Abstract
Detrimental exposures in mothers are recognized as risk factors for the development of metabolic dysfunction in offspring. In contrast, maternal exercise has been reported to be an effective strategy to maintain offspring health. However, the mechanisms underlying the protective effects of maternal exercise on adult offspring metabolic homeostasis are largely unclear. This study aims to investigate whether maternal exercise before and during pregnancy could combat the adverse effects of maternal high-fat diet (HFD) on metabolism in 24-week-old male offspring and to explore the role of miRNAs in mediating the effects. Female C57BL/6 mice were fed with either control diet or HFD 3-week prior to breeding and throughout pregnancy and lactation, among whom half of the HFD-fed mice were submitted to voluntary wheel running training 3-week before and during pregnancy. Male offspring were sedentary and fed with a control diet from weaning to 24 weeks. Body weight, the content of inguinal subcutaneous adipose tissue and perirenal visceral adipose tissue, glucose tolerance, and serum insulin and lipids in offspring were analyzed. Hepatic tissues were collected for transcriptome and miRNA sequencing and reverse transcription-quantitative polymerase chain reaction validation. The results showed that maternal HFD resulted in significant glucose intolerance, insulin resistance, and dyslipidemia in adult offspring, which were negated by maternal exercise. Transcriptome sequencing showed that maternal exercise reversed perinatal HFD-regulated genes in adult offspring, which were enriched in glucose and lipid metabolic-related signaling pathways. At the same time, maternal exercise significantly rescued the changes in the expression levels of 3 hepatic miRNAs in adult offspring, and their target genes were involved in the regulation of cholesterol biosynthesis and epigenetic modification, which may play an important role in mediating the intergenerational metabolic regulation of exercise. Overall, our research pioneered the role of miRNAs in mediating the programming effects of maternal exercise on adult offspring metabolism, which might provide novel insight into the prevention and treatment of metabolic disorders in early life.
Highlights
The worldwide prevalence of type 2 diabetes mellitus (T2DM) and obesity has caused unprecedented challenges on global health and economic burden
Maternal exercise dramatically decreased these two kinds of white fat mass induced by maternal high-fat diet (HFD) in adult offspring at 24 weeks (Figures 1C,D)
Since maternal HFD and exercise intervention have significant programming effects on the body weight and fat mass of the offspring, we further dynamically analyzed the effects of maternal intervention on glucose and lipid metabolism in offspring among the three groups
Summary
The worldwide prevalence of type 2 diabetes mellitus (T2DM) and obesity has caused unprecedented challenges on global health and economic burden. Aside from the direct influences of genetics and environmental factors on the susceptibility to developing obesity and T2DM, over the last few decades, substantial evidence has found an association between earlylife exposures and adult-onset diseases. Maternal lifestyle intervention may be a practical measure to break the intergenerational cycle of chronic metabolic diseases. The intensity and duration are still controversial, previous clinical studies have proved that maternal exercise reshaped pregnancy outcomes and future children’s health of reproductive-age women with overweight or gestational diabetes [10]. In terms of rodent models, our team and other groups have demonstrated that maternal exercise before and during pregnancy alleviated the adverse impact of maternal high-fat diet (HFD) on the metabolic health of adult offspring [11, 12]. The underlying mechanism responsible for the intergenerational metabolic benefits of maternal exercise has not been fully clarified
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