Differential Tissue‐Specific Effects of Fructokinase Blockade in Sugar‐Induced Metabolic Syndrome

The intake of fructose and the fructose‐containing sugars, sucrose and high fructose corn syrup, are strongly associated with the development of obesity and diabetes. Here we tested the hypothesis that the metabolism of fructose is the key feature whereby these added sweeteners cause metabolic syndrome. To this end, metabolic syndrome was induced by administering fructose‐glucose (10 or 30%) solutions in the drinking water. Of interest, we found that glucose enhances fructose intake and transport and that the blockade of fructose metabolism in fructokinase deficient ( KHK‐A/C KO) mice is sufficient to fully prevent sugar‐induced metabolic syndrome. Our data indicate that this protection is not only due to reduced fructose metabolism but also to decreased preference and intake of sugar. Furthermore, and by using tissue specific KHK‐A/C KO mice, we determined that the reduction in sugar preference was mainly driven by the deficiency of KHK in the jejunum. However, gut‐specific KHK‐A/C KO mice showed enhanced risk for metabolic syndrome when equal intake of fructose was consumed due to increased fructose delivery to the liver. In contrast, liver specific KHK‐A/C KO mice continued to show a preference for sugar despite being protected from metabolic syndrome. In conclusion, these studies document a pivotal role for fructose metabolism in the mechanism by which added sweeteners cause metabolic syndrome. Intestinal fructose metabolism plays a key role in sugar intake whereas liver fructose metabolism drives fatty liver, obesity and diabetes indicating that metabolic syndrome is a hepatocyte‐centered condition. Support or Funding Information This work has been supported by NIH Grants 1RO1DK105364‐01A1 (to M.A.L. and R.J.J.) and 1R01DK108859 (to M.A.L.)