Sweet but Bitter: Focus on Fructose Impact on Brain Function in Rodent Models

Abstract

Fructose consumption has drastically increased during the last decades due to the extensive commercial use of high-fructose corn syrup as a sweetener for beverages, snacks and baked goods. Fructose overconsumption is known to induce obesity, dyslipidemia, insulin resistance and inflammation, and its metabolism is considered partially responsible for its role in several metabolic diseases. Indeed, the primary metabolites and by-products of gut and hepatic fructolysis may impair the functions of extrahepatic tissues and organs. However, fructose itself causes an adenosine triphosphate (ATP) depletion that triggers inflammation and oxidative stress. Many studies have dealt with the effects of this sugar on various organs, while the impact of fructose on brain function is, to date, less explored, despite the relevance of this issue. Notably, fructose transporters and fructose metabolizing enzymes are present in brain cells. In addition, it has emerged that fructose consumption, even in the short term, can adversely influence brain health by promoting neuroinflammation, brain mitochondrial dysfunction and oxidative stress, as well as insulin resistance. Fructose influence on synaptic plasticity and cognition, with a major impact on critical regions for learning and memory, was also reported. In this review, we discuss emerging data about fructose effects on brain health in rodent models, with special reference to the regulation of food intake, inflammation, mitochondrial function and oxidative stress, insulin signaling and cognitive function.

Keywords: GLUT5; brain insulin resistance; brain mitochondria; brain oxidative stress; cognitive impairment; fructose diet; neuroinflammation.

Figure 1

Fructose is cleared by the small intestine, which converts it into different metabolic intermediates. High fructose doses overwhelm the intestinal capacity for fructose metabolism, and a part of fructose spills over to the liver, which can metabolize it. Gut- and liver-derived metabolic intermediates or fructose itself can reach the brain, exerting effects on regulation of food intake, brain inflammation, mitochondrial function and oxidative stress, insulin signaling and cognitive function. Down arrow indicates downregulated and up arrow indicates upregulated cellular pathways by fructose intake. GLUT5 = glucose transported 5.

Figure 2

Major brain changes following fructose dietary introduction. The boxes indicate proteins and mechanisms modulated by fructose treatment in the brain in the context of the regulation of food intake, neuroinflammation, mitochondrial function, oxidative stress, insulin signaling and cognitive function. Up arrows indicate parameters stimulated and down arrows indicate parameters reduced by fructose intake. p-IRS = phosphorylated insulin receptor and insulin receptor substrate 1; p-Akt = serine/threonine protein kinase B; GLUT1 = glucose transporter 1; NRF2 = nuclear factor 2; AGE = advanced glycation end products; BDNF = brain derived neurotrophic factor; LTP = long-term potentiation; LTD = long-term depression; PGC1-α = peroxisome proliferator-activated receptor gamma coactivator-1 alpha; TLR4 = toll-like receptor 4; NF-kB = nuclear factor kappa-light-chain-enhancer of activated B cells.