Adipocyte-Derived Th2 Cytokines and Myeloid PPARδ Regulate Macrophage Polarization and Insulin Sensitivity

Kang, Kihwa; Reilly, Shannon M.; Karabacak, Volkan; Gangl, Matthew R.; Fitzgerald, Kelly; Hatano, Ben; Lee, Chih-Hao

doi:10.1016/j.cmet.2008.04.002

Cited by 699Peroxisome Proliferator-Activated ReceptorsAdipokines, Inflammation, and Metabolic DiseasesAdipose Tissue and Metabolism

Adipocyte-Derived Th2 Cytokines and Myeloid PPARδ Regulate Macrophage Polarization and Insulin Sensitivity

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Kang, Kihwa, Reilly, Shannon M., Karabacak, Volkan, Gangl, Matthew R., Fitzgerald, Kelly, Hatano, Ben, Lee, Chih-Hao·2008·Cell Metabolism

DOI 10.1016/j.cmet.2008.04.002PMC PMC2586840

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Abstract

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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Macrophages that rely on fatty acid metabolism secrete anti-inflammatory cytokines and thus preserve insulin sensitivity of liver and adipose tissue (type M2).
“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]
IL-13 is a key TH2 cytokine that mediates anti-inflammatory polarization of resident macrophages in white adipose tissue.
“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]

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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
ORCID: Reilly, Shannon M.
Karabacak, Volkan
Fitzgerald, Kelly
Lee, Chih-Hao
Venue: Cell Metabolism
Publisher: Elsevier BV
Published: 2008-06
Volume: 7
Issue: 6
Pages: 485-495
ISSN: 1550-4131 (ISSN-L)
DOI: 10.1016/j.cmet.2008.04.002
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: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 1908 d)
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 › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
Health Sciences › Medicine › Physiology › 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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Adipocyte-Derived Th2 Cytokines and Myeloid PPARδ Regulate Macrophage Polarization and Insulin Sensitivity

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