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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.
Myeloid cells are able to utilize a variety of monosaccharides from our diet, including fructose. Here the authors show that when monocytes are reliant on fructose as a carbon energy source they are reprogrammed towards oxidative metabolism, glutamine anaplerosis and a pro-inflammatory phenotype owing to excess pro-inflammatory cytokine production.
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1 Swansea University, Institute of Life Science, Swansea University Medical School, Swansea, UK (GRID:grid.4827.9) (ISNI:0000 0001 0658 8800)
2 The Francis Crick Institute, London, UK (GRID:grid.451388.3) (ISNI:0000 0004 1795 1830)
3 University of Bristol, Cellular and Molecular Medicine, Bristol, UK (GRID:grid.5337.2) (ISNI:0000 0004 1936 7603)
4 University of Bristol, Cellular and Molecular Medicine, Bristol, UK (GRID:grid.5337.2) (ISNI:0000 0004 1936 7603); University of Bristol, MRC Integrative Epidemiology Unit, Bristol, UK (GRID:grid.5337.2) (ISNI:0000 0004 1936 7603)
5 Trinity College Dublin, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Dublin, Ireland (GRID:grid.8217.c) (ISNI:0000 0004 1936 9705)
6 San Raffaele Scientific Institute, San Raffaele Telethon Institute for Gene Therapy, Milan, Italy (GRID:grid.18887.3e) (ISNI:0000000417581884)