Cited by 1,035Adipokines, Inflammation, and Metabolic DiseasesAdipose Tissue and MetabolismCardiovascular Disease and Adiposity

A Subpopulation of Macrophages Infiltrates Hypertrophic Adipose Tissue and Is Activated by Free Fatty Acids via Toll-like Receptors 2 and 4 and JNK-dependent Pathways

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Nguyen, M. T. Audrey, Favelyukis, Svetlana, Nguyen, Anh-Khoi, Reichart, Donna, Scott, Peter A., Jenn, Alan, Liu-Bryan, Ru, Glass, Christopher K. +2 more·2007·Journal of Biological Chemistry

Abstract

Obesity and type 2 diabetes are characterized by decreased insulin sensitivity, elevated concentrations of free fatty acids (FFAs), and increased macrophage infiltration in adipose tissue (AT). Here, we show that FFAs can cause activation of RAW264.7 cells primarily via the JNK signaling cascade and that TLR2 and TLR4 are upstream of JNK and help transduce FFA proinflammatory signals. We also demonstrate that F4/80(+)CD11b(+)CD11c(+) bone marrow-derived dendritic cells (BMDCs) have heightened proinflammatory activity compared with F4/80(+)CD11b(+)CD11c(-) bone marrow-derived macrophages and that the proinflammatory activity and JNK phosphorylation of BMDCs, but not bone marrow-derived macrophages, was further increased by FFA treatment. F4/80(+)CD11b(+)CD11c(+) cells were found in AT, and the proportion and number of these cells in AT is increased in ob/ob mice and by feeding wild type mice a high fat diet for 1 and 12 weeks. AT F4/80(+)CD11b(+)CD11c(+) cells express increased inflammatory markers compared with F4/80(+)CD11b(+)CD11c(-) cells, and FFA treatment increased inflammatory responses in these cells. In addition, we found that CD11c expression is increased in skeletal muscle of high fat diet-fed mice and that conditioned medium from FFA-treated wild type BMDCs, but not TLR2/4 DKO BMDCs, can induce insulin resistance in L6 myotubes. Together our results show that FFAs can activate CD11c(+) myeloid proinflammatory cells via TLR2/4 and JNK signaling pathways, thereby promoting inflammation and subsequent cellular insulin resistance.

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Crossref · 10.1074/jbc.m706762200

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  • Free fatty acid products from necrotic adipocytes cause pro-inflammatory activation of macrophages through TLR-2 and TLR-4 signaling.

    “A number of free fatty acid products released from necrotic adipocytes have been shown to cause pro-inflammatory activation of macrophages through TLR-2 and TLR-4 signaling pathways, suggesting a potential mechanism by which obesity-induced inflammation may occur [73,74].”
  • M2 macrophages are positive for F4/80 and CD11b but negative for CD11c.

    “Similar to M1 macrophages, they are positive for F4/80 and CD11b, but they are negative for CD11c (105).”

    From Insulin sensitivity: Modulation by nutrients and inflammation (2008) · cites this paper as [105]

  • These proinflammatory macrophages are implicated in the development of insulin resistance.

    “Accordingly, because of their proinflammatory properties, these macrophages are implicated in the pathogenesis of insulin resistance (103, 105, 112, 113).”

    From Insulin sensitivity: Modulation by nutrients and inflammation (2008) · cites this paper as [105]

  • In obesity, most of the expanded adipose tissue macrophage population consists of proinflammatory macrophages positive for F4/80, CD11b, and CD11c.

    “In obesity, the major component of the increased ATM content is composed of proinflammatory macrophages that are triply positive for the surface markers F4/80, CD11b, and CD11c (92,105).”

    From Insulin sensitivity: Modulation by nutrients and inflammation (2008) · cites this paper as [105]

  • Macrophages and adipocytes lacking Tlr2, Tlr4, or both do not activate inflammation.

    “Activation of inflammation is prevented in macrophages and adipocytes that are deficient in Tlr2, Tlr4, or Tlr2/Tlr4 (105, 114-116).”

    From Insulin sensitivity: Modulation by nutrients and inflammation (2008) · cites this paper as [105]

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Authors
Nguyen, M. T. A., Favelyukis, S., Nguyen, A.-K., Reichart, D., Scott, P. A., Jenn, A., Liu-Bryan, R., Glass, C. K., Neels, J. G., & Olefsky, J. M.
Affiliations
University of California San Diego (US)
Corresponding author
Nguyen, M. T. Audrey
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2007-11
Volume
282
Issue
48
Pages
35279-35292
ISSN
0021-9258 (ISSN-L)
OpenAlex
W2063131576
Cited by
1,035
References
36
Citations by year
2026: 26 · 2025: 37 · 2024: 29 · 2023: 32 · 2022: 52 · 2021: 52 · 2020: 45 · 2019: 55 · 2018: 48 · 2017: 66 · 2016: 67 · 2015: 59 · 2014: 84 · 2013: 91 · 2012: 74
FWCI
31.77
Type
journal article
Language
en
Open access
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • American Heart Association
  • National Institutes of Health (5r03ar049416-03, DK 074868)
  • University of California, San Diego
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK 074868, DK-33651, P01DK074868)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR049416)
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
free fatty acids, adipose tissue macrophages, TLR2, TLR4, JNK signaling, dendritic cells, CD11c, bone marrow-derived macrophages, adipose tissue inflammation, insulin resistance, obesity, type 2 diabetes, high-fat diet, ob/ob mice, skeletal muscle inflammation, myotubes
MeSH terms
Adipose Tissue, Animals, Bone Marrow Cells, Fatty Acids, Nonesterified, Inflammation, Insulin Resistance, Macrophages, Male, Mice, Inbred C57BL, Models, Biological, Signal Transduction, CD11b Antigen, CD11c Antigen, MAP Kinase Kinase 4, Toll-Like Receptor 2, Toll-Like Receptor 4, Mice

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