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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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“It is clear that the fatty acids released from hypertrophied adipocytes also serve as ligands for TLR4 and contribute to further deterioration of physiological regulation (Suganami et al. 2005).”
BackgroundKobayashi, K., Tang, Y. T., & Sasaki, K. (2022) · Biochemistry and Biophysics Reports · doi:10.1016/j.bbrep.2022.101335 · Cited by 2
“The production of large adipocytes enhances macrophage infiltration and the production of macrophage-derived TNFα, which is known to augment inflammatory changes and insulin resistance [31].”
BackgroundKim, J. E., Kim, H., Lim, J., Moon, S., & Om, A. (2023) · Food Supplements and Biomaterials for Health · doi:10.52361/fsbh.2023.3.e10 · Cited by 2
Obesity decreases the oxidant stress induced by tobacco smoke in a rat model
Montaño, M., Pérez‐Ramos, J., Esquivel-Campos, A. L., Rivera-Rosales, R. M., González-Ávila, G., Becerril, C., Checa, M., & Ramos, C. (2016) · Toxicology Mechanisms and Methods · doi:10.1080/15376516.2016.1211208 · Cited by 2
“These cells secrete adipokines, cytokines and inflammatory mediators that contribute to the modulation of the energy metabolism of muscles, liver and other organs, thus altering the body weight (Gregor & Hotamisligil, 2007; Olefsky & Glass, 2010; Skyba et al., 2010; Suganami et al., 2005).”
BackgroundDietary Fatty Acids and C-Reactive Protein
Annuzzi, G., Griffo, E., Costabile, G., & Bozzetto, L. (2016) · Elsevier eBooks · doi:10.1016/b978-0-12-801585-8.00018-x · Cited by 2
Food Intake and Thermogenesis in Adipose Tissue
Goto, T., Kim, M., Takahashi, H., Takahashi, N., & Kawada, T. (2016) · The Korean Journal of Obesity · doi:10.7570/kjo.2016.25.3.109 · Cited by 2
The Beneficial Health Effects of Fucoxanthin
Miyashita, K., & Hosokawa, M. (2015) · Wiley eBooks · doi:10.1002/9781118930458.ch10 · Cited by 2
Budhram, S. (2015) · SUNScholar (Stellenbosch University) · Cited by 2
Novel Pleiotropic Effects of Niacin
Wanders, D. (2012) · Cited by 2
Aging-induced stem cell dysfunction: Molecular mechanisms and potential therapeutic avenues
Grajeda, Y., Arias, N., Barrios, A., Pervin, S., & Singh, R. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-820071-1.00005-0 · Cited by 1
(The CD36 receptor - the link between inflammation, lipid metabolism, and cardiovascular disease)
Poledne, R., & Lesná, I. K. (2024) · Cor et Vasa · doi:10.33678/cor.2024.005 · Cited by 1
Heo, Y.-J., Lyu, S., Lee, M., & Lee, H.-I. (2024) · Journal of Nutrition and Health · doi:10.4163/jnh.2024.57.6.619 · Cited by 1
Obesity-Associated Conditions Hinder Solute Drainage Function of Engineered Human Lymphatic Vessels
Seibel, A. J., Frosti, C. L., Tlemçani, A. R., Lahiri, N., Brammer-DePuy, J. A., Layne, M. D., & Tien, J. (2025) · Cellular and Molecular Bioengineering · doi:10.1007/s12195-024-00840-z · Cited by 1
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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