(P15-054-24) Effects of Diet and Sex on the Development of Non-Alcoholic Fatty Liver Disease During the Progression of Metabolic Syndrome

Objectives: The prevalence of Metabolic Syndrome and Non-Alcoholic Fatty Liver Disease are reaching epidemic levels globally with males experiencing both at higher rates. More research is required in order to understand this phenomenon and provide proper treatment. The purpose of this study was to investigate the sexually dimorphic differences in the development of Non-Alcoholic Fatty Liver Disease (NAFLD) and Metabolic Syndrome (MetS) in response to high fat or high sugar diet.

Methods: C57BL/6 (30 male and 30 female) mice were assigned one of the following diets after one week of acclimation: Chow, High Fat, or High Sugar. All mice were kept on a 12:12 light-dark cycle with ad libitum access to food and water. Body weight and food consumption was measured every three days. MRI was performed biweekly to determine fat and lean mass. Glucose tolerance testing was conducted at weeks 0, 6, 9, and 11. Mice were euthanized at either 6-week or 12-week on the diets. Frozen liver samples were used for metabolomic, mRNA, and protein analysis. Formalin fixed liver was used for histology.

Results: Male mice on a 12-week high fat diet exhibited significantly greater weight gain and fat mass when compared all other groups. Male 12-week mice on a high fat and high sugar diet showed greater lipid accumulation in the liver when compared to both controls and female 12-week mice on the same diet. While high fat diet showed greater lipid droplets, only the high sugar diet for both male and female had signs of fibrosis in the liver. Male mice on a high fat diet developed glucose intolerance at week 6. Male 12-week mice on a high fat diet had significantly higher levels of insulin than other groups. HOMA-IR was significantly elevated in Male mice on a high fat diet. Metabolite profiling showed diet sex interactions in Sphingolipid metabolism and Retinol metabolism.

Conclusions: Males on a high fat diet showed increases in weight gain as well as glucose intolerance at earlier time points than females on high fat diet. Histological results showed a high sugar diet for both sexes had indices of liver fibrosis whereas a high fat diet for both sexes did not.

Funding Sources: Memphis-Meharry Program to Enhance Collaborative and Interdisciplinary Research (PECIR) Grant 2021