Have trouble finding your car keys this morning because you forgot where you left them? Or maybe you can’t remember the name of the new person who just joined the department down the hall? Before you blame age for your faulty memory, take a look at your diet. New research suggests that low levels of omega-3 fatty acids in your diet could be disrupting biochemical signaling in your brain and impairing your ability to learn and remember. And, consumption of high levels of fructose, often found in sugary beverages, could be making it worse. So, put down that soda and keep reading to learn how those empty calories might be sabotaging your memory and what you can do about it.

Scientists have known for years that high-calorie diets can increase the risk of metabolic disorders such as diabetes and obesity and that these metabolic disorders can increase one’s susceptibility to mental illness. Also, consuming high-calorie diets rich in saturated fat and sugars harms synaptic plasticity, which is important for learning and memory. Unfortunately, little is known about the molecular mechanisms responsible. In a recent Journal of Physiology article (1), researchers carried out experiments to better understand the relationship between diet and memory by determining what effects omega-3 fatty acid deficiency and high levels of dietary fructose had on memory.

In a nutshell, they found that rats fed a diet deficient in omega-3 fatty acids and high in fructose had poorer memories and probably lower metabolism and a reduced ability to learn. Considering that rat and human biochemistries are similar in many ways, an omega-3-deficient, high-fructose diet could be having a similar effect on us humans.

OK, but how did the researchers determine this?

To start their experiments, the authors spent five days training rats to navigate a maze and measuring the time required to complete the maze. The rats then were assigned randomly to two groups: those fed a diet with omega-3 fatty acids and those fed a diet deficient in omega-3 fatty acids; half of each group had access to plain drinking water, while the other half had access to a 15% fructose solution. The total fat content and caloric intake was the same for both diets. After six weeks, the rats’ ability to remember their way through the maze was evaluated. Researchers discovered that rats fed an omega-3-deficient diet required significantly more time to complete the maze than rats fed an omega-3-containing diet, suggesting impaired memory. Rats that consumed high levels of fructose required even more time to navigate the maze, indicating an even higher level of cognitive impairment. The presence of omega-3 fatty acids in the high-fructose diet improved memory but did not reverse the memory deficit completely.

Why? What is happening on the molecular level?

Knowing that insulin signaling in the brain plays a role in memory (2) and that dysfunctional insulin receptor signaling is associated with impaired learning and memory, scientists collected blood samples to measure the levels of glucose, insulin and triglycerides and calculate the insulin resistance index. This index is a measure of insulin resistance, a condition where cells in the body are less able to import and utilize glucose, and as a result, glucose accumulates in the blood and can lead to harmful conditions such as atherosclerosis, heart attack, kidney disease and stroke. An omega-3-deficiency had no effect on insulin resistance index, but a high-fructose diet increased dramatically the index as well as serum triglyceride levels and resulted in hyperinsulinemia and hyperglycemia. The degree of cognitive impairment was proportional to the insulin resistance index and serum triglyceride levels. Adding omega-3 fatty acids, also known as n–3 fatty acids, to the diet reversed the fructose-induced memory deficit but only partially.

Hypothesizing that increased insulin resistance in the body leads to dysfunctional insulin receptor signaling in the brain, the scientists analyzed the rats’ brains and learned that insulin receptor signaling was disrupted in rats fed the omega-3-deficient diet. Activation of the insulin receptor and its downstream signaling molecule Akt were both reduced in the brains of omega-3-deficient rats, and activation levels were even further reduced in rats fed high levels of fructose. An omega-3 deficiency also decreased energy metabolism by decreasing activation of proteins involved in responding to low energy levels, including AMP-activated kinase and one of its upstream regulators LKB1. Omega-3 fatty acids in the diet partially reduced or completely reversed these negative effects.

The authors also monitored proteins and other factors important for synaptic plasticity and cognitive function and learned that an omega-3 deficient, high-fructose diet wreaked havoc here too, with significantly decreased levels of phosphorylated cAMP response element-binding transcription factor (CREB), as well as activated synapsin I and synaptophysin, which are a regulator of neurotransmitter release at the synapse and a marker of synaptic growth, respectively. Dietary omega-3 fatty acids reversed these effects and restored cognitive function, presumably by counteracting the effect of insulin resistance on synaptic plasticity mediated by CREB, synapsin I and synaptophysin.

Is fructose messing with your plasma membranes?

The metabolic burden of high fructose consumption can cause oxidative damage and altered lipid metabolism, so the authors turned their attention to plasma membranes within the rats’ brains. They found that an omega-3 deficiency made the brain more susceptible to fructose-induced free radical attack, as measured by the level of 4-hydroxynonenal, which acts as a marker of lipid peroxidation but also can inhibit insulin-dependent Akt signaling (3) and alter the function of key membrane proteins such as glucose transporter, glutamate transporter and sodium potassium ATPases. In addition, an omega-3 deficiency, with or without fructose, increased the ratio of n–6/n–3 polyunsaturated fatty acids, which could affect membrane fluidity, further disrupting insulin receptor signaling and altering synaptic plasticity and cognition. Once again, these negative effects were reversed by including omega-3 fatty acids to the diet.

So what? I’m not a rat.

Humans, like other mammals, require omega-3 fatty acid precursors in their diet because they cannot synthesize them de novo, and there is no reason to suspect that omega-3 fatty acids are any less important to cognition in humans. In this study, the omega-3 fatty acid diet included docosahexaenoic acid (DHA) and flaxseed oil, which contains high levels of alpha-linolenic acid. Other dietary sources of omega-3 fatty acids and their precursors include sardines, salmon, cod liver oil, soybeans, tofu, navy and other beans, winter squash, olive oil and walnuts. If you’re not getting enough omega-3 fatty acids in your diet, you could be suffering similar effects. Take heart. There is something that you can do. Even if you are not willing or able to increase your intake of omega-3 fatty acids, do your brain a favor and cut back on your fructose consumption.

References

1. Agrawal, R. and Gomez-Pinilla, F. (2012) ‘Metabolic syndrome’ in the brain: Deficiency in omega-3 fatty acid exacerbates dysfunctions in insulin receptor signalling and cognition. J. Physiol. 590, 2485–99 PMID: 22473784
2. Agrawal, R. et al. (2011) Insulin receptor signaling in rat hippocampus: A study in STZ (ICV) induced memory deficit model. Eur. Neuropsychopharmacol. 21, 261–73.
3. Shearn, C.T. et al. (2011) Modification of Akt2 by 4-hydroxynonenal inhibits insulin-dependent Akt signaling in HepG2 cells. Biochemistry 50, 3984–96.

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Terri Sundquist

Terri has worked as a Scientific Communications Specialist at Promega Corporation for more than 13 years, and prior to that, spent more than 5 years solving problems and answering questions as a Promega Technical Services Scientist. She graduated with B.S. degrees in Chemistry and Biology at the University of Wisconsin—River Falls, then earned her M.S. in Molecular Biology from the Mayo Graduate School in Rochester Minnesota.

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