�Metabolic syndrome� in the brain: deficiency in omega-3 fatty acid exacerbates dysfunctions in insulin receptor signalling and cognition

January 1, 2012 Human Health and Nutrition Data 0 Comments

�Metabolic syndrome� in the brain: deficiency in omega-3 fatty acid exacerbates dysfunctions in insulin receptor signalling and cognition

Year: 2012
Authors: Agrawal, R Gomez-Pinilla, F.
Publication Name: J Physiol
Publication Details: DOI: 10.1113/jphysiol.2012.230078


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 4hydroxynonenal, 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. (Authors abstract)
The rise in consumption of high caloric foods has triggered an explosives urge in metabolic syndrome (MetS), known for its effects of increasing morbidity and negatively impacting life expectancy. Metabolic disorders such as diabetes and obesity increase the vulnerability to mental illness; however, the mechanisms that link cellular metabolism and mental health are poorly understood. The North American diet is very high in sugar and high fructose corn syrup including soft drinks, candies, desserts, and processed foods. The average American�s consumption of high fructose corn syrup amounts to about 35 pounds in a year, with cane sugar totaling another 47 pounds. Abundant consumption of fructose is an important contributor to the metabolic syndrome, typically characterized by hyperinsulinaemia, hypertension and hypertriglyceridaemia. Research has shown a connection between these sugars and metabolic conditions such as obesity, elevated triglycerides and diabetes. This study investigated the association between high sugar intake and mental health.  Over a five-day period, two groups of rats were trained twice a day, to navigate a maze. Then, for a subsequent six week period, the rats were fed a fructose solution in place of drinking water, while the second group was also given one gram per day of the omega 3 fatty acid docosahexaenoic acid (DHA) and flaxseed oil (a rich source of omega 3 alpha-linolenic acid). Considering brain tissue is roughly 40% DHA, it was postulated that the  chemical connections between brain cells affecting learning and memory might be protected from the effects of fructose by the omega 3 fatty acids. After six weeks, the rats were tested as to their ability to recall landmarks that enabled them to navigate the maze and escape. The omega 3 fed group was able to recall the exit route and escape the maze faster than the group receiving only sugar. The brains of the rats were later examined. The rats fed only fructose had brains exhibiting signs of declined synaptic activity, as well as signs of insulin resistance, which regulates synaptic function and controls blood sugar. The scientists concluded that diets high in sugar and high fructose corn syrup disrupt memory and learning, however omega 3 fatty acids can help, at least partly, offset the disruption. Dietary n3 fatty acid deficiency compromised molecular mechanisms important for the maintenance of metabolic homeostasis, with subsequent effects on cognitive abilities. In particular, the deficiency of n3 reflected a decline in spatial memory in proportion to the intensity of the index of insulin resistance, and all parameters were further aggravated by an increase in the fructose intake. Increased consumption of fructose, particularly when combined with the DHA deficiency, resulted in hyperinsulinaemia, hyper-glycaemia and an increase in triglyceride (TG) levels. Further, the n3 deficient diet elicited a significant increase in n6/n3 ratio alone or in the presence of fructose. The increase in the ratio n-6/n-3 observed in the group of animals fed on n3 deficient diet and fructose might be indicative of a substitution of n-3 by the n-6 in the membrane, which may alter membrane fluidity. The results suggest that the lack of dietary n-3 fatty acids predisposes the organism to MetS, promotes brain insulin resistance, and increases the vulnerability to cognitive dysfunction. (Editors comments)

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