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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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“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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InfluentialIKK-β links inflammation to obesity-induced insulin resistance
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“The phenotypic switch from M2 to M1 may be an important determinant of insulin resistance in obese mice since conditional ablation of promoter-dependent CD11c (a known marker for dendritic cells) in AT macrophages improves insulin sensitivity (35).”
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γδ T cells promote inflammation and insulin resistance during high fat diet-induced obesity in mice
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BackgroundMuscle insulin resistance: assault by lipids, cytokines and local macrophages
Kewalramani, G., Bilan, P. J., & Klip, A. (2010) · Current Opinion in Clinical Nutrition & Metabolic Care · doi:10.1097/mco.0b013e32833aabd9 · Cited by 105
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“Improvement of insulin sensitivity following ablation of MNC-derived macrophages in muscle of insulin resistant animals corroborates this concept (Patsouris et al., 2008).”
ResultAdipocytes Secrete Leukotrienes
Mothe‐Satney, I., Filloux, C., Amghar, H., Pons, C., Bourlier, V., Galitzky, J., Grimaldi, P. A., Féral, C. C., Bouloumié, A., OBBERGHEN, E. V., et al. (2012) · Diabetes · doi:10.2337/db11-1455 · Cited by 106
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Self-citationAdipose tissue macrophages and their polarization in health and obesity
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BackgroundInteractions between inflammation, sex steroids, and Alzheimer’s disease risk factors
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“In support of this position, deletion of macrophages can restore insulin and glucose homeostasis associated with obesity (Patsouris et al., 2008).”
Targeted delivery of curcumin for treating type 2 diabetes
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“Selective depletion of CD11c+ macrophages by utilising mice expressing the diphtheria toxin receptor in CD11c+ cells resulted in reduction of the number of macrophages as well as of AT inflammation and led to improved insulin sensitivity in the diet-induced obesity-model (31).”
BackgroundAdipose tissue inflammation in glucose metabolism
Kammoun, H. L., Kraakman, M. J., & Febbraio, M. A. (2013) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-013-9274-4 · Cited by 101
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“On the other hand, selective depletion of CD11c macrophages resulted in rapid normalization of insulin sensitivity in mice [4].”
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“In obese rodents and humans, the gene expression level of CD11c (a marker of M1/inflammatory M ) within AAT has been linked to the development of IR (13, 17).”
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BackgroundNeuropeptide Y Is Produced by Adipose Tissue Macrophages and Regulates Obesity-Induced Inflammation
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“In addition, innate immune cell populations, especially macrophages enriched in the Nox2 system, are elevated in skeletal muscle in both obese humans and mice (61, 102, 158).”
BackgroundRole of the gut in visceral fat inflammation and metabolic disorders
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Macrophage VLDLR mediates obesity-induced insulin resistance with adipose tissue inflammation
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GABA-stimulated adipose-derived stem cells suppress subcutaneous adipose inflammation in obesity
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“It is well established that elevation of inflammatory responses in adipose tissue is one of the crucial risk factors for insulin resistance (23).”
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“Moreover, in ob/ob mice reconstituted with bone marrow from CD11c-diphtheria toxin receptor transgenic mice, ablation of CD11c+ ATMs with diphtheria toxin prevents insulin resistance (17).”
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“Adipose tissue of obese subjects is infiltrated by inflammatory macrophages positive for F4/80, CD11b and CD11c which predominantly display a classically activation, (M1-like macrophages) [205, 206].”
BackgroundMelatonin reduces obesity and restores adipokine patterns and metabolism in obese ( ob/ob ) mice
Favero, G., Stacchiotti, A., Castrezzati, S., Bonomini, F., Albanese, M., Rezzani, R., & Rodella, L. F. (2015) · Nutrition Research · doi:10.1016/j.nutres.2015.07.001 · Cited by 92
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“This was associated with downregulated CCL2 gene, less numerous hepatic mature mDCs (Figure 2), CD11b+Ly6C+ monocytes/macrophages and F4/80+CD11b+CD11c+ macrophages (Figure 3), the cell types that promote the development of NASH (37,40,41).”
BackgroundInfluentialDirect and macrophage-mediated actions of fatty acids causing insulin resistance in muscle cells
Bilan, P. J., Samokhvalov, V., Koshkina, A., Schertzer, J. D., Samaan, M. C., & Klip, A. (2009) · Archives of Physiology and Biochemistry · doi:10.1080/13813450903079314 · Cited by 88
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“immune system—macrophages [2,3], conventional T cells [4,5,6],”
PD-1 Is Involved in the Dysregulation of Type 2 Innate Lymphoid Cells in a Murine Model of Obesity
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“Accordingly, two reports demonstrate that macrophage ablation resulted in normalization of insulin sensitivity (Feng et al., 2011; Patsouris et al., 2008).”
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“CD11c (Itgax) gene expression, a marker of M1 macrophage proinflammatory polarization [23], increased with HFD in EWAT, a phenomenon that was not observed with OPN-deficiency (Fig.”
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Changes in Adipose Tissue Macrophages and T Cells During Aging
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“org 5 cell depletion led to decreased adipose tissue inflammation and rapid normalization of insulin sensitivity (77).”
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Innate immune cells in the adipose tissue
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“Previous studies have shown that suppressing macrophage proinflammatory activation or entirely depleting the macrophage population is protective against diet-induced metabolic dysregulation (67, 68).”
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“Diphtheria toxin-induced ablation of CD11c + cells in vivo normalised insulin sensitivity in obese mice coincident with reduced local and systemic inflammatory gene expression((58)).”
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“Accordingly, conditional deletion of CD11c proinflammatory (M1) macrophages normalizes insulin sensitivity and reduces inflammatory markers in dietinduced obesity (2).”
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“Indeed, HFD-fed mice exhibited an increased number of CD11c DCs in the AT whose ablation attenuated visceral AT inflammation (160, 161, 163).”
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“M1 macrophages seem to favor insulin resistance and in murine models their deactivation protects against insulin resistance (25, 26).”
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“To identify the cell origin of SR-A expression we further analyzed SR-A expression in microglia/ macrophages by flow cytometry using CD11c as the marker for M1 macrophages (Patsouris et al., 2008; Prieur Western blot of SR-A in postischemic brain tissues.”
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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