Adipose tissue macrophages in insulin-resistant subjects are associated with collagen VI and fibrosis and demonstrate alternative activation
Open accessAbstract
Adipose tissue macrophages are associated with insulin resistance and are linked to changes in the extracellular matrix. To better characterize adipose macrophages, the extracellular matrix, and adipocyte-macrophage interactions, gene expression from adipose tissue and the stromal vascular fraction was assessed for markers of inflammation and fibrosis, and macrophages from obese and lean subjects were counted and characterized immunohistochemically. Coculture experiments examined the effects of adipocyte-macrophage interaction. Collagen VI gene expression was associated with insulin sensitivity and CD68 ( r = −0.56 and 0.60, P < 0.0001) and with other markers of inflammation and fibrosis. Compared with adipose tissue from lean subjects, adipose tissue from obese subjects contained increased areas of fibrosis, which correlated inversely with insulin sensitivity ( r = −0.58, P < 0.02) and positively with macrophage number ( r = 0.70, P < 0.01). Although macrophages in crownlike structures (CLS) were more abundant in obese adipose tissue, the majority of macrophages were associated with fibrosis and were not organized in CLS. Macrophages in CLS were predominantly M1, but most other macrophages, particularly those in fibrotic areas, were M2 and also expressed CD150, a marker of M2c macrophages. Coculture of THP-1 macrophages with adipocytes promoted the M2 phenotype, with a lower level of IL-1 expression and a higher ratio of IL-10 to IL-12. Transforming growth factor-β (TGF-β) was more abundant in M2 macrophages and was further increased by coculture with adipocytes. Downstream effectors of TGF-β, such as plasminogen activator inhibitor-1, collagen VI, and phosphorylated Smad, were increased in macrophages and adipocytes. Thus adipose tissue of insulin-resistant humans demonstrated increased fibrosis, M2 macrophage abundance, and TGF-β activity.
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Most human studies have reported fibrosis in obese adipose tissue.
“The majority of human studies have reported fibrosis in obese AT (119-121).”
From The ominous triad of adipose tissue dysfunction: inflammation, fibrosis, and impaired angiogenesis. (2017) · cites this paper as [120]
A comprehensive in vivo macrophage phenotype cannot be deduced solely from a limited set of phenotypic markers.
“Additionally, a comprehensive in vivo Mp phenotype cannot be deduced solely from a limited set of phenotypic markers, as different M2a-associated genes or proteins can exhibit entirely different temporal regulation and can be coexpressed with M1-associated markers [19,25,33,60,78].”
From Macrophage phenotypes during tissue repair (2013) · cites this paper as [78]
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- Authors
- Spencer, M., Yao-Borengasser, A., Unal, R., Rasouli, N., Gurley, C. M., Zhu, B., Peterson, C. A., & Kern, P. A.
- Affiliations
- Division of Endocrinology, Department of Medicine, and Barnstable Brown Diabetes and Obesity Center, and
- Division of Endocrinology, Department of Medicine, University of Arkansas for Medical Sciences, and Central Arkansas Veterans Healthcare System, Little Rock, Arkansas
- University of Colorado Denver (US)
- Central Arkansas Veterans Healthcare System (US)
- University of Kentucky (US)
- Corresponding author
- Kern, Philip A.
- Venue
- American Journal of Physiology-Endocrinology and Metabolism
- Publisher
- American Physiological Society
- Published
- 2010-12
- Volume
- 299
- Issue
- 6
- Pages
- E1016-E1027
- ISSN
- 0193-1849 (ISSN-L)
- 1522-1555
- PMC
- PMC3006260
- OpenAlex
- W2122779261
- Cited by
- 439
- References
- 35
- Citations by year
- 2026: 15 · 2025: 14 · 2024: 26 · 2023: 29 · 2022: 40 · 2021: 27 · 2020: 26 · 2019: 24 · 2018: 26 · 2017: 41 · 2016: 27 · 2015: 24 · 2014: 43 · 2013: 30 · 2012: 24
- FWCI
- 17.45
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Physiology-Endocrinology and Metabolism (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Kentucky
- University of Arkansas
- National Institutes of Health (UL1TR001998)
- National Institute on Aging (AG-20941, R01AG020941)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 39176, DK-71349, DK-80327, R01DK039176, R01DK080327, R37DK039176, R01DK071349)
- National Center for Research Resources (P20RR021954, M01RR014288, RR-14288)
- NIH Clinical Center
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Disease and Adiposity
- Keywords
- adipose tissue macrophages, insulin resistance, collagen VI, adipose tissue fibrosis, M2 macrophage polarization, TGF-beta signaling, plasminogen activator inhibitor-1, Smad phosphorylation, obesity, extracellular matrix, CD150, IL-10/IL-12 ratio, CD68
- MeSH terms
- Adipose Tissue, Adult, Cell Line, Cells, Cultured, Female, Fibrosis, Fluorescent Antibody Technique, Humans, Inflammation, Insulin, Insulin Resistance, Macrophages, Male, Middle Aged, Obesity, Cytokines, Glucose Intolerance, Coculture Techniques, Reverse Transcriptase Polymerase Chain Reaction, Collagen Type VI
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