Transgenerational impact of maternal obesogenic diet on offspring bile acid homeostasis and nonalcoholic fatty liver disease

Abstract

Studies show maternal obesity is a risk factor for metabolic syndrome and nonalcoholic fatty liver disease (NAFLD) in offspring. Here we evaluated potential mechanisms underlying these phenotypes. Female C57Bl6 mice were fed chow or an obesogenic high-fat/high-sucrose (HF/HS) diet with subsequent mating of F1 and F2 female offspring to lean males to develop F2 and F3 generations, respectively. Offspring were fed chow or fibrogenic (high transfat, cholesterol, fructose) diets, and histopathological, metabolic changes, and bile acid (BA) homeostasis was evaluated. Chow-fed F1 offspring from maternal HF/HS lineages (HF/HS) developed periportal fibrosis and inflammation with aging, without differences in hepatic steatosis but increased BA pool size and shifts in BA composition. F1, but not F2 or F3, offspring from HF/HS showed increased steatosis on a fibrogenic diet, yet inflammation and fibrosis were paradoxically decreased in F1 offspring, a trend continued in F2 and F3 offspring. HF/HS feeding leads to increased periportal fibrosis and inflammation in chow-fed offspring without increased hepatic steatosis. By contrast, fibrogenic diet-fed F1 offspring from HF/HS dams exhibited worse hepatic steatosis but decreased inflammation and fibrosis. These findings highlight complex adaptations in NAFLD phenotypes with maternal diet.

Developmental Programming of NAFLD by Parental Obesity

“…In the maternal HF/HS diet model, a similar degree of steatosis occurs in F2 and F3 offspring, suggesting that the maternal HF/HS diet does not have a transgenerational impact on steatosis. ( 21 ) Barbosa et al showed no increase in intrahepatic TG levels in F2 offspring from a paternal HFD lineage. In fact, after offspring HFD feeding, intrahepatic TG levels increased to a lesser degree than control mice.…”

“…Offspring from a maternal obesogenic lineage were protected from fibrosis across all three generations. ( 21 ) The mechanism for this transgenerational effect has not been defined. However, one male lineage transmitted fibrosis protection across multiple generations in association with epigenetic changes in Pparγ .…”

“…The bile acid pool increased, and the abundance of specific intrahepatic bile acid species shifted, including increased muricholic acid and decreased deoxycholic acid. ( 21 ) These shifts occurred partly due to changes in bile acid synthesis, including increased cytochrome P450 7A1 ( Cyp7a1 ) expression and activity. Resident gut bacteria also modulate enterohepatic bile acid metabolism through enzymatic modification of intestinal bile acids.…”

Maternal Genistein Intake Mitigates the Deleterious Effects of High-Fat Diet on Glucose and Lipid Metabolism and Modulates Gut Microbiota in Adult Life of Male Mice

“…Although epigenetics, microbiome, and metabolome were all considered the potential mechanisms, the specific mechanism of the “fetal programming” is still largely unclear (Wankhade et al, 2016). Substantial research and our previous studies both showed that early-life overnutrition-maternal high-fat diet during pregnancy and lactation significantly increased susceptibility to glucose intolerance, insulin resistance and lipid disorders in adult offspring (Zheng et al, 2016; Huang et al, 2017; Thompson et al, 2019). Therefore, early-life might be a critical window for preventing the transmission of metabolic diseases across generation and reducing the prevalence of T2DM.…”

Nutrition Transition and Cancer

“…This, in turn, modifies the expression of critical genes associated with physiological and pathological processes, including embryonic development, aging, and carcinogenesis [36,37]. There is growing evidence that folate modulates anticarcinogenic properties through epigenetic changes, as low folate intake has been associated with DNA hypomethylation and increased risk of colorectal and pancreatic cancers [37,38]. Diets rich in fruits and vegetables and containing natural antioxidants may protect against cancer.…”