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

Clare M. Reynolds, Fiona C. Mcgillicuddy, Karen A. Harford, Orla M. Finucane, Kingston H G Mills, Helen M. Roche*

*Corresponding author for this work

Research output: Contribution to journalArticle

98 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1212-1222
Number of pages11
JournalMolecular Nutrition and Food Research
Volume56
Issue number8
DOIs
Publication statusPublished - 01 Aug 2012
Externally publishedYes

Keywords

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

ASJC Scopus subject areas

  • Food Science
  • Biotechnology

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