**3.1 Effects of maternal obesity on offspring metabolism**

While rodent models provide an insight into the effects of maternal exercise on progeny, a major obstacle is analogizing human and animal research considering the vast physiological difference between species. In humans, maternal obesity rates are rising and are in parallel with those of the general population [45, 46]. Pre-pregnancy obesity is likely to translate into excessive gestational weight gain, pre-eclampsia, gestational diabetes, and a greater propensity towards postpartum weight retention [47]. Moreover, maternal obesity increases the risk for congenital anomalies, fetal death, stillbirth, and neonatal, perinatal, and infant death [48, 49]. Increased maternal prepregnancy body mass index corelates with increased risk of offspring obesity [50]. Specifically, maternal obesity increases the odds of offspring obesity by 264%, while maternal overweight increases odds by 89% [50]. Neonates born to obese mothers are often large for gestational age with increased adiposity being a major determinant of fetal overgrowth [47]. Besides increasing adiposity, neonates of obese mothers have a higher propensity towards IR independent of maternal glycemia [51, 52]. Finally, maternal obesity is associated with an adverse lipid profile in offspring and an inclination towards the development of metabolic syndrome [53–55]. While this relationship between maternal and offspring metabolism is readily accepted, limitations in the understanding of epigenetic mechanisms governing infant metabolic reprograming remain. Moreover, the biological mechanisms behind metabolic adaptations that govern offspring metabolic phenotypes remain to be elucidated.

The use of umbilical cord derived mesenchymal stem cells (MSCs) has been recognized as a model for the investigation of metabolic programming of the human offspring donor. This model capitalizes on the multilineage potential of MSCs and their ability to differentiate into various lineages of mesenchymal tissue (muscle,

#### *Influence of Maternal Exercise on Maternal and Offspring Metabolic Outcomes DOI: http://dx.doi.org/10.5772/intechopen.106566*

fat, etc.) [56–61]. The phenotype of MSCs reflects that of the donor rendering it as an advantageous *in vitro* model to study offspring phenotypes on a molecular level [62–66]. MSCs from offspring of obese mothers exhibit a greater potential for adipogenesis associated with greater PPAR-γ, FABP4, and lipid content in adipogenically differentiated cells [65]. Further, evidence of lower β-catenin protein content paired with a lower inhibitory phosphorylation of GSK-3β in undifferentiated MSCs suggests a greater shift in cell commitment towards an adipocyte rather than myocyte lineage and will subsequently increase the propensity of the fetus towards greater adiposity [65]. Accordingly, greater MSC adipogenesis potential is positively correlated with infant body fat mass [65]. In line with greater potential for fetal adiposity, MSCs from offspring of obese mothers exhibit greater lipid accumulation and lower capacity for fatty acid oxidation when undergoing myogenesis, which will potentiate ectopic lipid accretion [64]. It is worth noting that fatty acid oxidation in MSCs from offspring of obese mothers is "less efficient" with more substrate flux towards incomplete rather than complete oxidation [64, 66]. Additionally, maternal obesity induces a MSC phenotype with lower metabolic flexibility and a decreased ability to meet metabolic demands, demonstrating primary deficits in fatty acid oxidation [66]. These factors have previously been observed in SkM of humans with non-gravid obesity and have been associated with the development of IR [67–69]. This suggests that maternal obesity may alter offspring metabolism with a predisposition towards metabolic disease (i.e., obesity). Accordingly, beta-oxidation decrements in myogenically differentiated MSCs from offspring of obese mothers are correlated with infant adiposity suggesting that fetal adiposity is in part predetermined by alterations in the fetal metabolic phenotype [63]. These inherent differences in MSC lipid metabolism seemingly stem from differential mitochondrial expression and methylation of genes involved in mitochondrial fatty acid metabolism and respiration (i.e., OXPHOS) and are correlated with neonatal adiposity [62, 63]. Particularly, alterations in lipid metabolism are associated with lower AMPK content and activation and hypermethylation of genes involved in fatty acid oxidation (i.e., ACC2, CPT1A) [64]. Overall, this data suggests that maternal obesity reprograms the offspring metabolic phenotype by increasing propensity towards adiposity, which, in part, occurs through the lowering of oxidative capacity. Moreover, considering that similar alterations are seen with non-gravid obesity, it is reasonable to postulate that this phenotype will predispose offspring to metabolic perturbations later in life. Accordingly, it is necessary to further our understanding of lifestyle interventions that could counteract the intergenerational transmission of metabolic disease. Specifically, non-pharmacological interventions, such as exercise could have a tremendous impact on fetal metabolic programing with overall metabolic disease lowering properties highlighting the need for more research studies. While alterations of the MSC phenotype as a consequence of maternal obesity have been shown, the effects of maternal exercise on offspring metabolic reprograming remain understudied in humans, especially on a molecular level.

#### **3.2 Effects of gestational exercise on offspring metabolism**

Prenatal maternal exercise elicits an array of positive benefits for both mother and offspring. Maternal aerobic exercise lowers the risk for the development of gestational diabetes mellitus and lowers gestational weight gain in both healthy and mothers with gestational diabetes [5, 7, 8, 70]. Further, there is an inverse relationship between gestational weight gain and exercise duration and volume with benefits increasing as exercise volume approaches American College of Obstetricians and Gynecologists

(ACOG) recommendations of 500 MET-minute weekly [7, 8, 71]. Maternal exercise alone reduces the risk of macrosomia and offspring being large for gestational age without increasing risk of pre-term birth or low birth weight [8, 72, 73]. Further, maternal exercise may have a greater influence on birth weight reduction in maternal obesity, however, evidence remains weak [72, 73]. Similarly, the association of maternal exercise and birth weight remains weeak across multiple meta-analysis including women of all body mass index categories and seems to be driven predominantly by exercise volume [8, 72, 73]. Accordingly, the exercise-induced reduction of offspring birth weight is predominantly observed with exercise volumes over 810 MET-min, which is much greater than the 500 MET-min per week recommendation by ACOG [72]. Finally, birth weight reductions observed with maternal exercise are often not clinically significant (i.e., >300 g) making it hard to conclude if prenatal exercise has a significant effect on fetal birth weight [74, 75]. Additionally, while body weight can be influenced by fat and lean mass, maternal exercise does not seem to effect child morphometrics based on two recent meta-analyses [73, 76]. Nonetheless, while alterations in birth weight are not significant, there is evidence to support the beneficial effects of a prenatal healthy lifestyle (i.e., normal BMI, regular exercise, etc.) on the risk of offspring childhood (child age of 9–14) obesity [77]. Overall, while prenatal exercise influences maternal gestational weight gain, the effects of maternal exercise on offspring birth weight and body composition seem to be minimal. Accordingly, and in line with rodent studies, exercise induced body composition alterations might be secondary to other metabolic improvements and may decrease the risk of obesity development with aging.

The positive effects of exercise extend to maternal metabolic health through improvements in lipid and glucose metabolism. Data suggests that maternal exercise improves maternal metabolism during pregnancy and subsequently alters pregnancy outcomes and the metabolic phenotype of offspring. Physical activity during pregnancy reduces the rise of low density lipoprotein and triglyceride, and lowers delivery and neonatal complications [78–82]. Maternal blood lipids are associated with infant adiposity and alterations in MSC metabolism in offspring from mothers with obesity [63, 64, 78] suggesting a potential *in-utero* influence of maternal lipids on fetal metabolic programing. Recently shown, maternal aerobic exercise during gestation may alter the MSC phenotype, however, improvements in lipid oxidation, oxidation efficiency or uptake, and accumulation were not significant [83]. While the lack of effect is surprising based on previously described effects in rodent models and MSCs from offspring of mothers with obesity, it must be noted that exercising mothers were seemingly healthy and thus potentially "diluting" the effect of maternal exercise on offspring metabolic reprograming. Accordingly, the positive effects of maternal exercise on offspring MSC lipid metabolism may be pronounced in situations where an adverse intrauterine environment is instilled by maternal metabolic disease (i.e., obesity) [63–65, 83]; however, there are currently no studies exploring these effects.

Aerobic exercise during pregnancy significantly improves maternal glucose metabolism with a greater effect in women with overweight, obesity, and gestational diabetes [84, 85]. In particular, maternal aerobic exercise lowers insulin levels late in pregnancy and reduces the increase in blood insulin levels from 15- to 36-weeks of gestation [86]. Maternal dysglycemia, with or without gestational or type 2 diabetes, has been associated with adverse pregnancy outcomes (i.e., preeclampsia), offspring outcomes (i.e., excessive fetal growth, congenital abnormalities), and an overall increase in postpartum risk of development of T2D in both

### *Influence of Maternal Exercise on Maternal and Offspring Metabolic Outcomes DOI: http://dx.doi.org/10.5772/intechopen.106566*

mother and offspring [87–89]. Evidence for maternal dysglycemia altering offspring metabolism can be further observed at the level of MSCs where metabolic derangements coincide with derangements in maternal glycemic control (i.e., HOMA-IR) [64]. Further, maternal aerobic exercise increases insulin-mediated glycogen synthesis rates in undifferentiated MSCs suggestive of greater insulin sensitivity [83]. This effect was paralleled with greater insulin-mediated phosphorylation of signaling marker GSK-3β in undifferentiated MSCs. Together, these promising effects could counter the previously described transmission of IR in the case of maternal glucose dysglycemia (i.e., during obesity). In addition to glycogen synthesis, enhanced glucose oxidation efficiency and partitioning of glucose towards oxidation is observed in both undifferentiated and myogenically differentiated MSCs from offspring of aerobically trained mothers. Interestingly, a trend towards a greater capacity for glucose oxidation was observed in myogenically differentiated but not undifferentiated MSCs [83]. It is worth noting that there is greater expression of complex I in myogenically differentiated MSCs, which could in part influence the greater glucose oxidation rates considering that glucose oxidation increases the input of electrons to complex I of mitochondria [83]; however, this effect needs to be further elucidated. As previously described, obesity driven metabolic derangements lead to less efficient mitochondria with a lower oxidative capacity; thus, it is possible that a greater capacity to oxidize glucose may attenuate the transmission of decrements in glucose metabolism across generations. The partitioning of glucose towards oxidation, rather than glycolytic intermediates (i.e., lactate), would lower the propensity towards metabolic disease considering that a lower oxidation capacity and greater lactate production have been linked with T2D [90–92]. While this data is associative in nature, the importance of exercise in improving the metabolism of both mother and offspring is clear (**Figure 2**).

#### **Figure 2.**

*Maternal obesity increases pregnancy complications and introduces an array of metabolic derangements in mother and offspring health. Maternal gestational exercise improves many aspects of obesity-induced metabolic alterations and enhances maternal and offspring metabolism. Abbreviations: GWG, gestational weight gain; GDM, gestational diabetes mellitus; MSCs, mesenchymal stem cells; FA, fatty acid; AMPK, AMP-activated protein kinase; and IR, insulin resistance.*
