The DOI matches its Crossref record; 34 of the 34 references it cites were found in a registry or an index.
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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Cites
Obesity 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 3×
“…shown that obesity is associated with increased macrophage content in skeletal muscle, including CD11c+ cells, and this muscle macrophage accumulation is accompanied by increased expression of inflammatory factors in muscle (Hevener et al., 2007; Nguyen et al., 2007; Weisberg et al., 2003).”
The chemokine system in diverse forms of macrophage activation and polarization
MANTOVANI, A., SICA, A., SOZZANI, S., ALLAVENA, P., VECCHI, A., & LOCATI, M. (2004) · Trends in Immunology · doi:10.1016/j.it.2004.09.015 · Cited by 6,534 · 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).”
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
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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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“…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).”
Jung, S., Unutmaz, D., Wong, P., Sano, G., Santos, K. D. L., Sparwasser, T., Wu, S., Vuthoori, S., Ko, K., Zavala, F., et al. (2002) · Immunity · doi:10.1016/s1074-7613(02)00365-5 · Cited by 1,953 · cited 3×
“While transient DC depletion was not associated with signs of illness or long-term defects, repeated DT induction is lethal to the mouse (Jung et al., 2002).”
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×
“In both humans and rodents, adipose tissue macrophages (ATMs) accumulate in adipose tissue (AT) with increasing body weight, and evidence is mounting that implicates ATMs as a significant contributor to inflammation in obesity and a mediator of IR (Shoelson et al., 2007).”
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
Self-citationAssociation of nonalcoholic fatty liver disease with insulin resistance
Marchesini, G., Brizi, M., Morselli‐Labate, A. M., Bianchi, G. P., Bugianesi, E., McCullough, A. J., Forlani, G., & Melchionda, N. (1999) · The American Journal of Medicine · doi:10.1016/s0002-9343(99)00271-5 · Cited by 1,570 · cited 1×
“Hepatic insulin resistance is usually accompanied by increased liver triglyceride (TG) content (Marchesini et al., 1999).”
CCR2 modulates inflammatory and metabolic effects of high-fat feeding
Weisberg, S. P., Hunter, D., Huber, R., Lemieux, J., Slaymaker, S., Vaddi, K., Charo, I., Leibel, R. L., & Jr., A. W. F. (2006) · Journal of Clinical Investigation · doi:10.1172/jci24335 · Cited by 1,497
CCR2 modulates inflammatory and metabolic effects of high-fat feeding
Weisberg, S. P. (2006) · Journal of Clinical Investigation · doi:10.1172/jci24335c1 · Cited by 1,425 · cited 2×
“…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 increase in ATMs is associated with a further deterioration of insulin sensitivity (Hirasaka et al., 2007; Kamei et…”
Cancello, R., Henegar, C., Viguerie, N., Taleb, S., Poitou, C., Rouault, C., Coupaye, M., Pelloux, V., Hugol, D., Bouillot, J.-L., et al. (2005) · Diabetes · doi:10.2337/diabetes.54.8.2277 · Cited by 1,164 · cited 3×
“In contrast, CD11c ATMs expressed high levels of the anti-inflammatory cytokine IL-10, while CD11c+ ATMs exhibited no detectable levels of IL-10 (Nguyen et al., 2007).”
Nguyen, M. T. A., Favelyukis, S., Nguyen, A.-K., Reichart, D., Scott, P. A., Jenn, A., Liu-Bryan, R., Glass, C. K., Neels, J. G., & Olefsky, J. M. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m706762200 · Cited by 1,035 · cited 12×
“Ablation of CD11c-Positive Cells and Inflammatory Gene Expression Given that the CD11c ATMs are important contributors to the increased expression of proinflammatory genes in obese AT (Lumeng et al., 2007; Nguyen et al., 2007), we quantified the expression of several of these genes in adipose tissue.”
InfluentialSelf-citationAdipocyte Death, Adipose Tissue Remodeling, and Obesity Complications
Strissel, K. J., Stancheva, Z., Miyoshi, H., Perfield, J. W., DeFuria, J., Jick, Z., Greenberg, A. S., & Obin, M. S. (2007) · Diabetes · doi:10.2337/db07-0767 · Cited by 1,007 · cited 1×
“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).”
Kamei, N., Tobe, K., Suzuki, R., Ohsugi, M., Watanabe, T., Kubota, N., Ohtsuka-Kowatari, N., Kumagai, K., Sakamoto, K. Q., Kobayashi, M., et al. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m601284200 · Cited by 916 · cited 2×
“, 2006), while an increase in ATMs is associated with a further deterioration of insulin sensitivity (Hirasaka et al., 2007; Kamei et al., 2006; Kanda et al., 2006).”
Solinas, G., Vilcu, C., Neels, J. G., Bandyopadhyay, G. K., Luo, J.-L., Naugler, W., Grivennikov, S., Wynshaw-Boris, A., Scadeng, M., Olefsky, J. M., et al. (2007) · Cell Metabolism · doi:10.1016/j.cmet.2007.09.011 · Cited by 513 · cited 2×
“Moreover, we showed that disabling the in- C flammatory pathway within macrophages by creating a myeloid cell-specific knockout of IkB kinase b (IKK-b) or JNK1 protected mice from diet-induced insulin resistance (Arkan et al., 2005; Solinas et al., 2007).”
Self-citationInflamed fat: what starts the fire?
Neels, J. G. (2005) · Journal of Clinical Investigation · doi:10.1172/jci27280 · Cited by 463 · cited 2×
“…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 increase in ATMs is associated with a further deterioration of…”
Self-citationHevener, A. L., Olefsky, J. M., Reichart, D., Nguyen, M. T. A., Bandyopadyhay, G., Leung, H.-Y., Watt, M. J., Benner, C., Febbraio, M. A., Nguyen, A.-K., et al. (2007) · Journal of Clinical Investigation · doi:10.1172/jci31561 · Cited by 459 · cited 2×
“…shown that obesity is associated with increased macrophage content in skeletal muscle, including CD11c+ cells, and this muscle macrophage accumulation is accompanied by increased expression of inflammatory factors in muscle (Hevener et al., 2007; Nguyen et al., 2007; Weisberg et al., 2003).”
Self-citationNomiyama, T., Perez-Tilve, D., Ogawa, D., Gizard, F., Zhao, Y., Heywood, E. B., Jones, K. L., Kawamori, R., Cassis, L. A., Tschöp, M. H., et al. (2007) · Journal of Clinical Investigation · doi:10.1172/jci31986 · Cited by 401 · cited 2×
“…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 increase in ATMs is associated with a further deterioration of insulin sensitivity (Hirasaka…”
Dendritic Cells Maximize the Memory CD8 T Cell Response to Infection
Zammit, D. J., Cauley, L. S., Pham, Q.-M., & Lefrançois, L. (2005) · Immunity · doi:10.1016/j.immuni.2005.03.005 · Cited by 324 · cited 1×
“However, when wild-type C57BL/6 mice were reconstituted with bone marrow from CD11c-DTR mice and were treated with the same dose of DT, no deleterious effects were observed in these chimeric animals, even with prolonged DT treatment (Zammit et al., 2005).”
Histological analysis of CD11c-DTR/GFP mice after in vivo depletion of dendritic cells
Probst, H. C., Tschannen, K., Odermatt, B., Schwendener, R. A., Zinkernagel, R. M., & van den Broek, M. F. (2005) · Clinical & Experimental Immunology · doi:10.1111/j.1365-2249.2005.02868.x · Cited by 235 · cited 4×
“This result suggested that in the CD11cDTR transgenic mice (Probst et al., 2005) essential nonhematopoietic cells expressed the transgene and were affected by DT treatment.”
InfluentialLiu, C., Fan, Y.-T., Dias, A., Esper, L., Corn, R. A., Báfica, A. L. B., Machado, F. S., & Aliberti, J. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.177.1.31 · Cited by 183 · cited 2×
“Although we did not measure CD11c+ cell content and inflammatory markers until 72 hr, previous studies have shown that DT treatment leads to near complete depletion of spleen and lymph node CD11c+ cells by 18 hr, accompanied by decreased infection-induced IL-12 levels (Liu et al., 2006; Probst et al., 2005).”
Determinants of intramyocellular triglyceride turnover: implications for insulin sensitivity
Moro, C., Bajpeyi, S., & Smith, S. R. (2008) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00624.2007 · Cited by 179 · cited 1×
“A clear relationship between increased intracellular muscle triglyceride (IMTG) accumulation and insulin resistance has been reported in obesity and type 2 diabetes (Moro et al., 2008).”
Disruption of CXC Motif Chemokine Ligand-14 in Mice Ameliorates Obesity-induced Insulin Resistance
Nara, N., Nakayama, Y., Okamoto, S., Tamura, H., Kiyono, M., Muraoka, M., Tanaka, K., Taya, C., Shitara, H., Ishii, R., et al. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m700412200 · Cited by 176 · cited 2×
“…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 increase in ATMs is associated with a further…”
Sugden, M. C., Bulmer, K., Gibbons, G. F., Knight, B. L., & Holness, M. J. (2002) · Biochemical Journal · doi:10.1042/bj20011699 · Cited by 152 · cited 1×
“…of hepatic TG metabolism, its lipogenic target genes stearoyl CoA desaturase-1 (SCD1) and acetyl-CoA carboxylase 1 (ACC1), and peroxisome proliferator-activated receptor (PPAR) a, a key regulator of hepatic lipid oxidation (Lee et al., 2008; Sugden et al., 2002; Weickert and Pfeiffer, 2006).”
ICAM-1 expression in adipose tissue: effects of diet-induced obesity in mice
Brake, D. K., Smith, E. O., Mersmann, H. J., Smith, C. W., & Robker, R. L. (2006) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00008.2006 · Cited by 147 · cited 1×
“Recent studies show that there is heterogeneity in ATMs, depending on the lean or obese state (Brake et al., 2006; Lumeng et al., 2007; Nguyen et al., 2007).”
Signalling mechanisms linking hepatic glucose and lipid metabolism
Weickert, M. O., & Pfeiffer, A. F. H. (2006) · Diabetologia · doi:10.1007/s00125-006-0295-3 · Cited by 127 · cited 2×
“…of hepatic TG metabolism, its lipogenic target genes stearoyl CoA desaturase-1 (SCD1) and acetyl-CoA carboxylase 1 (ACC1), and peroxisome proliferator-activated receptor (PPAR) a, a key regulator of hepatic lipid oxidation (Lee et al., 2008; Sugden et al., 2002; Weickert and Pfeiffer, 2006).”
Bone marrow–specific Cap gene deletion protects against high-fat diet–induced insulin resistance
Lesniewski, L. A., Hosch, S. E., Neels, J. G., de Luca, C., Pashmforoush, M., Lumeng, C. N.-K., Chiang, S.-H., Scadeng, M., Saltiel, A. R., & Olefsky, J. M. (2007) · Nature Medicine · doi:10.1038/nm1550 · Cited by 114 · cited 4×
“Mouse euglycemic clamp studies were performed as previously described (Lesniewski et al., 2007).”
InfluentialSelf-citationPXR and LXR in Hepatic Steatosis: A New Dog and an Old Dog with New Tricks
Lee, J. H., Zhou, J., & Xie, W. (2007) · Molecular Pharmaceutics · doi:10.1021/mp700121u · Cited by 74 · cited 2×
“…of hepatic TG metabolism, its lipogenic target genes stearoyl CoA desaturase-1 (SCD1) and acetyl-CoA carboxylase 1 (ACC1), and peroxisome proliferator-activated receptor (PPAR) a, a key regulator of hepatic lipid oxidation (Lee et al., 2008; Sugden et al., 2002; Weickert and Pfeiffer, 2006).”
Hirasaka, K., Kohno, S., Goto, J., Furochi, H., Mawatari, K., Harada, N., Hosaka, T., Nakaya, Y., Ishidoh, K., Obata, T., et al. (2007) · Diabetes · doi:10.2337/db06-1768 · Cited by 69 · cited 2×
“, 2006), while an increase in ATMs is associated with a further deterioration of insulin sensitivity (Hirasaka et al., 2007; Kamei et al., 2006; Kanda et al., 2006).”
Hoedemaekers, C., Pickkers, P., Netea, M. G., van Deuren, M., & van der Hoeven, J. G. (2005) · Critical Care · doi:10.1186/cc3911 · Cited by 57 · cited 1×
“…the IL-10 protein levels in serum and IL-10 mRNA and protein levels in AT agrees with previous findings showing that systemic IL-10 levels are not representative of the local inflammatory response (Hoedemaekers et al., 2005), and suggests that sources other than AT contribute to circulating IL-10.”
Ellacott, K. L. J., Murphy, J. G., Marks, D. L., & Cone, R. D. (2007) · Endocrinology · doi:10.1210/en.2007-0699 · Cited by 56 · cited 1×
“…showed that a decrease 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…”
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Inflammatory Mechanisms in Obesity
Gregor, M. F., & Hotamisligil, G. S. (2011) · Annual Review of Immunology · doi:10.1146/annurev-immunol-031210-101322 · Cited by 3,754
Macrophages, inflammation, and insulin resistance
Olefsky, J. M., & Glass, C. K. (2010) · Annual Review of Physiology · doi:10.1146/annurev-physiol-021909-135846 · Cited by 2,733
Self-citationThe NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance
Vandanmagsar, B., Youm, Y.-H., Ravussin, A., Galgani, J. E., Stadler, K., Mynatt, R. L., Ravussin, E., Stephens, J. M., & Dixit, V. D. (2011) · Nature Medicine · doi:10.1038/nm.2279 · Cited by 2,655
“The activation of classically activated M1 macrophages at the expense of anti-inflammatory M2 macrophages has been causally linked to the development of adipose tissue inflammation and metabolic syndrom”
BackgroundEvolution of inflammation in nonalcoholic fatty liver disease: The multiple parallel hits hypothesis
Tilg, H., & Moschen, A. R. (2010) · Hepatology · doi:10.1002/hep.24001 · Cited by 2,548
“macrophages (CD11cþ cells) improves insulin sensitivity and decreases inflammation.(77) Importantly, adiponectin and PPARc promote adipose tissue macrophage polarization toward an alternative/anti-inflammatory phenotype.”
BackgroundInflammatory links between obesity and metabolic disease
Lumeng, C. N., & Saltiel, A. R. (2011) · Journal of Clinical Investigation · doi:10.1172/jci57132 · Cited by 2,319
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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