Maternal exercise conveys protection against NAFLD in the offspring via hepatic metabolic programming

Background and aims: Maternal exercise (ME) during pregnancy has been shown to improve long-term metabolic health in offspring. However, the effects of ME on the development of non-alcoholic fatty liver disease (NAFLD) in offspring and its underlying mechanisms remain poorly understood. This study aimed at determining the long-term effects of ME during pregnancy on offspring body composition and development of NAFLD while focusing on proteomic-based analysis of the hepatic energy metabolism during postnatal developmental organ programming. Method(s): C57BL/6N Mouse dams were divided into a sedentary control group (CO) and a running intervention group (INT), which performed voluntary wheel running throughout gestation. At postnatal day (P)70, half of the offspring of both groups was challenged with a high fat diet (HFD) for the following six weeks until P112 (CO-HFD and INT-HFD). Male offspring was sacrificed at weaning (P21) and in later life (P112) and profiling of hepatic key metabolic processes was conducted. At P21, liver proteomic screens and at P112 liver histomorphology were performed. Result(s): Offspring of exercised dams were protected from HFD-induced body weight gain and NAFLD in later life (P112). This was associated with a significant activation of hepatic AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor alpha (PPARalpha) and PPAR coactivator-1 alpha (PGC1alpha) signaling and with reduced hepatic lipogenesis and increased intrahepatocellular beta-oxidation at a critical point in time of developmental programming in early life (P21). Concomitant proteomic analysis revealed a characteristic hepatic expression pattern in the offspring as a result of ME with the most prominent impact on Cholesterol 7 alpha-hydroxylase (CYP7A1). Conclusion(s):ME may offer protection against offspring HFD-induced NAFLD by shaping hepatic proteomics signature and metabolism in early life. The results highlight the potential of exercise during pregnancy for antagonizing the early origins of NAFLD.