Palmitic acid triggers inflammatory responses in N42 cultured hypothalamic cells partially via ceramide synthesis but not via TLR4

Domenico Sergi, Amanda C Morris, Darcy E Kahn, Fiona H McLean, Elizabeth A Hay, Phil Kubitz, Alasdair MacKenzie, Maria G Martinoli, Janice E Drew, Lynda M Williams

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

A high-fat diet induces hypothalamic inflammation in rodents which, in turn, contributes to the development of obesity by eliciting both insulin and leptin resistance. However, the mechanism by which long-chain saturated fatty acids trigger inflammation is still contentious. To elucidate this mechanism, the effect of fatty acids on the expression of the pro-inflammatory cytokines IL-6 and TNFα was investigated in the mHypoE-N42 hypothalamic cell line (N42). N42 cells were treated with lauric acid (LA) and palmitic acid (PA). PA challenge was carried out in the presence of either a TLR4 inhibitor, a ceramide synthesis inhibitor (L-cycloserine), oleic acid (OA) or eicosapentaenoic acid (EPA). Intracellular ceramide accumulation was quantified using LC-ESI-MS/MS. PA but not LA upregulated IL-6 and TNFα. L-cycloserine, OA and EPA all counteracted PA-induced intracellular ceramide accumulation leading to a downregulation of IL-6 and TNFα. However, a TLR4 inhibitor failed to inhibit PA-induced upregulation of pro-inflammatory cytokines. In conclusion, PA induced the expression of IL-6 and TNFα in N42 neuronal cells independently of TLR4 but, partially, via ceramide synthesis with OA and EPA being anti-inflammatory by decreasing PA-induced intracellular ceramide build-up. Thus, ceramide accumulation represents one on the mechanisms by which PA induces inflammation in neurons.

Original languageEnglish
Pages (from-to)321-334
Number of pages14
JournalNutritional Neuroscience
Volume23
Issue number4
Early online date21 Jul 2018
DOIs
Publication statusPublished - Apr 2020

Keywords

  • Journal Article
  • hypothalamic inflammation
  • fatty acids
  • hypothalamic neurons
  • ceramide
  • toll-like receptor 4
  • Toll-like receptor 4
  • ENDOPLASMIC-RETICULUM STRESS
  • SATURATED FATTY-ACIDS
  • Fatty acids
  • BETA/NF-KAPPA-B
  • LIPID-ACCUMULATION
  • OBESITY
  • INHIBITION
  • INSULIN-RESISTANCE
  • Ceramide
  • GENE-EXPRESSION
  • Hypothalamic inflammation
  • CARNITINE PALMITOYLTRANSFERASE
  • Hypothalamic neurons
  • ADIPOSE-TISSUE

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