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

Fructose intake has increased substantially throughout the western world and is associated with obesity, type 2 diabetes and non-alcoholic fatty liver disease. Currently, the metabolic and mechanistic implications for immune cells, such as monocytes and macrophages, exposed to elevated levels of dietary fructose are unknown. 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 murine 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 show 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 were demonstrated in a murine model of LPS-induced systemic inflammation, with mice exposed to fructose showing increased circulating IL-1β following 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.