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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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ResultInflammation and thrombosis in diabetes
Hess, K., & Grant, P. J. (2011) · Thrombosis and Haemostasis · doi:10.1160/ths10-11-0739 · Cited by 117
Kang, L., Wang, H., Yuan, A., Baolin, L., & Fang, H. (2010) · Biochimie · doi:10.1016/j.biochi.2010.02.024 · Cited by 121
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“Adipocytes themselves may produce chemokines and cytokines in the presence of infiltrated immune cells [146], as synergistic production of cytokines by adipocytes and macrophages has been shown in co-culture experiments [143].”
BackgroundInflamed adipose tissue, insulin resistance and vascular injury
Andersson, C. X., Gustafson, B., Hammarstedt, A., Hedjazifar, S., & Smith, U. (2008) · Diabetes/Metabolism Research and Reviews · doi:10.1002/dmrr.889 · Cited by 118
“the production of TNF-α and induces apoptosis [111].”
BackgroundKlimčáková, E., Roussel, B., Márquez-Quiñones, A., Kováčová, Z., Kováčiková, M., Combes, M., Šiklová, M., Hejnová, J., Šrámková, P., Bouloumié, A., et al. (2010) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2010-1575 · Cited by 122
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ATP-Induced Inflammation Drives Tissue-Resident Th17 Cells in Metabolically Unhealthy Obesity
Pandolfi, J. B., Ferraro, A., Sananez, I., Gancedo, M. C., Baz, P., Billordo, L. A., Fainboim, L., & Arruvito, L. (2016) · The Journal of Immunology · doi:10.4049/jimmunol.1502506 · Cited by 115
Obesity but not high-fat diet impairs lymphatic function
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Adipose Tissue Inflammation and Pulmonary Dysfunction in Obesity
Palma, G., Sorice, G. P., Genchi, V. A., Giordano, F., Caccioppoli, C., D’Oria, R., Marrano, N., Biondi, G., Giorgino, F., & Perrini, S. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23137349 · Cited by 126
“Moreover, adipocyte hypertrophy can promote activation of intracellular pro-inflammatory signalling pathways, altering the adipocyte secretory profile [44,45].”
BackgroundAutophagy regulates inflammation in adipocytes
Yoshizaki, T., 楠知里, Kondo, M., Yasuda, M., Kume, S., Morino, K., Sekine, O., Ugi, S., Uzu, T., Nishio, Y., et al. (2011) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2011.11.114 · Cited by 114
“Autophagy is decreased in hypertrophic 3T3-L1 adipocytes To clarify the in vivo results, we cultured 3T3-L1 adipocytes for 21 days after differentiation and generated hypertrophic 3T3-L1 adipocytes using the method previously reported [17].”
MethodYamada, H., Yoshida, M., Nakano, Y., Suganami, T., Satoh, N., Mita, T., Azuma, K., Itoh, M., Yamamoto, Y., Kamei, Y., et al. (2008) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.108.171736 · Cited by 112
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“In the advanced stages of obesity, various types of immune cells, such as macrophages, in fi l-trate into obese adipose tissue and thus enhance the in fl ammatory changes through cross-talk with adipose tissue-released NEFA (40,41) .”
Molecular Mechanisms Underlying the Relationship between Obesity and Male Infertility
Barbagallo, F., Condorelli, R. A., Mongioì, L. M., Cannarella, R., Cimino, L., Magagnini, M. C., Crafa, A., Vignera, S. L., & Calogero, A. E. (2021) · Metabolites · doi:10.3390/metabo11120840 · Cited by 117
“In obese patients, non-esterified fatty acids (NEFA) that are produced by hypertrophic adipocytes induce local macrophages to secrete high levels of TNFα, which, in turn, stimulates adipocytes to produce more NEFA, pro-inflammatory cytokines (interleukin 1ß (IL1β) and IL6), acute phase proteins, and chemokines [+(C-C…”
BackgroundMitochondrial oxidative stress and inflammation: an slalom to obesity and insulin resistance
Martínez, J. A. (2006) · Journal of Physiology and Biochemistry · doi:10.1007/bf03165759 · Cited by 112
Overman, A., Chuang, C.-C., & McIntosh, M. (2011) · International Journal of Obesity · doi:10.1038/ijo.2010.272 · Cited by 112
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Gustafson, B., & Smith, U. (2015) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2015.04.812 · Cited by 114
Neutrophils Actively Contribute to Obesity-Associated Inflammation and Pathological Complications
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“Free fatty acids (FFA) produced by lipolysis are released by adipocytes and bind to fetuin-A, which is then recognized by toll-like receptor 4 (TLR-4) on macrophages.”
BackgroundInfluentialAgeing, adipose tissue, fatty acids and inflammation
Pararasa, C., Bailey, C. J., & Griffiths, H. R. (2015) · Biogerontology · doi:10.1007/s10522-014-9536-x · Cited by 110
“Saturated fatty acids are capable of inducing the production of proinflammatory cytokines from adipocytes (Permana et al. 2006; Suganami et al. 2005, 2007 ).”
Mechanisms of obesity-induced metabolic and vascular dysfunctions
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“This TLR-4 activation results in increased activity of the transcription factor, nuclear factor kappa -light-chain-enhancer of activated B cells (NF-kappaB), which upregulates expression of TNF-alpha (57, 58).”
Is Obesity a Risk Factor for Crohn’s Disease?
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“Circulating free fatty acids are associated with enhanced pro-inflammatory cytokine production by a number of cells including macrophages providing another mechanism for the association [13, 14].”
BackgroundFunctional Food Targeting the Regulation of Obesity-Induced Inflammatory Responses and Pathologies
Hirai, S., Takahashi, N., Goto, T., Lin, S., Uemura, T., Yu, R., & Kawada, T. (2010) · Mediators of Inflammation · doi:10.1155/2010/367838 · Cited by 111
“In this way, adipocytes and macrophages interact in a paracrine manner and create a vicious cycle of inflammation that augments the inflammatory changes and insulin resistance in obese adipose tissue [11] (Figure 1).”
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“TNFα has been directly implicated in a paracrine loop, also involving fatty acids, between adipocytes and macrophages in the stimulation of inflammation in adipose tissue [ 35 ].”
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The Role of JNK Proteins in Metabolism
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Emerging factors affecting peri‐implant bone metabolism
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“In addition to their capacity to secrete a myriad of inflammatory molecules, macrophages could also influence the biological states of visceral adipocytes by enhancing their proinflammatory state and lipolytic capacities as suggested by in vitro experiments [32,33].”
BackgroundInflammation in subcutaneous adipose tissue: relationship to adipose cell size
McLaughlin, T., Deng, A., Yee, G., Lamendola, C., Reaven, G., Tsao, P. S., Cushman, S. W., & Sherman, A. (2010) · Diabetologia · doi:10.1007/s00125-009-1496-3 · Cited by 105
γδ T cells promote inflammation and insulin resistance during high fat diet-induced obesity in mice
Mehta, P., Nuotio-Antar, A. M., & Smith, C. W. (2014) · Journal of Leukocyte Biology · doi:10.1189/jlb.3a0414-211rr · Cited by 111
“Macrophages, through their ability to produce various inflammatory mediators, such as TNF-a, have been shown to enhance adipocyte inflammation and diminish insulin sensitivity [12, 53].”
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Epicardial Fat: Physiological, Pathological, and Therapeutic Implications
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Adipocytes, Innate Immunity and Obesity: A Mini-Review
Blaszczak, A. M., Jalilvand, A., & Hsueh, W. A. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.650768 · Cited by 109
“Once accumulated, these macrophages release TNFa which increases adipocyte release of FFAs (82).”
BackgroundTalbot, N. A., Wheeler-Jones, C. P. D., & Cleasby, M. E. (2014) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2014.06.010 · Cited by 105
“…pathways are activated in macrophages, leading to IR in adipocytes through a paracrine loop involving tumour necrosis factor (TNF)a (Suganami et al., 2005), which has been repeatedly shown to induce IR in muscle cells in vitro and in vivo (de Alvaro et al., 2004; Hotamisligil et…”
Background
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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