Fructose re-programmes glutamine-dependent oxidative metabolism to support LPS-induced inflammation

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.

Typically, activation of the human innate immune system requires the rewiring of cellular metabolic pathways largely to favour glucose metabolism1,2,3,4,5. However, 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. Fructose is metabolised by glycolysis either by ketohexokinase producing fructose-1-phosphate, a substrate for aldolase B6 (in the liver, kidneys and intestines for example) or converted to the glycolytic intermediate fructose-6-phosphate by hexokinase (HK), albeit at a lower rate than glucose7,8.

Fructose intake has increased substantially throughout the Western world, largely attributed to elevated sucrose and high fructose corn syrup consumption9 and is thought to exacerbate various non-communicable conditions such as obesity, type 2 diabetes and non-alcoholic fatty liver disease9. Chronic fructose consumption in these conditions has recently been shown to drive hepatic fructolysis, where the expression of lipogenic genes is enhanced10,11,12.

Typically, physiological levels of fructose in the circulation range from 0.04 to 0.2 mM13; however, there are several pathophysiological scenarios in which levels of fructose are elevated. For example, peripheral blood levels can exceed 1 mM in patients with haematological malignancies such as acute myeloid leukaemia and acute lymphoblastic leukaemia14. In addition, fructose concentrations in the bone marrow microenvironment of haematological cancer patients can reach up to 5 mM14. Alterations in the glucose to fructose ratio, particularly when glucose is scarce, enables acute myeloid leukaemia blasts to significantly enhance fructose uptake14. Localised mouse tissue microenvironments, such as the liver, kidneys and jejunum, also have elevated levels of fructose metabolism15. Therefore, there are various pathophysiological scenarios and tissue microenvironments where monocytes will be exposed to either equimolar concentrations of fructose and glucose or concentrations of fructose exceeding that of glucose.

The impact of elevated fructose exposure on the immune system has not been investigated extensively. Chronic fructose exposure in rats results in a more inflammatory phenotype of bone marrow mononuclear cells16. 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 investigated17.

Here we characterise how human monocytes and mouse macrophages respond metabolically and functionally to fructose exposure. We show that activated mononuclear phagocytes demonstrate plasticity in engaging metabolism of this alternative carbon source, yet it leaves the cells metabolically inflexible and vulnerable to further metabolic challenge. Fructose exposure reprogrammes cellular pathways to favour glutaminolysis and oxidative metabolism, which support an inflammatory phenotype in both human and mouse mononuclear phagocytes. Finally, we demonstrate that a short-term high fructose diet promotes inflammation in vivo, suggesting that our findings have pathophysiological significance.