Maternal Exercise and Its Beneficial Effects on Glucose Metabolism in Offspring
The incidence of obesity and type 2 diabetes has risen rapidly in recent years worldwide. The International Diabetes Federation reported that in 2019, 9.3% of adults aged 20 to 79 years, amounting to 463 million people, were living with diabetes, and this number is projected to rise to 700 million by 2045. Notably, one in six live births, or 20 million annually, is affected by hyperglycemia during pregnancy, with 84% of these cases being gestational diabetes mellitus (GDM). This condition places individuals at risk for a host of diabetes-associated complications. The World Health Organization has also highlighted that 50% of women of childbearing age and 20% to 25% of pregnant women in Europe are affected by overweight or obesity. The global health expenditure on diabetes is estimated to be 10%, amounting to USD 760 billion. Thus, obesity, type 2 diabetes, and their complications pose an enormous burden on healthcare systems and individuals alike.
In recent years, it has become increasingly clear that susceptibility to obesity and type 2 diabetes is strongly influenced by exposure to an adverse intrauterine environment during early development, a phenomenon known as “metabolic programming.” Human epidemiological studies and rodent experiments have established that the nutritional status of the mother during pregnancy is a critical factor influencing the development of obesity and type 2 diabetes in offspring. For instance, maternal undernutrition during the Dutch Famine between 1944 and 1945 resulted in the development of obesity in the offspring during adulthood. Studies have also shown that low birth weight is associated with an increased risk of obesity, impaired glucose tolerance, and type 2 diabetes. Interestingly, maternal obesity has also been identified as a risk factor for obesity and diabetes in offspring. Therefore, gestational diabetes mellitus and maternal obesity can significantly increase the incidence of impaired glucose metabolism in offspring. However, intervention measures are particularly limited. This review aims to demonstrate the evidence linking maternal exercise during critical periods of development and its implications for glucose metabolism in offspring, and to further examine the potential role of epigenetic modifications in this process.
Implications of Human Studies: Maternal Exercise
It is well established that exercise has important health benefits for people with obesity and type 2 diabetes, and regular exercise is one of the most effective strategies to treat type 2 diabetes. Emerging data in humans suggest that physical exercise during pregnancy can improve the health of offspring in infancy and childhood. Moderate exercise during pregnancy is very beneficial to the health of both the mother and the fetus. Several human studies have aimed to examine the beneficial effects of maternal exercise on pregnancy outcomes and metabolic health in progeny. These studies have shown that exercise during pregnancy protects against the development of hypertension, excessive weight gain, and pre-eclampsia in the mother, while also protecting against macrosomia and low birth weight in the offspring. Regular exercise during pregnancy can effectively reduce the risks of gestational diabetes in overweight and obese pregnant women. These studies indicate that maternal exercise can effectively reduce the occurrence of adverse pregnancy outcomes. Maternal exercise also has beneficial effects on progeny. Weight-bearing exercise during pregnancy results in lower body weight of children at age 5, without adverse postnatal effects. Another study recruiting 5,125 children found that weight gain during pregnancy significantly increased the risk of obesity in the child at 8 years of age, and proper exercise during pregnancy was effective in reducing body mass index levels in children. However, these studies only focused on the effects in childhood, and the long-term effects on glucose metabolism are still not clear.
Implications of Rodent Experiments: Maternal Exercise and Glucose Metabolism in Offspring
While these important studies in humans strongly suggest that exercise during pregnancy is important for the health of young offspring, it has not been possible to determine if maternal exercise in humans can result in lower rates of diabetes or obesity in adulthood or middle age, which is the time point of high risk for the development of metabolic diseases. Therefore, investigations using rodent models have been imperative in delineating the effects of maternal exercise on offspring as they age.
Different Intervention Timing of Maternal Exercise
Determining the optimal maternal intervention timing is an important question, as it can confer maximal benefits of maternal exercise on metabolic health in offspring. Stanford et al found that a maternal high-fat diet during the pre-conception and gestation periods induced obesity, impaired glucose tolerance, and insulin resistance in offspring mice at 52 weeks of age, while maternal voluntary wheel running during pre-conception and gestation significantly reversed these adverse effects. They further explored the effects of maternal exercise at specific time points (pre-conception or gestation or pre-conception and gestation) on glucose metabolism in offspring mice. Female mice were randomly divided into four groups: exercise only during pre-conception, exercise only during gestation, exercise during both pre-conception and gestation, and sedentary. Maternal exercise only during pre-conception showed no difference in glucose tolerance of offspring at any age. Maternal exercise only during gestation improved glucose tolerance at a young age. Maternal exercise during both pre-conception and gestation improved glucose tolerance, lowered fasting insulin, and decreased body fat percentage in male offspring compared to all other three groups. Sheldon et al found that maternal exercise only during gestation can reduce body fat percentage and significantly improve high-fat diet-induced hepatic steatosis in rat offspring at 8 months of age. Maternal exercise before and during pregnancy protects adult mouse offspring from diet-induced obesity. Raipuria et al showed that maternal voluntary wheel running prior to mating and until the lactation period decreased the metabolic risks in offspring induced by maternal obesity. These data suggest that different intervention timing of maternal exercise is important for metabolic health in offspring, and current studies suggest that both pre-conception and gestation exercise has more benefits. However, further research about the optimal intervention timing of maternal exercise on glucose metabolism in offspring is warranted.
Sexual Dimorphism in Offspring of Maternal Exercise
Increasing evidence shows that numerous metabolic states can differentially affect males and females. It indicates that the metabolic response to maternal diet may be different in male and female offspring. Maternal exercise before and during pregnancy negates the detrimental effects of a maternal high-fat diet on the metabolic health of male offspring. It is imperative to examine sex differences of maternal exercise on glucose metabolism in both male and female offspring. Stanford et al further determined if maternal exercise could attenuate the detrimental effects of maternal high-fat feeding in female offspring. It showed that maternal exercise also confers benefits to female offspring, including decreasing body weight and increasing insulin sensitivity. Raipuria et al found that maternal voluntary wheel running improves insulin and glucose metabolism, with greater effects in male than female offspring. Carter et al found that maternal voluntary exercise before mating and during pregnancy and nursing can improve glucose tolerance (at 30 and 72 weeks of age) in both male and female offspring. However, it can only reduce body fat percentage (at 39 and 68 weeks of age) in male offspring. Carter et al further found that maternal voluntary wheel running can improve insulin sensitivity (at 14 months of age) in female offspring measured by euglycemic-hyperinsulinemic clamps. Eclarinal et al found that maternal exercise before and during pregnancy can increase physical activity in offspring, and this effect was observed earlier in female offspring (at sexual maturation). It also showed that greater fat loss in response to a 3-week voluntary exercise program was achieved in female offspring at 300 days of age. Therefore, it indicates that the metabolic response to maternal exercise may be different in male and female offspring, and most studies indicate that the beneficial effects of maternal exercise on glucose metabolism are greater in male than in female offspring. However, more studies focused on examining the sexual dimorphism in offspring of maternal exercise are needed.
Different Type and Intensity of Maternal Exercise
In addition to voluntary wheel running, treadmill exercise was also commonly used to observe the effects of maternal exercise on glucose metabolism in offspring. Quiclet et al showed that maternal treadmill exercise 4 weeks before as well as during gestation at a constant submaximal intensity can reduce body weight, fat content, and increase insulin sensitivity in young adult offspring at 10 weeks of age. The intensity of maternal exercise is also an important factor, which can influence glucose metabolism in offspring. It also indicated that maternal treadmill exercise before and during gestation at a submaximal intensity increased insulin secretory capacity in offspring at weaning. Fidalgo et al showed that maternal moderate-low physical training by treadmill can reverse offspring obesity, glucose intolerance, and hypercholesterolemia caused by maternal protein restriction during gestation and lactation. In addition to voluntary wheel running and treadmill exercise, swim training of dams before and during pregnancy protected adult male offspring from diet-induced obesity and fat gain. However, it is difficult to conclude which exercise type or intensity is the best, and further studies should be investigated.
Maternal Exercise and Epigenetic Modifications
How a transient stimulus during in utero development, or pre-conception, can have lasting effects manifesting in adult life is a critical question. It is likely that epigenetic mechanisms of inheritance play a major role. Epigenetic modifications are labile alterations to DNA (e.g., methylation) or DNA structure (e.g., histone modifications) or non-coding RNA (e.g., microRNA) that influence patterns of gene expression and are inherited from parent cells. Interestingly, both exercise and nutrition can influence epigenetic modifications, including those in offspring. Methyl-supplementation of the maternal diet influenced DNA methylation patterns of offspring. High-fat diet feeding of pregnant mice resulted in hypermethylation of the peroxisome proliferator-activated receptor gamma coactivator-1 promoter in skeletal muscle of offspring, an effect that was attenuated by maternal exercise. Other studies have shown that maternal exercise alters gene expression patterns in metabolically important tissues such as liver and skeletal muscle of offspring. A recent study showed that each additional hour of pre-pregnancy leisure time physical activity duration was associated with hypermethylation in C1orf212 and higher circulating miR-146b-5p. Each additional metabolic equivalent hour of early-pregnancy leisure time physical activity energy expenditure was associated with higher circulating miR-21-3p in women carrying female offspring and lower circulating miR-146b-5p and miR-517-5p in women carrying male offspring. Thus, it suggests the potential role of epigenetic inheritance in the transmission of maternal exercise benefits in offspring, and it can facilitate a virtuous cycle of metabolic health, propagating benefits to subsequent generations.
Conclusions
Pre-conception and pregnancy are critical periods of growth and development of humans, which are susceptible to an unhealthy environment. Our study indicates that maternal exercise significantly improves the metabolic health of offspring, raising the possibility that these effects are regulated by epigenetic mechanisms. The increasing rates of obesity and diabetes in individuals of reproductive age can initiate a vicious cycle, propagating risks to subsequent generations. The cycle of metabolic risk transmission could be greatly reduced if mothers knew they could improve their children’s health by exercising before and during pregnancy. Further research about the role and mechanism of maternal exercise on metabolic health in offspring is warranted, which can provide critical implications for the early prevention of obesity and diabetes and ensure a healthier future for subsequent generations. It may also promote the translation to humans about the potential clinical implications of maternal exercise.
doi.org/10.1097/CM9.0000000000000731
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