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

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

doi:10.1038/s41467-021-21461-4

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.

Highlights

Fructose intake has increased substantially throughout the developed world and is associated with obesity, type 2 diabetes and non-alcoholic fatty liver disease
While oxygen consumption rate (OCR) of both glucose or fructose LPS-simulated monocytes decreased to the same level upon oligomycin treatment (Fig. 2A), the drastic reduction of OCR in fructose-cultured monocytes reflects a greater reliance on oxidative phosphorylation (OXPHOS)
We demonstrate that mononuclear phagocytes from both species are metabolically plastic in engaging in the metabolism of an alternative carbon source and reprogramme cellular pathways to favour oxidative metabolism

Summary

Introduction

Fructose intake has increased substantially throughout the developed world and is associated with obesity, type 2 diabetes and non-alcoholic fatty liver disease. 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. 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. In the various nutrient environments they inhabit, monocytes will be exposed to a range of different carbon sources, the availability of which will likely dictate their metabolism and phenotype One such carbon source is fructose, the second most abundant dietary sugar found in humans. While there is some evidence that lipopolysaccharide (LPS)-stimulated human dendritic cells are able to produce enhanced levels of pro-inflammatory cytokines when cultured in fructose as opposed to glucose, the underlying metabolic rewiring that enables this pro-inflammatory phenotype has not been investigated[17]

Methods

Results

Conclusion