ABSTRACT
【Objective】 To explore the effect of high-fat and high-fructose diet on mouse intestinal barrier function, as well as the role of ketohexokinase (KHK), the key enzyme in fructose metabolism, in intestinal barrier impairment. 【Methods】 Eight-week-old male control C57BL/6J mice and Khk-/- mice were randomly divided into control + normal diet (ND), control + high-fat and high-fructose diet (HFHFD), Khk-/-+ normal diet (ND+Khk-/-), and Khk-/-+ high-fat and high-fructose diet (HFHFD+Khk-/-) groups, with eight mice in each group. During the high-fat and high-fructose diet and normal diet, the body weight changes of mice in different groups were recorded. After the intervention, the blood glucose and insulin levels of mice in each group were detected. The intestinal barrier function and inflammation level of mice were evaluated by detecting intestinal water content, permeability, tight junction protein expression, serum and intestinal inflammatory factor levels. 【Results】 Compared with ND group, HFHFD group significantly increased the body weight, blood glucose and insulin levels of mice, increased the intestinal water content and permeability, decreased the expression of tight junction proteins, and increased inflammatory factors of the serum and intestines. In the two groups fed with high-fat and high-fructose diet, the body weight, blood glucose and insulin levels of the HFHFD+Khk-/- group were significantly lower than those of HFHFD group, and the intestinal barrier dysfunction and inflammation were significantly improved. 【Conclusion】 KHK, a key enzyme in fructose metabolism, is involved in the impairment of intestinal barrier caused by high-fat and high-fructose diet. Knockout of Khk gene significantly improved intestinal barrier dysfunction and the inflammation level.
ABSTRACT
【Objective】 Diabetic mice could show learning and memory dysfunction, and we aimed to investigate the effect of Sigma-1 receptor agonist, PRE-084, on neurons and cognitive impairment in mice with type 1 diabetes (T1DM). 【Methods】 Twenty mice with T1DM induced by streptozocin, aged 8-10 weeks, and 20 control mice (CON) were randomly divided into four groups (CON+Vehicle, CON+PRE-084, T1DM+Vehicle and T1DM+PRE-084). Mouse primary neurons were cultured in high glucose medium with PRE-084 and control solvent, respectively. The body weight, food and water intake, and fasting blood glucose level of mice in each group were detected and recorded. The learning and memory abilities of mice were detected by new object recognition experiment. The mitochondria-associated endoplasmic reticulum membrane (MAM) structure of neurons in hippocampal CA1 area of mice was detected by transmission electron microscope. And the expression levels of ATP and reactive oxygen species (ROS) in hippocampus of mice were detected by biochemical kit. Cell viability and ROS level of primary neurons were detected by CCK8 and cellular ROS kit. 【Results】 PRE-084 reduced the increase of body weight, food and water intake, and blood glucose caused by diabetes. PRE-084 significantly ameliorated the learning and memory impairment of the mice with T1DM, improved the changes of MAM structure in neurons of hippocampal CA1 area of diabetic mice, increased the level of ATP in hippocampus of diabetic mice, and decreased the increase of ROS expression in diabetic hippocampus and neurons under high glucose conditions. 【Conclusion】 Sigma-1 receptor agonist, PRE-084, could improve learning and memory impairment in the mice with T1DM, which might be related to the structural changes of MAM, the increase of ATP production, and the decrease of ROS production in hippocampal neurons.