Fructose Metabolism in the Brain

Sarah A. Oppelt, Dean R. Tolan


Liver and kidneys are responsible for metabolism of 40-60% of ingested fructose, while the physiological fate of the remaining fructose remains poorly understood.  Currently, fructose may constitute 5-15% of daily caloric intake in the Western diet.  In humans, chronic fructose ingestion correlates with the development of a number of disease states, including insulin resistance, microvascular damage, and inflammation in liver and kidneys, while effects on other organs able to metabolize fructose remains unknown. This highlights the need for a better understanding of fructose metabolism throughout the body. Recently, the brain has been identified as one of the extrahepatic tissues that participate in fructose metabolism.  It has been known for nearly 50 years that fructose can be metabolized by brain tissue from experiments conducted on cultured brain slices, and more recent research has identified specific regions of the brain that can metabolize fructose.  Here, metabolic pathways for fructose are reviewed. Experiments are described that establish the brain as contributing to fructose metabolism outside the liver in a physiologically meaningful way.  In addition to dietary fructose, the brain is capable of de novo fructose production via the polyol pathway.  The polyol pathway is an important pathway in maintaining osmotic homeostasis.  In this pathway, excess dietary glucose is converted to fructose, exposing cells to fructose independent of dietary ingestion.  Lastly, high fructose diets, type II diabetes, and metabolic syndrome have been associated with impaired memory formation, increased insulin resistance, and inflammation in the brain, and development of dementia in humans.  The underlying mechanisms are still not understood, and will probably be multi-factorial, but it may be possible to target enzymes in the fructose metabolism.  Because the incidence rates of both type II diabetes and metabolic syndrome are rising in Western populations, understanding the contribution of fructose metabolism to these conditions is imperative. 

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