The Impact Of Parental Obesity On The Development Of NAFLD In Offspring

The dramatic rise of nonalcoholic fatty liver disease (NAFLD) among children in the past decade does not solely result from the over consumption of high fat diet (HFD) in kids. Recent animal studies suggest that the offspring of HFD-fed obese mothers develop nonalcoholic steatohepatitis (NASH) more easily when weaned on the HFD than those weaned on the normal chow (NC), indicating that HFD feeding may exacerbate the progression of metabolic syndromes through generation to generation transmission under certain conditions. The author investigated the development of NAFLD in the offspring of maternal obesity using mouse model under continuous HFD feeding for three maternal generations. In addition, sex differences exist in the prevalence of obesity and related diseases, including NAFLD. Therefore, the author further examined whether there were any sex differences in the development of NAFLD under the continuous maternal over-nutrition. Moreover, paternal obesity has also been proved to affect the progression of disease in the offspring. Thus, the author also established a mouse model with continuous HFD feeding for three paternal generations to investigate the impact of paternal obesity on the development of NAFLD in the male offspring.In both continuous maternal obesity and paternal obesity mouse model, C57BL/6mice were fed with either a HFD or NC for three consecutive generations, named FO, F1and F2generation. The author examined the body weight (BW), food intake, hepatic histology and serum levels of insulin, leptin, triglycerides, liver injury markers and estrogen, as well as hepatic triglyceride level of the offspring in maternal obesity mouse model; the author also investigated expression levels of the factors involved in lipogenesis, glucose metabolism, endoplasmic reticulum (ER) stress pathways, as well as the markers of cell proliferation and macrophages and histone methylation status in their livers. In addition, BW, hepatic histology, mRNA levels of genes related to lipid and glucose metabolism and content of glycogen in the livers were investigated in male offspring of paternal obesity.The data showed that1) Obesity occurred earlier and became more severe through generations, and it was accompanied by a gradual increase of hepatic steatosis (F2>F1>FO) in the male offspring of maternal obesity with continuous HFD feeding. The highest serum levels of insulin and leptin were also found in the male F2generation. In addition, lipogenesis and ER stress pathway were transgenerationally accumulated in male offspring of maternal obesity under continuous HFD feeding. A trend of trans generational changes of LXRα and ERO1-α, histone methylations and H3K9me2were detected. Furthermore, CHIP assay demonstrated a significant reduction of histone methylation on the promoters of LXRα and ERO1-α in the male F2generation.2) Sex differences were existed in the progression of hepatic steatosis in the offspring of maternal obesity under continuous HFD feeding. Although pathological score of the liver, serum ALT and AST levels were similar between the HFD fed male F2mice and female F2mice, the makers of cell proliferation and inflammatory macrophages were gradually increased through generations in the male offspring but not in the female offspring under the continuous HFD-fed stress. Furthermore, the gradually increased phosphorylation of estrogen receptor a through generations was observed in the female offspring but not in the male offspring.3) BW and liver weight were not transgenerationally increased in both2-month-old and4-month-old male offspring of paternal obesity with continuous HFD feeding. However, transgenerationally exacerbated hepatic steatosis was shown in the4-month-old male offspring of paternal obesity with continuous HFD feeding.Therefore, the present thesis suggested that under continuous HFD feeding stress, there are a gradual susceptible to the development of obesity and hepatic steatosis over generations in the offspring of maternal obesity. This is presumably a consequence of transgenerational accumulation of epigenetic modifications which lead to activation of lipogenesis and ER stress pathways in the liver, at least in male offspring of maternal obesity under continuous HFD feeding. Moreover, different mechanisms were involved in the development of NAFLD in offspring of maternal obesity. The transgenerational accumulation of cell proliferation and inflammation in the male offspring but not in the female offspring of maternal obesity under continuous HFD feeding, may be one of the reasons why male NAFLD patients are easier to develop more severe liver diseases. Additionally, paternal obesity has transgenerational impact on the development of NAFLD but not obesity in the male offspring under continuous HFD feeding stress, however, the underlying mechanism needs further investigation.