Maternal high-fat diet consumption induces sex-dependent alterations of the endocannabinoid system and redox homeostasis in liver of adult rat offspring

Abstract

Maternal diet plays a critical role in health development. Perinatal overnutrition induces metabolic dysfunctions and obesity in the offspring. Obesity is associated with endocannabinoid system (ECS) over activation and oxidative stress. Liver ECS activation induces hepatic steatosis, inflammation and fibrosis while the antagonism of cannabinoid receptors ameliorates these alterations. Here, we investigated the effect of perinatal maternal high-fat diet (HF, 29% of calories as fat) on the ECS and antioxidant system in liver of male and female adult rat offspring (180 days old). Maternal HF diet increased hepatic cannabinoid receptors, ECS metabolizing enzymes and triglyceride content, with male offspring more affected. ECS changes are likely independent of estradiol serum levels but associated with increased hepatic content of estrogen receptor, which can stimulate the expression of ECS components. Differently, maternal HF diet decreased the activity of the antioxidant enzymes glutathione peroxidase, superoxide dismutase and catalase, and increased oxidative stress markers in both sexes. Alterations in the redox homeostasis were associated with mitochondria damage but not with liver fibrosis. Our data suggest that maternal HF diet induces ECS over activation in adulthood, and that male offspring are at higher risk to develop liver disease compared with female rats.

Maternal high‐fat diet disrupted one‐carbon metabolism in offspring, contributing to nonalcoholic fatty liver disease

“…Finally, our study suggests that the sex‐specific phenotype of NAFLD in offspring mice exposed to maternal overnutrition in utero could be because of male offspring being more sensitive to methionine cycle disruption. We previously reported that more severe hepatic steatosis was only observed in male, but not female, offspring exposed to overnutrition in utero, 10,11 consistent with the reports of others 41,42 . In our current study, the male HF offspring displayed disrupted one‐carbon metabolism and methionine cycles, which were associated with exacerbated hepatic steatosis induced by a postweaning HF diet, while the female HF offspring displayed no or very mild changes.…”

“…We previously reported that more severe hepatic steatosis was only observed in male, but not female, offspring exposed to overnutrition in utero, 10,11 consistent with the reports of others. 41,42 In our current study, the male HF offspring displayed disrupted one-carbon metabolism and methionine cycles, which were associated with exacerbated hepatic steatosis induced by a postweaning HF diet, while the female HF offspring displayed no or very mild changes.…”

Phytocannabinoids—A Green Approach toward Non-Alcoholic Fatty Liver Disease Treatment

“…As shown in a rat model, the first changes in the endocannabinoid system that represent a higher risk of NAFLD development may already occur in prenatal life. Maternal high-fat diet feeding during the perinatal phase induced sex-specific long-term changes in the liver ECS components (i.e., increased protein expression of CB1R and CB2R) of the adult offspring [40]. The upregulation of hepatic CB1R in liver steatosis and fibrosis was repeatedly confirmed by human, animal, and in vitro studies [41,42].…”

Lifestyle and Metabolic Syndrome: Contribution of the Endocannabinoidome

“…In utero or neonatal exposure to dietary perturbations can have long-lasting effects on an individual and, indeed, the eCBome is significantly impacted by exposure to high-fat diets early on in life with long-lasting consequences. Maternal high-fat feeding resulted in sustained elevation of CB1/2, FAAH, and MAGL levels in the livers of adult male rats, with changes in redox homeostasis [45]. Maternal exposure to high-fat diet also increased CB1 in the male, and CB2 in the female hypothalamus at birth, while CB1 and FAAH expression were increased, and CB2 and MGLL were decreased in the BAT of males and females, respectively.…”