Maternal Exercise Protects Male Offspring From Maternal Diet–Programmed Nonalcoholic Fatty Liver Disease Progression

Abstract

Maternal obesity programs the risk for development of nonalcoholic fatty liver disease (NAFLD) in offspring. Maternal exercise is a potential intervention to prevent developmentally programmed phenotypes. We hypothesized that maternal exercise would protect from progression of NAFLD in offspring previously exposed to a maternal obesogenic diet. Female mice were fed chow (CON) or high fat, fructose, cholesterol (HFFC) and bred with lean males. A subset had an exercise wheel introduced 4 weeks after starting the diet to allow for voluntary exercise. The offspring were weaned to the HFFC diet for 7 weeks to induce NAFLD. Serum, adipose, and liver tissue were collected for metabolic, histologic, and gene expression analyses. Cecal contents were collected for 16S sequencing. Global metabolomics was performed on liver. Female mice fed the HFFC diet had increased body weight prior to adding an exercise wheel. Female mice fed the HFFC diet had an increase in exercise distance relative to CON during the preconception period. Exercise distance was similar between groups during pregnancy and lactation. CON-active and HFFC-active offspring exhibited decreased inflammation compared with offspring from sedentary dams. Fibrosis increased in offspring from HFFC-sedentary dams compared with CON-sedentary. Offspring from exercised HFFC dams exhibited less fibrosis than offspring from sedentary HFFC dams. While maternal diet significantly affected the microbiome of offspring, the effect of maternal exercise was minimal. Metabolomics analysis revealed shifts in multiple metabolites including several involved in bile acid, 1-carbon, histidine, and acylcarnitine metabolism. This study provides preclinical evidence that maternal exercise is a potential approach to prevent developmentally programmed liver disease progression in offspring.