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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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“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).”
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InfluentialIKK-β links inflammation to obesity-induced insulin resistance
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“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 the diet in which…”
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“Moreover, Patsouris et al. (2008) have reported that selective depletion of CD11c+ macrophages in adipose tissue reverses insulin resistance in high-fat diet-induced obese mice.”
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“Ablation of inflammatory macrophages (Patsouris et al. 2008, Weisberg et al. 2006) or deletion of IKKβ (Arkan et al. 2005), JNK1 (Solinas et al. 2007), the insulin receptor (Mauer et al. 2010), Annu Rev Cell Dev Biol.”
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“flammation (7) and protects mice from insulin resistance (8, 9).”
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“…it is generally accepted that proinflammatory ATMs are linked with the development of systemic insulin resistance and other metabolic diseases (Patsouris et al, 2008), even though the complete spectrum of initiators and the pathophysiological consequences of this infiltration have yet to be 1…”
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“In particular, CD11c-positive macrophages promote the development of insulin 251 resistance in adipocytes, and elimination of these cells by a gene-targeting method 252 improved insulin sensitivity [15].”
BackgroundThe transcriptional coregulator GRIP1 controls macrophage polarization and metabolic homeostasis
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“It has been found that obese mice treated with two distinct chemical chaperones exhibits reduced ER stress that eventually increases glucose tolerance and insulin sensitivity along with decreased JNK activity which showed same results on human trial as well [124,125].”
BackgroundDietary Methionine Restriction Reduces Inflammation Independent of FGF21 Action
Sharma, S., Dixon, T., Jung, S., Graff, E. C., Forney, L. A., Gettys, T. W., & Wanders, D. (2019) · Obesity · doi:10.1002/oby.22534 · Cited by 55
“In fact, macrophages that express F4/80, CD11B, and CD11C represent a specific population of macrophages that are recruited to adipose tissue in response to HFD feeding (26).”
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“Ablation of pro-inflammatory CD11c(M1) macrophages ameliorates IR coincident with diminished systemic inflammation in obese mice [40].”
BackgroundFunctional crosstalk of PGC-1 coactivators and inflammation in skeletal muscle pathophysiology
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“In addition, depletion of CD11c MNPs in bone marrow (BM) chimeric mice transplanted with Itgax-DTR BM cells also dampens the inflammatory cytokine expression and improves the insulin sensitivity in diet-induced obese mice but not in lean mice, without affecting the body weight (Patsouris et al., 2008).”
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“Discussion Recent studies have detected elevated numbers of myeloid cell or macrophage markers in skeletal muscle during HFD and obesity [13,25-27], but how these immune cells are influenced by the surrounding tissue and their role in the progression of insulin resistance are unknown.”
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“Another study with same model, showed that CD11c+ cell ablation results in the reduction of CLS formation with increased Il10 and decreased Il6 and Mcp1 expression in VAT [54].”
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“…different sets of markers, they are all part of our newly discovered meta-signature together with other genes that were previously implicated in IR in WAT ( Cd9 [Hill et al., 2018], Cd36 [Kennedy et al., 2011], Lgals3 [Li et al., 2016; Pejnovic et al., 2013], and Itgax [Patsouris et al., 2008]).”
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“Proinflammatory adipose tissue macrophages promote insulin resistance in obese mice”
BackgroundAdipose tissue macrophage dysfunction is associated with a breach of vascular integrity in NASH
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“For example, in male mice, Patsouris et al. [153] demonstrated that the depletion of CD11c + cells (M1-like macrophages) from epididymal fat pads caused rapid normalization of insulin sensitivity along with decreases in local and systemic inflammatory markers [153].”
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“Furthermore, ablation of CD11c+ ATM in obese adipose tissue attenuates adipose tissue inflammation and improves in glucose tolerance, supporting the importance of M1 ATMs in obesity-induced adipose tissue inflammation (13, 14).”
BackgroundA Macrophage NBR1-MEKK3 Complex Triggers JNK-Mediated Adipose Tissue Inflammation in Obesity
Hernandez, E. D., Lee, S. J., Kim, J. Y., Durán, Á., Linares, J. F., Yajima, T., Müller, T. D., Tschöp, M. H., Smith, S. R., Díaz-Meco, M. T., et al. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.06.008 · Cited by 49
“Also, experiments from a number of research groups have demonstrated that the ablation of macrophages in mice normalizes glucose homeostasis in the context of obesity (Gordon, 2003; Gordon and Taylor, 2005; Lumeng et al., 2007a, 2007b, 2007c; Mantovani et al., 2004; Patsouris et al., 2008).”
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“Once again, further study is needed to determine whether a different status of macrophages [77] between Hfe knockout mice and high-iron diet-induced diabetic mice is also contributed to this difference in insulin sensitivity.”
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Background
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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