ChREBP-Knockout Mice Show Sucrose Intolerance

We have previously reported that 60% sucrose diet-fed ChREBP knockout mice (KO) 13 showed body weight loss resulting in lethality. We aimed to elucidate whether sucrose and 14 fructose metabolism are impaired in KO. Wild type mice (WT) and KO were fed a diet containing 15 30% sucrose with/without 0.08% miglitol, an α-glucosidase inhibitor, and these effects on 16 phenotypes were tested. Furthermore, we compared metabolic changes of oral and peritoneal 17 fructose injection. Thirty percent sucrose diet feeding did not affect phenotypes in KO. However, 18 miglitol induced lethality in 30% sucrose-fed KO. Thirty percent sucrose plus miglitol diet-fed KO 19 showed increased cecal contents, increased fecal lactate contents, increased growth of 20 lactobacillales and Bifidobacterium and decreased growth of clostridium cluster XIVa. ChREBP gene 21 deletion suppressed the mRNA levels of sucrose and fructose related genes. Next, oral fructose 22 injection did not affect plasma glucose levels and liver fructose contents; however, intestinal 23 sucrose and fructose related mRNA levels were increased only in WT. In contrast, peritoneal 24 fructose injection increased plasma glucose levels in both mice; however, the hepatic fructose 25 content in KO was much higher owing to decreased hepatic Khk mRNA expression. Taken 26 together, KO showed sucrose intolerance and fructose malabsorption owing to decreased gene 27 expression. 28