The DOI matches its Crossref record; 33 of the 33 references it cites were found in a registry or an index.
Macrophage-specific PPARγ controls alternative activation and improves insulin resistance
Open accessAbstract
Obesity and insulin resistance, the cardinal features of metabolic syndrome, are closely associated with a state of low-grade inflammation. In adipose tissue chronic overnutrition leads to macrophage infiltration, resulting in local inflammation that potentiates insulin resistance. For instance, transgenic expression of Mcp1 (also known as chemokine ligand 2, Ccl2) in adipose tissue increases macrophage infiltration, inflammation and insulin resistance. Conversely, disruption of Mcp1 or its receptor Ccr2 impairs migration of macrophages into adipose tissue, thereby lowering adipose tissue inflammation and improving insulin sensitivity. These findings together suggest a correlation between macrophage content in adipose tissue and insulin resistance. However, resident macrophages in tissues display tremendous heterogeneity in their activities and functions, primarily reflecting their local metabolic and immune microenvironment. While Mcp1 directs recruitment of pro-inflammatory classically activated macrophages to sites of tissue damage, resident macrophages, such as those present in the adipose tissue of lean mice, display the alternatively activated phenotype. Despite their higher capacity to repair tissue, the precise role of alternatively activated macrophages in obesity-induced insulin resistance remains unknown. Using mice with macrophage-specific deletion of the peroxisome proliferator activated receptor-gamma (PPARgamma), we show here that PPARgamma is required for maturation of alternatively activated macrophages. Disruption of PPARgamma in myeloid cells impairs alternative macrophage activation, and predisposes these animals to development of diet-induced obesity, insulin resistance, and glucose intolerance. Furthermore, gene expression profiling revealed that downregulation of oxidative phosphorylation gene expression in skeletal muscle and liver leads to decreased insulin sensitivity in these tissues. Together, our findings suggest that resident alternatively activated macrophages have a beneficial role in regulating nutrient homeostasis and suggest that macrophage polarization towards the alternative state might be a useful strategy for treating type 2 diabetes.
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In the citing paper
“Specifically, STAT1 and IRF5 have been shown to be involved in polarization and maintenance of an M1 phenotype while STAT6, IRF4, CREB-C/EBPβ, and PPARγ are involved in polarization and maintenance of an M2 phenotype [23–30].”
From Macrophage polarization: an opportunity for improved outcomes in biomaterials and regenerative medicine (2012) · cites this paper as [29]
In the citing paper
“Studies in PPARγ deficient mice exhibit impaired M2 macrophage function and susceptibility to diet-induced inflammation and insulin resistance [29,65–67].”
From Macrophage polarization: an opportunity for improved outcomes in biomaterials and regenerative medicine (2012) · cites this paper as [29]
In the citing paper
“In normal, non-obese subjects ATMs have a polarized M2 phenotype characterized by increased baseline STAT6 and PPARγ expression [29].”
From Macrophage polarization: an opportunity for improved outcomes in biomaterials and regenerative medicine (2012) · cites this paper as [29]
In the citing paper
“Importantly, the PPARγ nuclear receptor appears to be required for the maturation of alternatively activated macrophages (112, 113).”
From Insulin sensitivity: Modulation by nutrients and inflammation (2008) · cites this paper as [113]
In the citing paper
“Accordingly, because of their proinflammatory properties, these macrophages are implicated in the pathogenesis of insulin resistance (103, 105, 112, 113).”
From Insulin sensitivity: Modulation by nutrients and inflammation (2008) · cites this paper as [113]
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Cites
Mootha, V. K., Lindgren, C. M., Eriksson, K.-F., Subramanian, A., Sihag, S., Lehar, J., Puigserver, P., Carlsson, E., Ridderstråle, M., Laurila, E., et al. (2003) · Nature Genetics · doi:10.1038/ng1180 · Cited by 10,197
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
Self-citationInflammation and metabolic disorders
Hotamisligil, G. S. (2006) · Nature · doi:10.1038/nature05485 · Cited by 9,199
Xu, H., Barnes, G. T., Yang, Q., Tan, G., Yang, D., Chou, C. J., Sole, J., Nichols, A., Ross, J. S., Tartaglia, L. A., et al. (2003) · Journal of Clinical Investigation · doi:10.1172/jci200319451 · Cited by 6,760
Alternative activation of macrophages
Gordon, S. (2003) · Nature Reviews Immunology · doi:10.1038/nri978 · Cited by 6,189
Monocyte and macrophage heterogeneity
Gordon, S., & Taylor, P. R. (2005) · Nature Reviews Immunology · doi:10.1038/nri1733 · Cited by 5,190
Inflammation and insulin resistance
Shoelson, S. E. (2006) · Journal of Clinical Investigation · doi:10.1172/jci29069 · Cited by 4,769
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
Kim, 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
Kanda, H. (2006) · Journal of Clinical Investigation · doi:10.1172/jci26498 · Cited by 2,682
Cited by
Sorted by citations
Macrophage plasticity and polarization: in vivo veritas
Sica, A., & Mantovani, A. (2012) · Journal of Clinical Investigation · doi:10.1172/jci59643 · Cited by 6,335
“Mice with macrophage-selective genetic inactivation of PPAR γ , PPAR δ , and KLF4 show inhibition of obesity-induced insulin resistance (19, 20, 24, 106, 110), although these results may be strain specific (112).”
InfluentialProtective and pathogenic functions of macrophage subsets
Murray, P. J., & Wynn, T. A. (2011) · Nature Reviews Immunology · doi:10.1038/nri3073 · Cited by 5,269
“These macrophages are induced by peroxisome proliferator activated receptor-γ (PPARγ) signalling and maintain adipocyte function, insulin sensitivity and glucose tolerance, which can prevent the development of diet-induced obesity and type 2 diabete”
BackgroundMacrophage biology in development, homeostasis and disease
Wynn, T. A., Chawla, A., & Pollard, J. W. (2013) · Nature · doi:10.1038/nature12034 · Cited by 4,684
Self-citationMacrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm
Biswas, S. K., & Mantovani, A. (2010) · Nature Immunology · doi:10.1038/ni.1937 · Cited by 3,840
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
Metadata
- Authors
- Odegaard, J. I., Ricardo-Gonzalez, R. R., Goforth, M. H., Morel, C. R., Subramanian, V., Mukundan, L., Eagle, A. R., Vats, D., Brombacher, F., Ferrante, A. W., & Chawla, A.
- Affiliations
- Stanford Medicine (US)
- Columbia University Irving Medical Center (US)
- University of Cape Town (ZA)
- Corresponding author
- Chawla, Ajay
- Venue
- Nature
- Published
- 2007-05-21
- Volume
- 447
- Issue
- 7148
- Pages
- 1116-1120
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC2587297
- OpenAlex
- W2167485774
- Cited by
- 2,107
- References
- 32
- Citations by year
- 2026: 91 · 2025: 67 · 2024: 98 · 2023: 101 · 2022: 103 · 2021: 139 · 2020: 131 · 2019: 118 · 2018: 117 · 2017: 126 · 2016: 110 · 2015: 132 · 2014: 124 · 2013: 151 · 2012: 125
- FWCI
- 36.07
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL076746)
- National Institute of Allergy and Infectious Diseases (F31AI066402, T32AI007290)
- National Institute of Diabetes and Digestive and Kidney Diseases (K08DK062386, R01DK076760, R01DK066525)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- PPARγ, macrophage polarization, alternative activation, insulin resistance, obesity, adipose tissue inflammation, CCR2, diet-induced obesity, impaired glucose tolerance, oxidative phosphorylation, skeletal muscle, liver, type 2 diabetes, myeloid cells, nutrient homeostasis
- MeSH terms
- Adipose Tissue, Animals, Cell Line, Dietary Fats, Glucose, Homeostasis, Insulin, Insulin Resistance, Macrophage Activation, Macrophages, Male, Mice, Inbred BALB C, Organ Size, Weight Gain, Leishmaniasis, Cutaneous, Leishmania major, Mice, Knockout, Genetic Predisposition to Disease, PPAR gamma, Mice, Adiponectin
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