Long chain W3 PUFA and insulin resistance: unhealthy effects of fructose on the brain

http://jp.physoc.org/content/590/10/2485.full

Proposed mechanism by which insulin resistance leads to disruption of brain metabolism with subsequent effects on synaptic plasticity and cognition. It is also depicted how dietary n-3 fatty acid content in the diet may influence the vulnerability to metabolic dysfunction. Abundant consumption of fructose leads to an increase in triglyceride and insulin levels in the body, which can affect brain function after crossing the blood–brain barrier. The changes in membrane n-3 and n-6 fatty acids may alter the membrane fluidity, thereby disrupting membrane insulin receptor function. This, in turn, can influence downstream insulin receptor cascades such as IRS-1, Akt and CREB, leading to alteration in synaptic plasticity and cognition. Release of n-6 arachidonic acid from the phospholipid membrane by phospholipase A2 (PLA2) and subsequent peroxidation result in the generation of 4-HNE, which produces alterations in insulin receptor signalling via inhibiting Akt signalling. These alterations can result in abnormal neuronal signalling, which can reduce learning capacity and other functions that rely on synaptic plasticity and neuronal excitability. Dietary components can also affect mitochondrial energy production by modulating energy molecules LKB1, AMPK and Sir2, which are important for maintaining neuronal excitability and synaptic function via CREB. Regulation of synaptic functions by dietary intervention can also be directly mediated by synapsin I and synaptophysin (SYP). These events are important for our understanding of how dietary factors can interact to regulate brain plasticity, and how dietary management can be used to promote brain health.

Abundant consumption of fructose is an important contributor to the metabolic syndrome, typically characterized by hyperinsulinaemia, hypertension and hypertriglyceridaemia (Gerrits & Tsalikian, 1993). Studies have shown that rats fed on a high fructose diet display hepatic oxidative damage and altered lipid metabolism as a result of the burden of fructose metabolism (Kelley et al. 2004). We have conducted studies using fructose drinking as an animal model to assess the effects of MetS on insulin signalling, synaptic plasticity, and behaviour.