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A Paracrine Loop Between Adipocytes and Macrophages Aggravates Inflammatory Changes: Role of Free Fatty Acids and Tumor Necrosis Factor α
Abstract
Objective— Weight gain is associated with infiltration of fat by macrophages, suggesting that they are an important source of inflammation in obese adipose tissue. Here we developed an in vitro coculture system composed of adipocytes and macrophages and examined the molecular mechanism whereby these cells communicate. Methods and Results— Coculture of differentiated 3T3-L1 adipocytes and macrophage cell line RAW264 results in the marked upregulation of proinflammatory cytokines, such as tumor necrosis factor α (TNF-α), and the downregulation of the antiinflammatory cytokine adiponectin. Such inflammatory changes are induced by the coculture without direct contact, suggesting the role of soluble factors. A neutralizing antibody to TNF-α, which occurs mostly in macrophages, inhibits the inflammatory changes in 3T3-L1, suggesting that TNF-α is a major macrophage-derived mediator of inflammation in adipocytes. Conversely, free fatty acids (FFAs) may be important adipocyte-derived mediators of inflammation in macrophages, because the production of TNF-α in RAW264 is markedly increased by palmitate, a major FFA released from 3T3-L1. The inflammatory changes in the coculture are augmented by use of either hypertrophied 3T3-L1 or adipose stromal vascular fraction obtained from obese ob/ob mice. Conclusions— We postulate that a paracrine loop involving FFAs and TNF-α between adipocytes and macrophages establishes a vicious cycle that aggravates inflammatory changes in the adipose tissue.
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“However, FFAs can also serve as ligands for the TLR4 complex (33), thereby activating the classical inflammatory response in the context of increased local extracellular lipid concentrations, which ultimately drives ATMΦ accumulation (34,35).”
From Adipose tissue remodeling and obesity (2011) · cites this paper as [34]
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“Interaction between inflammatory adipocytokines and infiltrated macrophages causes chronic inflammation of adipose tissue.(16,17) Activation of macrophages has been causally linked to the development of adipose tissue inflammation and metabolic syndrome.”
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“TNF-a, which is derived mostly from infiltrated macrophages, induces adipocyte lipolysis and such released saturated fatty acids activate macrophages via Toll like receptor 4, increasing adipose tissue inflammation [41].”
BackgroundToyoda, T., Kamei, Y., Kato, H., Sugita, S., Takeya, M., Suganami, T., & Ogawa, Y. (2008) · Obesity · doi:10.1038/oby.2008.62 · Cited by 35
“Because TNF-α is a major paracrine mediator of inflammation in adipocytes in the coculture system (12), we also examined the effect of Wy-14,643 on the TNF-α-induced MCP-1 expression.”
BackgroundMethodResultInfluentialSelf-citationErythrocyte saturated fatty acids and systemic inflammation in adults
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ε-Viniferin, a resveratrol dimer, prevents diet-induced obesity in mice
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“Palmitic acid can also activate a macrophage cell line to express TNF-α by a TLR4 and NFKB dependent mechanism [11, 35].”
BackgroundDevelopment of an Insert Co-culture System of Two Cellular Types in the Absence of Cell-Cell Contact
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Molecular mechanism of obesity‐induced ‘metabolic’ tissue remodeling
Tanaka, M., Itoh, M., Ogawa, Y., & Suganami, T. (2017) · Journal of Diabetes Investigation · doi:10.1111/jdi.12769 · Cited by 34
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ANT2 drives proinflammatory macrophage activation in obesity
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Lipid droplets hypertrophy: a crucial determining factor in insulin regulation by adipocytes
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“[39] demonstrated that TNF-α produced by adipose tissue macrophages promotes the appearance of the adipocyte “inflammatory” phenotype and is also related to insulin resistance, thus suggesting that the cross-talk between adipose tissue macrophages and adipocytes generates a vicious circle of aggravating adipose tissue…”
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Chronic kidney disease promotes chronic inflammation in visceral white adipose tissue
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Extracellular DNA Traps: Origin, Function and Implications for Anti-Cancer Therapies
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“Four types of fatty acid accumulated in culture medium of L-Alanine-treated macrophages (Fig 6C), suggesting that murine macrophages secrete fatty acids, as previously suggested (Suganami et al , 2005).”
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Bariatric surgery, adipose tissue and gut microbiota
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“PA treatment can also increase endoplasmic reticulum stress, inflammation, and apoptosis in adipocytes in vitro (Permana et al., 2006; Suganami et al., 2005; Guo et al., 2007; Suganami et al., 2007; Takahashi et al., 2008; Kennedy et al., 2009).”
Explant Cultures of White Adipose Tissue
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“This paracrine loop involving FFAs and TNF-a between adipocytes and macrophages appears to establish a vicious cycle that further aggravates adipose tissue inflammation (Suganami et al., 2005).”
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Metadata
- Authors
- Suganami, T., Nishida, J., & Ogawa, Y.
- Affiliations
- Tokyo Medical and Dental University (JP)
- Venue
- Arteriosclerosis, Thrombosis, and Vascular Biology
- Published
- 2005-10
- Volume
- 25
- Issue
- 10
- Pages
- 2062-2068
- ISSN
- 1079-5642 (ISSN-L)
- 1524-4636
- OpenAlex
- W2105448220
- Cited by
- 1,056
- References
- 45
- Citations by year
- 2026: 25 · 2025: 27 · 2024: 27 · 2023: 36 · 2022: 38 · 2021: 57 · 2020: 51 · 2019: 47 · 2018: 34 · 2017: 66 · 2016: 62 · 2015: 66 · 2014: 57 · 2013: 91 · 2012: 54
- FWCI
- 30.26
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Arteriosclerosis Thrombosis and Vascular Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Research Foundation for Clinical Pharmacology
- Ministry of Education, Culture, Sports, Science and Technology
- Novo Nordisk
- Smoking Research Foundation
- Kanae Foundation for the Promotion of Medical Science
- Mishima Kaiun Memorial Foundation
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Disease and Adiposity
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Keywords
- adipocytes, macrophages, paracrine signaling, adipose tissue inflammation, obesity, TNF-α, adiponectin, free fatty acids, palmitate, 3T3-L1 adipocytes, RAW264 macrophages, co-culture, ob/ob mice, adipose stromal vascular fraction, adipocyte hypertrophy
- MeSH terms
- Adipose Tissue, Animals, Cell Communication, Fatty Acids, Nonesterified, Gene Expression Regulation, Hypertrophy, Inflammation, Macrophages, Obesity, Tumor Necrosis Factor-alpha, Adipocytes, Coculture Techniques, Chemokine CCL2, Paracrine Communication, Metabolic Syndrome, 3T3-L1 Cells, Atherosclerosis, Mice
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