Journal
NATURE COMMUNICATIONS
Volume 12, Issue 1, Pages -Publisher
NATURE RESEARCH
DOI: 10.1038/s41467-021-21461-4
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Funding
- Wales Gene Park
- Life Sciences Research Network Wales (NRN)
- Versus Arthritis Career Development Fellowship [20305]
- Canadian Institute for Health Research Postdoctoral Fellowship
- Kuok Family Postdoctoral Fellowship
- Diabetes UK RD Lawrence Fellowship [17/0005587]
- Cancer Research UK [C18281/A29019, C596/A10419, C596/A26855]
- Francis Crick Institute - Cancer Research UK [FC001557]
- UK Medical Research Council [FC001557]
- Wellcome Trust [FC001557]
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The research demonstrates that fructose intake can alter immune cell metabolism, leading to increased production of inflammatory cytokines, and reducing metabolic flexibility.
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-1 beta 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.
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