Fructose reprogrammes glutamine-dependent oxidative metabolism to support LPS-induced inflammation

Nicholas Jones, Julianna Blagih, Fabio Zani, April Rees, David G Hill, Benjamin Jenkins, Caroline J Bull, Diana Moreira, Azari Bantan, James G Cronin, Daniele Avancini, Gareth Jones, David K Finlay, Karen Vousden, Emma E Vincent*, Caroline Thornton*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

12 Citations (Scopus)
50 Downloads (Pure)

Abstract

Fructose intake has increased substantially throughout the developed world and is associated with obesity, type 2 diabetes and non-alcoholic fatty liver disease. Currently, our understanding of the metabolic and mechanistic implications for immune cells, such as monocytes and macrophages, exposed to elevated levels of dietary fructose is limited. Here, we show that fructose reprograms cellular metabolic pathways to favour glutaminolysis and oxidative metabolism, which are required to support increased inflammatory cytokine production in both LPS-treated human monocytes and mouse macrophages. A fructose-dependent increase in mTORC1 activity drives translation of pro-inflammatory cytokines in response to LPS. LPS-stimulated monocytes treated with fructose rely heavily on oxidative metabolism and have reduced flexibility in response to both glycolytic and mitochondrial inhibition, suggesting glycolysis and oxidative metabolism are inextricably coupled in these cells. The physiological implications of fructose exposure are demonstrated in a model of LPS-induced systemic inflammation, with mice exposed to fructose having increased levels of circulating IL-1β after LPS challenge. Taken together, our work underpins a pro-inflammatory role for dietary fructose in LPS-stimulated mononuclear phagocytes which occurs at the expense of metabolic flexibility.
Original languageEnglish
Article number1209 (2021)
Number of pages13
JournalNature Communications
Volume12
Issue number1
DOIs
Publication statusPublished - 22 Feb 2021

Structured keywords

  • ICEP

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