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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FFAs can serve as ligands for the TLR4 complex, thereby activating the classical inflammatory response in the context of increased local extracellular lipid concentrations, which ultimately drives adipose tissue macrophage accumulation.
“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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- 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 › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Disease and Adiposity
- Health Sciences › Medicine › Physiology › 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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