Research Article

Dietary saturated fatty acids prime the NLRP3 inflammasome via TLR4 in dendritic cells—implications for diet-induced insulin resistance

  1. Clare M. Reynolds1,
  2. Fiona C. McGillicuddy1,
  3. Karen A. Harford1,
  4. Orla M. Finucane1,2,
  5. Kingston H. G. Mills3,
  6. Helen M. Roche1,*

Article first published online: 15 JUN 2012

DOI: 10.1002/mnfr.201200058

Issue

Molecular Nutrition & Food Research

Molecular Nutrition & Food Research

Volume 56, Issue 8, pages 1212–1222, August 2012

Additional Information

How to Cite

Reynolds, C. M., McGillicuddy, F. C., Harford, K. A., Finucane, O. M., Mills, K. H. G. and Roche, H. M. (2012), Dietary saturated fatty acids prime the NLRP3 inflammasome via TLR4 in dendritic cells—implications for diet-induced insulin resistance. Mol. Nutr. Food Res., 56: 1212–1222. doi: 10.1002/mnfr.201200058

Author Information

  1. 1

    Nutrigenomics Research Group, UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland

  2. 2

    Institute of Molecular Medicine, School of Medicine, Trinity Centre for Health Sciences, St. James Hospital, Dublin 2, Ireland

  3. 3

    Immune Regulation Research Group, Trinity College Dublin, Dublin 2, Ireland

*Correspondence: Professor Helen Roche, Nutrigenomics Research Group, UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland
E-mail: helen.roche@ucd.ie
Fax: +353-1-7166701

Publication History

  1. Issue published online: 10 AUG 2012
  2. Article first published online: 15 JUN 2012
  3. Manuscript Accepted: 17 APR 2012
  4. Manuscript Revised: 5 APR 2012
  5. Manuscript Received: 26 JAN 2012

Funded by

  • Science Foundation Ireland PI Programme

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Keywords:

  • Adipose tissue;
  • Dendritic cell;
  • Inflammasome;
  • Palmitic acid;
  • TLR4

Scope

Inflammasome-mediated inflammation is a critical regulator of obesity-induced insulin resistance (IR). We hypothesized that saturated fatty acids (SFA) directly prime the NLRP3 inflammasome via TLR4 concurrent with IR. We focused on dendritic cells (DCs) (CD11c+CD11b+F4/80−), which are recruited into obese adipose tissue following high-fat diet (HFD) challenge and are a key cell in inflammasome biology.

Methods and results

C57BL/6 mice were fed HFD for 16 weeks (45% kcal palm oil), glucose homeostasis was monitored by glucose and insulin tolerance tests. Stromal vascular fraction (SVF) cells were isolated from adipose and analyzed for CD11c+CD11b+F480− DC. Following coculture with bone marrow derived DC (BMDC) insulin-stimulated 3H-glucose transport into adipocytes, IL-1β secretion and caspase-1 activation was monitored. BMDCs primed with LPS (100 ng/mL), linoleic acid (LA; 200 μM), or palmitic acid (PA; 200 μM) were used to monitor inflammasome activation. We demonstrated significant infiltration of DCs into adipose after HFD. HFD-derived DCs reduce adipocyte insulin sensitivity upon coculture co-incident with enhanced adipocyte caspase-1 activation/IL-1β secretion. HFD-derived DCs are skewed toward a pro-inflammatory phenotype with increased IL-1β secretion, IL-1R1, TLR4, and caspase-1 expression. Complementary in vitro experiments demonstrate that TLR4 is critical in propagating SFA-mediated inflammasome activation.

Conclusion

SFA represent metabolic triggers priming the inflammasome, promoting adipocyte inflammation/IR, suggesting direct effects of SFA on inflammasome activation via TLR4.

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