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

Abstract

Maternal obesity programs risk for development of non-alcoholic 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 maternal obesogenic diet. Female mice were fed chow (CON) or HFFC and bred with lean males. A subset had an exercise wheel introduced 4 weeks after starting diet to allow for voluntary exercise. The offspring were weaned to 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 HFFC diet had increased body weight prior to adding an exercise wheel. Female mice fed HFFC diet had an increase in exercise distance relative to CON during the pre-conception period. Exercise distance was similar between groups during pregnancy and lactation. CON-Active and HFFC-Active offspring exhibited decreased inflammation compared to offspring from sedentary dams. Fibrosis increased in offspring from HFFC-sedentary dams compared to 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, one-carbon, histidine, and acylcarnitine metabolism. This study provides pre-clinical evidence that maternal exercise is a potential approach to prevent developmentally programmed liver disease progression in offspring.

Metabolomics to Understand Alterations Induced by Physical Activity during Pregnancy

“…Among the reported changes, the observed increase for histidine is of great importance as histidine has been previously reported to have a protective effect against hepatic fibrosis in an experimental model [101]. Given these results, exercise in pregnancy can potentially protect the offspring against the development of liver disease caused by maternal obesity, in part by mediating changes in the offspring metabolome [72].…”

“…Most of the published literature in this field focuses on individuals with obesity or pregnancies with complications. The beneficial effects of PA are well established for gestational individuals and their offspring [6,8,72]; however, how PA affects their metabolite profile has not yet been elucidated. While data are limited, this section strives to provide a concise overview of the available literature that characterizes the metabolomic patterns of gestational parents and their offspring, with a particular focus on the impact of physical activity on these profiles (Figure 3).…”

“…A mouse model was used to examine the effect of an eight-week exercise intervention on the development of NAFLD in the offspring of high-fat diet-fed mice [72]. Liver samples gathered from the offspring of the intervention and control groups were used for untargeted metabolomics using LC-MS.…”

Gestational and Developmental Contributors of Pediatric MASLD

“…Exercise-attenuated hepatic inflammation and fibrosis was accompanied by changes in metabolites involved in bile acid and fatty acid metabolism. 75 In other studies, the decreased hepatic steatosis seen in offspring born to mothers exposed to physical activity during gestation has been associated with increased protein expression of markers of mitochondrial biogenesis (such as PCG1α). 76 Additional studies have implicated different pathways in the altered lipid handling seen in offspring exposed to unhealthy cardiometabolic environments in utero.…”

Maternal Weight Management to Prevent the Developmental Programming of MAFLD in Offspring of Obese Mothers

“…However, similar to the study in Japanese macaques, this was avoided in the offspring of mothers with dietary intervention 9 weeks prior to conception, suggesting that early maternal dietary intervention is effective in reducing the risk of MAFLD in the offspring of mothers with obesity [52]. Animal studies investigating maternal exercise in the prenatal period have yielded similar results; maternal exercise prior to conception in rodent mothers with obesity was shown to reduce hepatic fibrosis and regulate the expression of genes involved in β-oxidation and lipogenesis in the liver of the offspring [53,54]. Maternal diet: chow (CON) or western-style (OB-WSD).…”