Table sugar and high-fructose corn syrup are widely used sweeteners that promote obesity and the metabolic syndrome. Molecularly, they consist of glucose and fructose. Previous studies in model organisms have shown that blocking fructose metabolism prevents metabolic syndrome induced either by fructose or by glucose. However, the tissue-specific roles of fructose metabolism in metabolic syndrome induced by a mixture of fructose and glucose has not been directly tested.
A new study investigates the contribution of fructose metabolism to the development of the metabolic syndrome in mice in response to a sugar solution resembling that which is used in the human diet. “We decided to test the response of whole-body as well as tissue-specific fructokinase-deficient mice to a fructose–glucose solution similar to high-fructose corn syrup,” explains Miguel Lanaspa, corresponding author of the study.
The researchers observed that animals that received the fructose–glucose solution consumed more test solution than animals that received a fructose solution and that this effect was dependent on functional fructose metabolism. Blocking fructose metabolism by deleting the gene that encodes fructokinase in the whole animal prevented hallmarks of sugar-induced metabolic dysfunction, such as lipid accumulation in the liver and the rise of fasting blood levels of insulin.
Next, the researchers examined the contributions of intestinal as well as liver fructose metabolism to sugar intake and its metabolic consequences. When fructose metabolism was blocked in the intestine, fructose–glucose solution intake and overall caloric intake was reduced. When fructose metabolism was blocked in the liver, fructose-glucose solution intake remained similar to that of control mice. However, unlike control mice, liver fructokinase-deficient mice did not develop the metabolic syndrome as a result of sugar intake.
This study reveals a tissue-specific role for fructose metabolism in sugar-induced metabolic syndrome.
“Deletion of fructokinase in the liver does not reduce the appetite for sugar, unlike intestinal fructokinase knockout, and is enough to prevent metabolic syndrome induced by sugar,” summarized Lanaspa.
This research could inform the development of therapeutics that target fructokinase to treat hallmarks of the metabolic syndrome. Future work is needed to determine whether liver fructokinase activity can be leveraged to improve already existing metabolic dysfunction.
Andres-Hernando, A. et al. Deletion of fructokinase in the liver or in the intestine reveals differential effects on sugar-induced metabolic dysfunction. Cell Metab. https://doi.org/10.1016/j.cmet.2020.05.012 (2020)
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Kriebs, A. Fructose and metabolic health. Nat Rev Endocrinol 16, 402 (2020). https://doi.org/10.1038/s41574-020-0383-3