouris et al., 200…”
BackgroundGonzález, F., Nair, K. S., Daniels, J. K., Basal, E., Schimke, J. M., & Blair, H. E. (2012) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2012-1259 · Cited by 121
Mannan-oligosaccharide modulates the obesity and gut microbiota in high-fat diet-fed mice
Wang, H., Zhang, X., Wang, S., Li, H., Lu, Z., Shi, J., & Xu, Z. (2018) · Food & Function · doi:10.1039/c8fo00209f · Cited by 125
Fuentes, L., Rőszer, T., & Ricote, M. (2010) · Mediators of Inflammation · doi:10.1155/2010/219583 · Cited by 122
“Interestingly, conditional bone marrow depletion of CD11c+ cells in obese mice results in a rapid normalization of insulin sensitivity [24].”
BackgroundThe Role of Lipophagy in the Development and Treatment of Non-Alcoholic Fatty Liver Disease
Grefhorst, A., van de Peppel, I. P., Larsen, L. E., Jonker, J. W., & Holleboom, A. G. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.601627 · Cited by 122
ATP-Induced Inflammation Drives Tissue-Resident Th17 Cells in Metabolically Unhealthy Obesity
Pandolfi, J. B., Ferraro, A., Sananez, I., Gancedo, M. C., Baz, P., Billordo, L. A., Fainboim, L., & Arruvito, L. (2016) · The Journal of Immunology · doi:10.4049/jimmunol.1502506 · Cited by 115
Lipotoxicity in macrophages: evidence from diseases associated with the metabolic syndrome
Prieur, X., Rőszer, T., & Ricote, M. (2009) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2009.09.017 · Cited by 121
Role and function of macrophages in the metabolic syndrome
Bhargava, P., & Lee, C. (2012) · Biochemical Journal · doi:10.1042/bj20111708 · Cited by 117
Lipoxin A 4 attenuates adipose inflammation
Börgeson, E., McGillicuddy, F. C., Harford, K. A., Corrigan, N., Higgins, D. F., MADERNA, P., Roche, H. M., & Godson, C. (2012) · The FASEB Journal · doi:10.1096/fj.12-208249 · Cited by 114
“Promoting a shift of M1 to M2 phenotype may, however, be a more physiological approach to subverting adipose inflammation, since the M s are required for effective resolution (40).”
BackgroundInsights into the Link Between Obesity and Cancer
Ackerman, S. E., Blackburn, O. A., Marchildon, F., & Cohen, P. (2017) · Current Obesity Reports · doi:10.1007/s13679-017-0263-x · Cited by 121
Metadata
- Authors
- Patsouris, D., Li, P.-P., Thapar, D., Chapman, J., Olefsky, J. M., & Neels, J. G.
- Affiliations
- University of California San Diego (US)
- Pfizer (United States) (US)
- Corresponding author
- Neels, Jaap G.
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2008-10
- Volume
- 8
- Issue
- 4
- Pages
- 301-309
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC2630775
- OpenAlex
- W2011255130
- Cited by
- 804
- References
- 34
- Citations by year
- 2026: 13 · 2025: 24 · 2024: 24 · 2023: 31 · 2022: 29 · 2021: 65 · 2020: 45 · 2019: 47 · 2018: 52 · 2017: 60 · 2016: 62 · 2015: 60 · 2014: 70 · 2013: 70 · 2012: 50
- FWCI
- 25.07
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Moores Cancer Center, UC San Diego Health
- University of California, San Diego
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 074868, DK 033651, R37DK033651, P01DK074868, R01DK033651)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P50HD012303, HD012303, U54HD012303)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Disease and Adiposity
- Keywords
- CD11c+ macrophages, obesity, insulin resistance, adipose tissue macrophages, macrophage depletion, diphtheria toxin receptor, inflammation, type 2 diabetes, therapeutic target
- MeSH terms
- Adipose Tissue, Animals, Glucose, Homeostasis, Humans, Insulin, Insulin Resistance, Liver, Macrophages, Male, Mice, Inbred C57BL, Mice, Transgenic, Obesity, Gene Expression, Cytokines, Chemokines, Chemokine CCL2, Intercellular Signaling Peptides and Proteins, CD11c Antigen, Mice, Heparin-binding EGF-like Growth Factor
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