| dc.description.abstract | Background. Obesity is associated with adipose tissue inflammation, development of nonalcoholic fatty liver disease (NAFLD) and altered gut microbiota composition. Niacin is beneficial in inhibiting obesity-associated adipose tissue inflammation, decreasing hepatic triglyceride content in NAFLD and suppressing colitis and colorectal cancer. B6129SF2/J (B6129) mice have emerged in recent years to meet the need for better appropriate controls for genetically engineered strains maintained on a mixed B6;129 background. However, a limited number of studies have characterized the physiological and metabolic changes which occur in B6129 mice during diet-induced obesity compared with that of C57BL/6J (B6) mice. Objectives. Therefore, the objectives of this dissertation are to comparatively assess the impact of high-fat diet (HFD) and niacin on 1) adipose tissue inflammation, 2) NAFLD development, and 3) gut microbiota composition in B6 and B6129 mice. Method. Three-week old male B6 (n=32) and B6129 (n=32) mice were maintained on a chow (10% fat) or HFD (60% fat) for 20 weeks. Niacin (360 mg/kg/day) or vehicle was added to the drinking water from week 5 until the end of the study. Results. Adipose tissue inflammation was increased in HFD-fed mice of both strains, but it was more advanced in B6 mice. Niacin decreased adipose tissue inflammation in HFD-fed B6129 but not B6 mice. Both strains of mice fed a HFD developed NAFLD with increased histological score. Surprisingly, niacin treatment increased normalized liver weight, hepatic triglyceride content and histological score in HFD-fed B6129 mice but had no impact on B6 mice. Metabolomic analysis revealed that niacin affected a greater number of metabolites in HFD-fed B6129 than B6 mice. In HFD-fed B6 mice, no specific pathway was identified as impacted by niacin. However, 5 pathways were impacted by niacin in HFD-fed B6129 mice. Of the metabolites that were changed in these pathways, 4-HPP did not change with HFD feeding but significantly decreased with niacin treatment. Decreased 4-HPP by niacin is associated with decreased b-oxidation in the liver. Lipidomic analysis suggested different hepatic lipid profiles with HFD feeding and niacin treatment in B6129 mice. The abundance of phosphocholine (PC), which is critical for very low-density lipoprotein (VLDL) triglyceride production and secretion, was not changed in B6 mice with either HFD feeding or niacin treatment. In contrast, PC was increased in HFD-fed B6129 mice, and decreased with niacin treatment. Utilizing a live bacteria culture technique to evaluate microbiota composition, we observed that the anaerobes/aerobes ratio dramatically decreased in HFD-fed B6129 mice. Firmicutes/Bacteroidetes ratio remained relatively consistent in B6 mice, whereas it was increased in HFD-fed B6129 mice, which was reversed by niacin treatment. HFD remarkably increased the proportion of hemolytic bacteria and decreased proportion of Bifidobacterium and Bacteroides in B6129 mice, which was reversed by niacin treatment. In B6 mice, HFD and niacin had minor impact on gut microbiota composition. Colon length did not change in B6 mice but increased in HFD-fed B6129 mice treated with niacin. Goblet and Paneth cell number did not change in B6 mice. In contrast, goblet cell number was increased in HFD-fed B6129 mice. Paneth cell number was increased in HFD-fed B6129 mice treated with niacin. Conclusions. In conclusion, both B6 and B6129 mice developed adipose tissue inflammation and NAFLD after HFD feeding, but to a lesser degree in B6129 mice. Niacin had no impact on NAFLD development in B6 mice but potentiated hepatic steatosis in HFD-fed B6129 mice. Metabolomics and lipidomics analysis revealed that the mechanisms of niacin-induced hepatic steatosis in HFD-fed B6129 mice involved decreased b-oxidation and VLDL triglyceride production and secretion. B6 mice were more resistant to HFD and niacin-induced alterations in gut microbiota composition and histological changes of small intestine than B6129 mice. Niacin improved gut microbiota composition and small intestine histology in HFD-fed B6129 mice. | en_US |
