The DOI matches its Crossref record; 41 of the 41 references it cites were found in a registry or an index.
Adipocyte-Derived Th2 Cytokines and Myeloid PPARδ Regulate Macrophage Polarization and Insulin Sensitivity
Open accessAbstract
The polarization of adipose tissue-resident macrophages toward the alternatively activated, anti-inflammatory M2 phenotype is believed to improve insulin sensitivity. However, the mechanisms controlling tissue macrophage activation remain unclear. Here we show that adipocytes are a source of Th2 cytokines, including IL-13 and to a lesser extent IL-4, which induce macrophage PPARdelta/beta (Ppard/b) expression through a STAT6 binding site on its promoter to activate alternative activation. Coculture studies indicate that Ppard ablation renders macrophages incapable of transition to the M2 phenotype, which in turns causes inflammation and metabolic derangement in adipocytes. Remarkably, a similar regulatory mechanism by hepatocyte-derived Th2 cytokines and macrophage PPARdelta is found to control hepatic lipid metabolism. The physiological relevance of this paracrine pathway is demonstrated in myeloid-specific PPARdelta(-/-) mice, which develop insulin resistance and show increased adipocyte lipolysis and severe hepatosteatosis. These findings provide a molecular basis to modulate tissue-resident macrophage activation and insulin sensitivity.
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“Conversely, macrophages that rely on fatty acid metabolism secrete anti-inflammatory cytokines and thus preserve insulin sensitivity of liver and adipose tissue (type M2) (167, 168).”
From Metabolic Flexibility as an Adaptation to Energy Resources and Requirements in Health and Disease (2018) · cites this paper as [168]
In the citing paper
“IL-13 is an important main T helper 2 (TH2) cell cytokine that mediates the anti-inflammatory polarization of resident macrophages in WAT135.”
From Exerkines in health, resilience and disease (2022) · cites this paper as [135]
Citations
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
Inflammation 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
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
Alternative activation of macrophages
Gordon, S. (2003) · Nature Reviews Immunology · doi:10.1038/nri978 · Cited by 6,189
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, J.-W., Tchernyshyov, I., Semenza, G. L., & Dang, C. V. (2006) · Cell Metabolism · doi:10.1016/j.cmet.2006.02.002 · Cited by 3,905
TLR4 links innate immunity and fatty acid-induced insulin resistance
Shi, H., Kokoeva, M. V., Inouye, K., Tzameli, I., Yin, H., & Flier, J. S. (2006) · Journal of Clinical Investigation · doi:10.1172/jci28898 · Cited by 3,690
Stimulation of adipogenesis in fibroblasts by PPARγ2, a lipid-activated transcription factor
Tontonoz, P., Hu, E., & Spiegelman, B. M. (1994) · Cell · doi:10.1016/0092-8674(94)90006-x · Cited by 3,564
A central role for JNK in obesity and insulin resistance
Hirosumi, J., Tuncman, G., Chang, L., Görgün, C. Z., Uysal, K. T., Maeda, K., Karin, M., & Hotamisligil, G. S. (2002) · Nature · doi:10.1038/nature01137 · Cited by 3,359
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Macrophage plasticity and polarization: in vivo veritas
Sica, A., & Mantovani, A. (2012) · Journal of Clinical Investigation · doi:10.1172/jci59643 · Cited by 6,335
Macrophage biology in development, homeostasis and disease
Wynn, T. A., Chawla, A., & Pollard, J. W. (2013) · Nature · doi:10.1038/nature12034 · Cited by 4,684
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
Alternative Activation of Macrophages: An Immunologic Functional Perspective
Martinez, F. O., Helming, L., & Gordon, S. (2009) · Annual Review of Immunology · doi:10.1146/annurev.immunol.021908.132532 · Cited by 2,745
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
Metadata
- Authors
- Kang, K., Reilly, S. M., Karabacak, V., Gangl, M. R., Fitzgerald, K., Hatano, B., & Lee, C.-H.
- Affiliations
- Harvard University (US)
- Corresponding author
- Lee, Chih-Hao
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2008-06
- Volume
- 7
- Issue
- 6
- Pages
- 485-495
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC2586840
- OpenAlex
- W2046935888
- Cited by
- 699
- References
- 41
- Citations by year
- 2026: 14 · 2025: 24 · 2024: 25 · 2023: 21 · 2022: 25 · 2021: 44 · 2020: 42 · 2019: 32 · 2018: 39 · 2017: 40 · 2016: 43 · 2015: 46 · 2014: 40 · 2013: 76 · 2012: 51
- FWCI
- 18.81
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5t32es007155-24)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK34845, R90DK071507, R01DK075046, P30DK034854)
- National Institute of Environmental Health Sciences (T32-ES07155, T32-ES007155, T32ES016645)
- 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
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Keywords
- adipose tissue macrophages, macrophage polarization, M2 phenotype, Th2 cytokines, IL-13, IL-4, PPARδ, STAT6, adipocytes, hepatocytes, insulin sensitivity, insulin resistance, hepatic lipid metabolism, hepatic steatosis, adipocyte lipolysis, paracrine signaling, myeloid-specific knockout
- MeSH terms
- Animals, Gene Expression Regulation, Inflammation, Insulin Resistance, Macrophage Activation, Macrophages, Promoter Regions, Genetic, Cytokines, Adipocytes, Mice, Knockout, Th2 Cells, Coculture Techniques, Paracrine Communication, Hepatocytes, PPAR delta, PPAR-beta, Lipid Metabolism, Mice
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