Adipose tissue hypoxia induces inflammatory M1 polarity of macrophages in an HIF-1α-dependent and HIF-1α-independent manner in obese mice
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Aims/hypothesis As obesity progresses, adipose tissue exhibits a hypoxic and inflammatory phenotype characterised by the infiltration of adipose tissue macrophages (ATMs). In this study, we examined how adipose tissue hypoxia is involved in the induction of the inflammatory M1 and anti-inflammatory M2 polarities of ATMs.Methods The hypoxic characteristics of ATMs were evaluated using flow cytometry after the injection of pimonidazole, a hypoxia probe, in normal-chow-fed or high-fat-fed mice. The expression of hypoxia-related and inflammation-related genes was then examined in M1/M2 ATMs and cultured macrophages.Results Pimonidazole uptake was greater in M1 ATMs than in M2 ATMs. This uptake was paralleled by the levels of inflammatory cytokines, such as TNF-α, IL-6 and IL-1β. The expression level of hypoxia-related genes, as well as inflammation-related genes, was also higher in M1 ATMs than in M2 ATMs. The expression of Il6, Il1β and Nos2 in cultured macrophages was increased by exposure to hypoxia in vitro but was markedly decreased by the gene deletion of Hif1a. In contrast, the expression of Tnf, another inflammatory cytokine gene, was neither increased by exposure to hypoxia nor affected by Hif1a deficiency. These results suggest that hypoxia induces the inflammatory phenotypes of macrophages via Hif1a-dependent and -independent mechanisms. On the other hand, the expression of inflammatory genes in cultured M2 macrophages treated with IL-4 responded poorly to hypoxia.Conclusions/interpretation Adipose tissue hypoxia induces an inflammatory phenotype via Hif1a-dependent and Hif1a-independent mechanisms in M1 ATMs but not in M2 ATMs.
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Monocytes migrate to hypoxic areas and differentiate into proinflammatory macrophages.
“Immune cells, particularly monocytes, migrate to areas of hypoxia, where they differentiate into proinflammatory macrophages (13,14).”
From The ominous triad of adipose tissue dysfunction: inflammation, fibrosis, and impaired angiogenesis. (2017) · cites this paper as [14]
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Self-citation
- Authors
- Fujisaka, S., Usui, I., Ikutani, M., Aminuddin, A., Takikawa, A., Tsuneyama, K., Mahmood, A., Goda, N., Nagai, Y., Takatsu, K., & Tobe, K.
- Affiliations
- University of Toyama (JP)
- Waseda University (JP)
- Toyama Prefectural Institute for Pharmaceutical Research (JP)
- Corresponding author
- Usui, I.
- Tobe, K.
- Venue
- Diabetologia
- Published
- 2013-03-15
- Volume
- 56
- Issue
- 6
- Pages
- 1403-1412
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- OpenAlex
- W2093500588
- Cited by
- 239
- References
- 43
- Citations by year
- 2026: 13 · 2025: 13 · 2024: 34 · 2023: 23 · 2022: 17 · 2021: 15 · 2020: 27 · 2019: 20 · 2018: 12 · 2017: 20 · 2016: 12 · 2015: 10 · 2014: 14 · 2013: 9
- FWCI
- 10.92
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Diabetologia (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ministry of Education, Culture, Sports, Science and Technology (18209033, 21591126)
- Japan Society for the Promotion of Science (25461333, 18209033, 22590971, 23590370, 21591126, 24390119, 24390181, 24590577)
- Topics
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Disease and Adiposity
- Keywords
- adipose tissue hypoxia, adipose tissue macrophages, macrophage polarization, M1 macrophages, M2 macrophages, HIF-1α, obesity, inflammation, inflammatory cytokines, interleukin-6, IL-1β, TNF-α, IL-4, high-fat diet, pimonidazole
- MeSH terms
- Adipose Tissue, Alleles, Animals, Hypoxia, Bone Marrow Cells, Flow Cytometry, Inflammation, Macrophages, Male, Mice, Inbred C57BL, Mice, Obese, Nitroimidazoles, Phenotype, Cell Polarity, Mice, Knockout, Mice, Hypoxia-Inducible Factor 1, alpha Subunit
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