- • We provide novel evidence for the effects of metabolic dysfunctions on brain function using the rat model of metabolic syndrome induced by high fructose intake.
- • We describe that the deleterious consequences of unhealthy dietary habits can be partially counteracted by dietary supplementation of n-3 fatty acid.
- • High sugar consumption impaired cognitive abilities and disrupted insulin signalling by engaging molecules associated with energy metabolism and synaptic plasticity; in turn, the presence of docosahexaenoic acid, an n-3 fatty acid, restored metabolic homeostasis.
- • These findings expand the concept of metabolic syndrome affecting the brain and provide the mechanistic evidence of how dietary habits can interact to regulate brain functions, which can further alter lifelong susceptibility to the metabolic disorders.
Abstract We pursued studies to determine the effects of the metabolic syndrome (MetS) on brain, and the possibility of modulating these effects by dietary interventions. In addition, we have assessed potential mechanisms by which brain metabolic disorders can impact synaptic plasticity and cognition. We report that high-dietary fructose consumption leads to an increase in insulin resistance index, and insulin and triglyceride levels, which characterize MetS. Rats fed on an n-3 deficient diet showed memory deficits in a Barnes maze, which were further exacerbated by fructose intake. In turn, an n-3 deficient diet and fructose interventions disrupted insulin receptor signalling in hippocampus as evidenced by a decrease in phosphorylation of the insulin receptor and its downstream effector Akt. We found that high fructose consumption with an n-3 deficient diet disrupts membrane homeostasis as evidenced by an increase in the ratio of n-6/n-3 fatty acids and levels of 4-hydroxynonenal, a marker of lipid peroxidation. Disturbances in brain energy metabolism due to n-3 deficiency and fructose treatments were evidenced by a significant decrease in AMPK phosphorylation and its upstream modulator LKB1 as well as a decrease in Sir2 levels. The decrease in phosphorylation of CREB, synapsin I and synaptophysin levels by n-3 deficiency and fructose shows the impact of metabolic dysfunction on synaptic plasticity. All parameters of metabolic dysfunction related to the fructose treatment were ameliorated by the presence of dietary n-3 fatty acid. Results showed that dietary n-3 fatty acid deficiency elevates the vulnerability to metabolic dysfunction and impaired cognitive functions by modulating insulin receptor signalling and synaptic plasticity.