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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]
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“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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“CD11c-CD206þ cells secrete IL10, are involved in tissue maintenance and repair, and may facilitate adipogenesis.(6,7) In contrast, CD11cþCD206þ macrophages increase in obesity and aggregate around necrotic adipocytes in crown-like structures and have been associated with the production of proinflammatory cytokines and…”
BackgroundElias, I., Franckhauser, S., Ferré, T., Vilà, L., Tafuro, S., MUÑOZ, S. A., Roca, C., Ramos, D., Pujol, A., Riu, E., et al. (2012) · Diabetes · doi:10.2337/db11-0832 · Cited by 332
“In line with our studies, the ablation of CD11c cells in mice leads to a marked reduction in proinflammatory cytokines and an improvement of insulin sensitivity (42).”
ResultMacrophage functions in lean and obese adipose tissue
Thomas, D. D., & Apovian, C. M. (2017) · Metabolism · doi:10.1016/j.metabol.2017.04.005 · Cited by 333
Chronic adipose tissue inflammation: all immune cells on the stage
Cildir, G., Akıncılar, S. C., & Tergaonkar, V. (2013) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2013.05.001 · Cited by 329
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“It has also been reported that the ablation of CD11c cells decreases the inflammatory condition and protects against high-fat diet-induced insulin resistance [37].”
BackgroundDeFuria, J., Bennett, G., Strissel, K. J., James, W. P., Milbury, P. E., Greenberg, A. S., & Obin, M. S. (2009) · The Journal of Nutrition · doi:10.3945/jn.109.105155 · Cited by 313
“Consistent with the notion that the actions of BB to prevent adipocyte apoptosis reflect the salutary effects of BB on ATMF are recent observations (7,33) suggesting that inflammatory CD11c+ ATMF participate in adipocyte execution as well as clearance [see also (8)].”
BackgroundMechanisms of Inflammatory Responses in Obese Adipose Tissue
Sun, S., Ji, Y., Kersten, S., & Qi, L. (2012) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-071811-150623 · Cited by 322
Harford, K. A., Reynolds, C. M., McGillicuddy, F. C., & Roche, H. M. (2011) · Proceedings of The Nutrition Society · doi:10.1017/s0029665111000565 · Cited by 309
“More recently, it was shown that CD11c depletion results in a rapid normalisation of glucose and insulin tolerance and a decrease in inflammatory markers both at the transcriptional and translational levels((49)).”
BackgroundHematopoietic-Derived Galectin-3 Causes Cellular and Systemic Insulin Resistance
Li, P., Liu, S., Lu, M. M., Bandyopadhyay, G. K., Oh, D., Imamura, T., Johnson, A. M. F., Sears, D. D., Shen, Z., Cui, B., et al. (2016) · Cell · doi:10.1016/j.cell.2016.10.025 · Cited by 305
Self-citationSirT1 regulates adipose tissue inflammation
Gillum, M. P., Kotas, M. E., Erion, D. M., Kursawe, R., Chatterjee, P., Nead, K. T., Muise, E. S., Hsiao, J. J., Frederick, D. W., Yonemitsu, S., et al. (2011) · Diabetes · doi:10.2337/db11-0616 · Cited by 260
“This is consistent with data showing that although “M1” macrophages are disproportionately increased, “M2” macrophages (CD11c-) are also dramatically increased in obese WAT (44).”
BackgroundResultSelf-citationCoats, B. R., Schoenfelt, K. Q., Barbosa-Lorenzi, V. C., Peris, E., Cui, C., Hoffman, A., Zhou, G., Fernandez, S., Zhai, L., Hall, B. A., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.08.096 · Cited by 291
“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).”
Yang, Z., & Ming, X.-F. (2014) · Frontiers in Immunology · doi:10.3389/fimmu.2014.00533 · Cited by 290
Dong, J., Zhang, X., Zhang, L., Bian, H., Xu, N., Bao, B., & Liu, J. (2014) · Journal of Lipid Research · doi:10.1194/jlr.m038786 · Cited by 299
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“On the other hand, a number of more in-depth studies have repeatedly observed increased macrophage numbers in skeletal muscle in association with obesity (34, 46, 89, 99, 154, 163).”
BackgroundRodríguez, A., Ezquerro, S., Méndez-Giménez, L., Becerril, S., & Frühbeck, G. (2015) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00297.2015 · Cited by 287
Macrophages in obesity and non-alcoholic fatty liver disease: crosstalk with metabolism
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AGE restriction in diabetes mellitus: a paradigm shift
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“In addition, responses to 'unique' antigens by expanded subpopulations of activated T-helper-1 (T H 1) cells that are present in muscle and adipose tissue were shown to promote insulin resistance”
Kraakman, M. J., Murphy, A. J., Jandeleit-Dahm, K. A. M., & Kammoun, H. L. (2014) · Frontiers in Immunology · doi:10.3389/fimmu.2014.00470 · Cited by 278
“They demonstrated that ablation of M1 macrophages, achieved by targeting diphtheria-sensitive CD11c cells with diphtheria toxin, was associated with improved glucose tolerance (17).”
BackgroundStrissel, K. J., DeFuria, J., Shaul, M. E., Bennett, G., Greenberg, A. S., & Obin, M. S. (2010) · Obesity · doi:10.1038/oby.2010.1 · Cited by 276
Role of immune cells in obesity induced low grade inflammation and insulin resistance
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Heme Oxygenase-1 Drives Metaflammation and Insulin Resistance in Mouse and Man
Jaïs, A., Einwallner, E., Sharif, O., Gossens, K., Lu, T. T.-H., Soyal, S. M., Medgyesi, D., Neureiter, D., Paier-Pourani, J., Dalgaard, K., et al. (2014) · Cell · doi:10.1016/j.cell.2014.04.043 · Cited by 270
Macrophages, Chronic Inflammation, and Insulin Resistance
He, L., Meng, Y., He, S., Tan, X., Zhang, Y., Zhang, X., Wang, L., & Zheng, W. (2022) · Cells · doi:10.3390/cells11193001 · Cited by 286
Ying, W., Lee, Y. S., Dong, Y. W., Seidman, J. S., Yang, M., Isaac, R., Seo, J. B., Yang, B.-H., Wollam, J., Riopel, M., et al. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.12.003 · Cited by 281
“While CD11cDTR mice are a useful model to deplete CD11c cells with diphtheria toxin (DT) treatment, this method deletes macrophages throughout the body, including adipose tissue, liver, and islets (Patsouris et al., 2008).”
MethodSelf-citationAdipocyte-Macrophage Cross-Talk in Obesity
Engin, A. B. (2017) · Advances in experimental medicine and biology · doi:10.1007/978-3-319-48382-5_14 · Cited by 275
Kraakman, M. J., Kammoun, H. L., Allen, T. L., Deswaerte, V., Henstridge, D. C., Estevez, E., Matthews, V. B., Neill, B., White, D. A., Murphy, A. J., et al. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.02.006 · Cited by 257
“Based on our data, it is likely that in previous studies where macrophages have been ablated (Feng et al., 2011; Patsouris et al., 2008), improved insulin action was mediated by effects of macrophage independent of the adipose tissue.”
BackgroundResultInfluentialAdipose tissue macrophages: phenotypic plasticity and diversity in lean and obese states
Morris, D. L., Singer, K., & Lumeng, C. N.-K. (2011) · Current Opinion in Clinical Nutrition & Metabolic Care · doi:10.1097/mco.0b013e328347970b · Cited by 262
FoxO1 regulates Tlr4 inflammatory pathway signalling in macrophages
Fan, W., Morinaga, H., Kim, J. J., Bae, E., Spann, N. J., Heinz, S., Glass, C. K., & Olefsky, J. M. (2010) · The EMBO Journal · doi:10.1038/emboj.2010.268 · Cited by 259
“Recent studies, including those from our group, have further suggested that macrophages are the most pro- minent immune cells underlying the proinflammatory tissue response associated with obesity and type 2 diabetes mellitus (Patsouris et al, 2008; Schenk et al, 2008).”
ResultSelf-citationKupffer cell activation is a causal factor for hepatic insulin resistance
Lanthier, N., Molendi‐Coste, O., Horsmans, Y., van Rooijen, N., Cani, P. D., & Leclercq, I. A. (2009) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00391.2009 · Cited by 269
“Accordingly, F4/ 80 CD11b CD11c M1 adipose tissue macrophages (ATM) increase in number in obese adipose tissue (28, 34) and suppression of such inflammation improves insulin sensitivity and dissociates adiposity from insulin resistance (15, 37, 42, 48, 55).”
Macrophage function in adipose tissue homeostasis and metabolic inflammation
Chavakis, T., Alexaki, V. I., & Ferrante, A. W. (2023) · Nature Immunology · doi:10.1038/s41590-023-01479-0 · Cited by 279
“For example, depletion of CD11c + cells improves insulin sensitivity in mice with diet-induced obesity 100 .”
BackgroundPatel, V. B., Mori, J., McLean, B. A., Basu, R., Das, S. K., Ramprasath, T., Parajuli, N., Penninger, J. M., Grant, M. B., Lopaschuk, G. D., et al. (2015) · Diabetes · doi:10.2337/db15-0399 · Cited by 260
“, TNF-a) and the ablation of CD11c cells (38,39).”
BackgroundKim, J. J., & Sears, D. D. (2010) · Gastroenterology Research and Practice · doi:10.1155/2010/212563 · Cited by 260
“These macrophages contribute to the development of inflammation in adipose tissue and are believed to be a key contributor to insulin resistance [69].”
BackgroundInterplay between the immune system and adipose tissue in obesity
Exley, M. A., Hand, L., O'Shea, D., & Lynch, L. (2014) · Journal of Endocrinology · doi:10.1530/joe-13-0516 · Cited by 242
“2006) and, similarly, selective depletion of M1 macrophages in obese animal models reduces WAT inflammation without affecting diet-induced obesity (Patsouris et al. 2008).”
BackgroundEsser, N., L’homme, L., Roover, A. D., Kohnen, L. P., Scheen, A. J., Moutschen, M. P., Piette, J. G., Legrand-Poels, S., & Paquot, N. (2013) · Diabetologia · doi:10.1007/s00125-013-3023-9 · Cited by 248
“While well established in mice [16, 17, 21, 22], the existence of M1 and M2 subsets of ATMs in humans has not been confirmed and human ATMs subtypes have rather been described with a mix of M1 and M2 gene expression profile [20].”
BackgroundFunctional Heterogeneity of CD11c-positive Adipose Tissue Macrophages in Diet-induced Obese Mice
Li, P., Lu, M. M., Nguyen, M. T., Bae, E. J., Chapman, J., Feng, D., Hawkins, M. A., Pessin, J. E., Sears, D. D., Nguyen, A.-K., et al. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.100263 · Cited by 249
Self-citation
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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