Evidence that TLR4 Is Not a Receptor for Saturated Fatty Acids but Mediates Lipid-Induced Inflammation by Reprogramming Macrophage Metabolism

Graeme I. Lancaster, Katherine G. Langley, Nils Anton Berglund, Helene L. Kammoun, Saskia Reibe, Emma Estevez, Jacquelyn Weir, Natalie A. Mellett, Gerard Pernes, James R.W. Conway, Man K.S. Lee, Paul Timpson, Andrew J. Murphy, Seth L. Masters, Steve Gerondakis, Nenad Bartonicek, Dominik C. Kaczorowski, Marcel E Dinger, Peter J. Meikle, Peter J. BondMark A. Febbraio

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Chronic inflammation is a hallmark of obesity and is linked to the development of numerous diseases. The activation of toll-like receptor 4 (TLR4) by long-chain saturated fatty acids (lcSFAs) is an important process in understanding how obesity initiates inflammation. While experimental evidence supports an important role for TLR4 in obesity-induced inflammation in vivo, via a mechanism thought to involve direct binding to and activation of TLR4 by lcSFAs, several lines of evidence argue against lcSFAs being direct TLR4 agonists. Using multiple orthogonal approaches, we herein provide evidence that while loss-of-function models confirm that TLR4 does, indeed, regulate lcSFA-induced inflammation, TLR4 is not a receptor for lcSFAs. Rather, we show that TLR4-dependent priming alters cellular metabolism, gene expression, lipid metabolic pathways, and membrane lipid composition, changes that are necessary for lcSFA-induced inflammation. These results reconcile previous discordant observations and challenge the prevailing view of TLR4's role in initiating obesity-induced inflammation. Saturated fatty acids are believed to be TLR4 agonists, promoting macrophage activation and obesity-associated inflammation. Lancaster et al. demonstrate that the inflammatory fatty acid palmitate is actually not a TLR4 agonist. TLR4 is, however, required for palmitate-induced inflammation through TLR4-dependent priming and altered cellular metabolism, thus reconciling discordant observations.

Original languageEnglish
Pages (from-to)1096-1110
Number of pages16
JournalCell Metabolism
Issue number5
Publication statusPublished - 1 May 2018


  • inflammation
  • innate immunity
  • metabolism
  • obesity
  • toll-like receptors

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