Influence of Maternal Exercise on Maternal and Offspring Metabolic Outcomes

*Filip Jevtovic and Linda May*

## **Abstract**

Epigenetic transmission of metabolic disease to an offspring increases their risk for development of metabolic disease later in life. With the increasing rates of obesity in women of child-bearing age it is critical to develop strategies to prevent perpetuating metabolic disease across generations. Maternal exercise during gestation imprints offspring metabolic phenotype, thus increasing their imperviousness to metabolic assaults later in life. In rodent models, maternal exercise before and during gestation leads to enhanced offspring glycemic control, mitochondrial bioenergetics, and lower adiposity, which decreases their risk for development of future metabolic disease. In humans, maternal gestational exercise decreases pregnancy complications and improves maternal and offspring metabolism on both the whole-body and the cellular level. Maternal exercise restores the obesity-induced metabolic derangements, restoring maternal and offspring metabolic phenotype. While unknown, different exercise modalities might have a differential effect, however, evidence remains scarce.

**Keywords:** pregnancy, prenatal, exercise, fetal, metabolism

#### **1. Introduction**

Rates of pediatric obesity are escalating worldwide. Increasing rates of childhood obesity are likely to translate into a high cumulative incidence of metabolic disease (i.e., type 2 diabetes mellitus (T2D)) and further exacerbate the strain on the healthcare system, public health, and global economy [1]. The development of obesity is often attributed to a combination of genetic and acquired environmental factors. It is well established that the epigenetic transmission of metabolic diseases to offspring will increase their risk for the development of metabolic disorders later in life [2]. Accordingly, environmental exposures (i.e., overnutrition) experienced by parents during intrauterine and early postnatal life will have profound effects on offspring health. Because of the increasing rates of obesity among individuals of child-bearing age, it is critical to develop strategies to prevent the transgenerational propagation of metabolic disease.

It is widely understood that physical activity induces an array of positive metabolic changes that can delay and/or reverse the deleterious effects of obesity. While the mechanisms of action behind the benefits of regular physical exercise are welldocumented, research has mostly focused on the person performing the exercise. Consequently, there is limited understanding in the mechanisms by which regular maternal exercise influences the metabolic phenotype of offspring. Further, while studies regarding the effects of maternal exercise on pregnancy, maternal, and offspring outcomes are available and reviewed [3–8], data which characterizes the mediating factors affecting offspring developmental programming is limited [9]. This is partly due to limitations in revealing the cellular and molecular mechanisms behind maternal exercise-derived benefits that stem from the inability to obtain neonate tissue samples (i.e., skeletal muscle (SkM)).

An understanding of the explicit alterations that maternal exercise causes in the offspring phenotype would allow for the characterization of novel targets and could be used to render different therapeutics for metabolic diseases. Further, elucidating the specific biological mechanisms induced by different exercise modalities could permit this lifestyle intervention to serve analogous to a targeted therapy. Thus, there is potential for different exercise modalities to be used in a prescription-like manner to generate a unique set of metabolic adaptations suitable for treating and/or reducing offspring predispositions to metabolic disease. In view of this possibility, the focus of this chapter will be on describing the mechanisms behind the effects of the maternal exercise on offspring metabolic programing. Emphasis will be on the analysis of the biological mechanisms behind specific metabolic adaptations that promote imperviousness to metabolic challenges (i.e., overnutrition) leading to obesity and T2D. Further, considering that mitochondrial dysfunction and insulin resistance (IR) are major constituents of these metabolic diseases, a focus will be on the alterations in offspring mitochondrial bioenergetics and glycemic control.

## **2. Learning from rodent models**

#### **2.1 Maternal obesity and offspring health**

The use of rodent models has allowed researchers to study how various environmental factors during critical windows of prenatal and early postnatal development alter metabolic phenotype and elicit tissue specific adaptations in progeny. Considering the ever-increasing rates of obesity, dietary habits, particularly overnutrition, during gestation have a critical role in fetal development and are often the focus of investigations. Maternal obesity and often concomitant IR increase the propensity of the development and transmission of metabolic disease onto progeny. A maternal obesogenic diet during fetal life readily programs first and second generation offspring into a T2D-like phenotype, even without additional dietary insults (i.e., overnutrition) administered to these generations [10].

Maternal obesity elicits multifaceted effects on offspring behavioral habits and physiology. Offspring from obese mothers have a tendency to be physically inactive and hyperphagic [11, 12]. Further, offspring adopt a metabolic syndrome-like phenotype with impaired glucose tolerance, higher blood triglycerides, cholesterol, and leptin, but lower adiponectin levels, which increases offspring predisposition for the development of cardiometabolic disease later in life [11, 12]. Maternal obesogenic diet consumption during gestation increases offspring adiposity primarily through adipocyte hypertrophy [12–14]. Adipocyte hypertrophy, rather than

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

hyperplasia, is associated with lower insulin responsiveness, inflammation, and an overall dysregulation of systemic energy metabolism [15]. Increased adiposity is further accompanied by a greater intramuscular fat accretion associated with higher PPARγ mRNA expression which could contribute to the development of lipotoxicity-induced SkM IR observed in these offspring [13]. Offspring from obese mothers have a restricted SkM growth potential which subsequently decreases their SkM cross-sectional area [13]. These alterations combined with lower GLUT4 and insulin receptor mRNA expression, as observed in SkM of offspring from obese mothers, attenuates their potential for insulin-stimulated glucose uptake and increase the propensity of offspring to develop hyperglycemia [13]. Considering that SkM is responsible for the majority of postprandial glucose uptake, these alterations have a profound effect on glucose homeostasis and could increase the risk for the development of T2D. Finally, maternal overnutrition leads to the downregulation of pathways associated with mitochondrial oxidation and lowers mitochondrial electron transport protein expression, leading to mitochondrial dysfunction [14].

Together, these alterations can lead to derangements in energy metabolism later in offspring life and increase their proclivity for metabolic disease. In view of this, it is essential to explore the effects of different lifestyle interventions that can alleviate the detrimental effects of maternal obesity on offspring metabolic dysregulation. Regular exercise is known to be protective against metabolic derangements observed in obesity and T2D in mother and offspring. Accordingly, illumination of the effects of maternal exercise on offspring body composition, glycemic control, and mitochondrial functioning will underline mechanistic alterations behind enhanced metabolic phenotype.

### **2.2 Maternal exercise enhances offspring metabolic phenotype**

#### *2.2.1 Body composition*

While most studies support the notion that exercise before and during gestation has an effect on offspring body weight (BW), findings are inconsistent [9]. Reports remain divided between maternal exercise causing a decrease [16–20], increase [21, 22], or having no effect on litter [23–25] or pup BW [26–30]. Additionally, these studies remain divided between maternal exercise leading to less weight gain with aging in offspring or having no effect on age-related weight gain. For example, Quiclet and associates found no effect of maternal exercise on male offspring BW at weaning or at 7 months of age; however, in their subsequent study, a decrease in BW was observed at weaning and 3 months of age, despite using the same animal and exercise model [17, 28]. Similarly, despite the use of the same animal species and exercising method across studies, change in BW is inconsistent in male offspring from exercising mothers at ~12 months of age [29, 30]. In addition to BW, discrepancies regarding the effect of maternal exercise on body composition have been observed across studies and offspring gender [16–18, 21, 23–25, 27–29, 31]. Carter et al. [26] reported an increase in lean mass and subsequent decrease in fat mass in males ~12 months of age; however, this was not observed in female offspring. Conversely, lower body fat percentages in female offspring have been shown in other studies [16, 19, 31]. Nonetheless, it is worth noting that body composition changes seem to be more prominent in male offspring. This is potentially because of a tendency for

greater weight gain with aging; however, the exact reason for the sex-specific differences remains unknown [9].

With consideration of these inconsistencies, it is difficult to determine if offspring BW is a causal factor or is determined by alterations in the metabolic phenotype of the offspring. Interestingly, it has been observed that the alterations in BW, lean and fat mass are secondary to other metabolic improvements and often develop later in offspring life. For instance, improvements in glucose metabolism have been observed in multiple studies regardless of inconsistencies in BW and body composition changes between studies [16, 26, 29, 31]. This suggests that metabolic reprograming is, at least in part, independent of body composition changes and is more likely causal of these alterations with aging or subsequent metabolic challenges (i.e., overnutrition). Accordingly, significantly smaller BW and fat mass gains were observed in sedentary pups from exercised mothers who were fed a high-fat-high-sugar diet (HFHS) compared to HFHS-diet fed pups from non-exercising mothers [17, 20]. This suggests that subsequent nutritional manipulations in offspring may be needed to elicit changes in BW and body composition and to better understand the relationship between changes in BW and metabolic reprogramming.

#### *2.2.2 Glucose tolerance*

Since SkM and liver metabolic alterations have a profound impact on the development of systemic metabolic disease, it is important to address how maternal exercise alters metabolism of these tissues. Exercise prior to and during pregnancy increases glucose tolerance and insulin sensitivity across offspring lifespan independent of changes in BW [16, 17, 19, 26, 27, 30, 31] and persist in second generation progeny [32]. Interestingly, in offspring from metabolically healthy exercising mothers, improvements in glucose tolerance are mostly observed in adulthood of the animal rather than early stages of life (i.e., at weaning) [16, 18, 25, 26]. This might be the case considering that the effects of maternal exercise are "diluted" in offspring from metabolically healthy mothers, and therefore these effects might be more pronounced in offspring from mothers with obesity, considering the previously described metabolic derangements that maternal obesity elicits. Accordingly, offspring and maternal glucose intolerance stemming from maternal obesity can be rescued by maternal pregestational and gestation exercise, and this effect is evident in early offspring life [18, 25, 29–31, 33]. These findings suggest that maternal exercise could enhance the ability of offspring to resist the future development of IR; however, these improvements may not be readily observed in healthy offspring before adulthood or without a subsequent metabolic challenge.

Multiple *in vivo* and *in vitro* techniques have been used in studies to confirm that enhanced glucose disposal stems from improved offspring peripheral (i.e., SkM) insulin sensitivity as a result of maternal exercise. Improved insulin sensitivity in offspring from obese mothers seems to be driven by an increase in SkM GLUT4 expression [16, 18, 23, 26, 27]; however, improved glucose tolerance independent of the changes in GLUT4 expression has similarly been observed [29, 31]. This indicates that an improvement in glucose transport capacity is not the only mechanism responsible for improved glucose clearance. Offspring from exercising compared to sedentary mothers exhibit improved SkM insulin signaling cascade activation with insulin stimulation; this is evidenced by higher phosphorylation of Protein Kinase B, also known as AKT, a key mediator of insulin-stimulated glucose uptake [17]. In addition

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

to the effects of maternal exercise on SkM, it is important to recognize that these adaptations extend to offspring liver, a major organ for regulating glucose disposal and production. Maternal exercise improves mature offspring hepatic insulin sensitivity and lowers hepatic glucose production during hyperinsulinemic-euglycemic clamp [16]. Similar effects have been observed in an *in vitro* model where isolated hepatocytes of offspring from exercising mothers exhibit enhanced glucose control across basal and insulin- and glucagon-stimulated states [31]. Greater glucagonmediated hepatocyte glucose production and insulin-mediated inhibition of glucose production suggest that maternal exercise improves liver glucose metabolism across different physiologic states (fasted vs. fed) [31]. Interestingly, it is worth noting that this effect is observed in offspring from exercising mothers independent of maternal metabolic status (healthy or obese). This suggests that while metabolic enhancements may be present, they may not be evident with measurements at the whole-organism level considering the multifaceted input of several organs [31]. In rodent models, it is clear, that maternal exercise negates the effects of maternal obesity through enhancements in offspring glucose metabolism, which lowers the potential for glycemic dysregulation in subsequent generations.

#### *2.2.3 Mitochondrial remodeling*

Maternal exercise lowers SkM and liver triglyceride content in offspring from both healthy and obese mothers [24, 29, 31]. Lower SkM and liver triglyceride content will decrease the chance of lipid accumulation-induced impairments with insulin signaling and are suggestive of an enhanced oxidative capacity. Maternal exercise increases offspring SkM mitochondrial density, length, and mitochondrial DNA content [19, 34]. These mitochondrial alterations predominantly stem from the effects of maternal exercise on PGC-1α, a key mediator of mitochondrial functioning and biogenesis [19, 34]. Maternal exercise before and during pregnancy attenuates high-fat diet (HFD) induced PGC-1α promoter hypermethylation in offspring SkM, and is able to rescue a HFD induced decrease in PGC-1α gene expression [19, 27]. Interestingly, the effect of maternal exercise on PGC-1α expression has only been observed in adult offspring [27]. This, however, may be an artifact of the rapid proliferation and differentiation of SkM cells during early growth compared to mature SkM, when myogenic cells are quiescent and transcription of genes is predominantly influenced by gene methylation [27]. Higher PGC-1α expression in SkM increases expression of its downstream targets including cytochrome C, a central component of the electron transport chain, which potentiates improvements in the regulation of oxidative phosphorylation [27]. Additionally, in SkM of offspring from exercising mothers, greater cytochrome C oxidase and citrate synthase activities have been observed [34], suggesting that maternal exercise has an effect on mitochondrial oxidative capacity. It is worth noting that similar hypermethylation and lower mRNA expression of PGC-1α is seen in SkM of individuals with T2D [35]. This points to maternal exercise as a potential therapy to ameliorate the transgenerational transmission of mitochondrial dysfunction in humans, by increasing the oxidative capacity as well.

In liver, the maternal exercise induced increase in PGC-1α mRNA expression is accompanied by higher protein expression of phosphorylated AMP-activated protein kinase (AMPK), which is considered to be a master regulator of energy metabolism [36]. This AMPK-PGC-1α axis and its increase is paralleled by an increase in PPARα mRNA expression and is suggestive of a greater potential for fatty acid oxidation.

Specifically, maternal exercise enhances gene expression of Acox1 and Acacb, enzymes involved in fatty acid handling and oxidation [36]. Interestingly, while improving the capacity for fatty acid oxidation, maternal exercise simultaneously decreases the potential for fatty acid storage by lowering PPARγ mRNA expression, a gene associated with hepatic steatosis [36, 37]. Further, greater phosphorylated AMPK expression in offspring from exercising mothers leads to greater phosphorylation of acetyl-CoA carboxylase which lowers the availability of malonyl-CoA, a precursor for fatty acid synthesis [36]. It is important to note that these adaptations on a cellular level extend to elicit whole-body protection and lead to lower BW gain and hepatic steatosis after pups are challenged with an obesogenic diet [36]. Overall, maternal exercise driven improvements of offspring mitochondrial bioenergetics are often seen as vital for proper metabolic functioning and resilience to metabolic challenges in adult life. These adaptations could influence the predisposition for the development of metabolic disease by altering mitochondrial substrate "preference" and oxidation capacity.

Maternal exercise increases the affinity for pyruvate and palmitoyl-CoA in offspring SkM mitochondria suggesting easier access of these substrates for the oxidative phosphorylation system (OXPHOS) [17]. Further, maternal exercise has no effect on the Km for palmitoyl-carnitine, which suggests that maternal exercise might be acting specifically on CPT-1, a commonly altered enzyme in obesity-related diseases. Finally, a larger decrease in enzyme affinity is seen for palmitoyl-CoA compared to pyruvate suggesting that maternal exercise increases offspring SkM preference for fatty acid oxidation and potentially explains the previously described decrease in triglyceride content [17, 29]. In addition to altering SkM metabolic pathways, offspring from exercising mothers exhibit greater levels of liver mRNA expression of genes involved in pyruvate metabolism (Pklr, Pcx), the tricarboxylic acid cycle (Pdha1, Pdk4, CS, Idh3a, Mdh2), and fatty acid transport and oxidation (Cd36, Fatp4, Acox, Cpt1) [31]. Together, this data shows that maternal exercise induces an array of adaptations that enhance substrate handling and subsequently increase resilience against future metabolic disease.

Data regarding maternal exercise and offspring OXPHOS capacity is limited. Maternal exercise decreases complex II and III activity and increases complex IV activity [22]. Additionally, when ADP-stimulated respiration is measured in SkM mitochondria from offspring of exercising mothers, there seems to be no effect on complex I and complex I + II respiration; however, data regarding respiration through complex II only is inconsistent with maternal exercise resulting in a decrease or having no effect on complex II maximal respiration [22, 23]. Interestingly, in isolated liver mitochondria from offspring of exercising mothers, lower complex II and higher complex IV activity and content is observed, and accompanied by lower maximal respiration through complex I, II, and I + II. Interestingly, respiratory control ratio (RCR) is lower in offspring mitochondria from both liver and SkM when respiration is supported through complex I and complex I + II [22]. As an index of how coupled respiration is to ADP phosphorylation, this would suggest a lower capacity for phosphorylating respiration to offset electron leak; however, implications about the effect of maternal exercise on offspring mitochondrial efficiency cannot be made as RCR, when used as a proxy of mitochondrial coupling, does not always match the ATP/O ratio, which is a direct measure of mitochondrial coupling [38]. Data regarding alterations in offspring energy efficiency come from oxygen consumption rates in free living conditions. Accordingly, on the level of the whole organism, maternal exercise increases the basal oxygen consumption rate, subsequently protecting offspring

from overnutrition-induced obesity by increasing their energy expenditure [20, 30] Together, the limited data suggests that maternal exercise results in adaptations in mitochondrial respiration, but no conclusive remarks can be made considering the inconsistencies between and limited number of studies.

#### *2.2.4 Mitochondrial redox balance*

While mitochondria are often described predominantly in the light of energy metabolism, it is important to recognize their function in maintaining redox homeostasis. Mitochondria are mediators of redox balance, and this is influenced by alterations to pro- and antioxidant systems. Disruption of the redox balance due to alterations in mitochondrial bioenergetics or the redox buffering capacity are considered to be an integral part in the etiology of metabolic disease (i.e., IR) [39]. Maternal exercise lowers hydrogen peroxide production with complex II only and complex I + II supporting substrates in both SkM and liver mitochondria [22]; however, the effects seen in SkM are inconsistent across studies indicating maternal exercise may not affect hydrogen peroxide emission [23]. Interestingly, SkM and liver mitochondria from offspring of exercising mothers are protected from reverse electron transport linked hydrogen peroxide emission [22]. Hydrogen peroxide emission via reverse electron flow is often associated with overnutrition and suggests that maternal exercise has a protective effect on offspring redox balance during future metabolic challenges such as overnutrition [39]. In addition to lower hydrogen peroxide emission and subsequently lower reactive oxygen species (ROS) production, maternal exercise enhances glutathione activity in blood and liver [22]. Further, offspring from exercising mothers have lower blood thiol content suggestive of a higher antioxidant capacity. These adaptations are paralleled with higher offspring liver alpha-tocopherol which increases free radical scavenging ability and decreases lipid peroxidation [40–42]. Maternal exercise further induces a mitochondrial fatty acid profile shift by increasing short-chain and decreasing long-chain fatty acid content [22]. These changes can be beneficial considering that short-chain fatty acids are more resistant to free radical attack and peroxidation and have a positive influence on redox signaling [43, 44]. Finally, maternal exercises increases offspring LON protease (an oxidative stress induced mitochondrial degradation catalyst) and TFAM induced autophagy; these changes are suggestive of a greater mitochondrial turnover rate and overall lower susceptibility to oxidative stress induced mitochondrial dysfunction [24, 34]. Together, these findings suggest that maternal exercise increases antioxidant capacity, decreases ROS production, and lowers the potential accumulation of less functional mitochondria in offspring.

Together, maternal exercise will protect offspring from maternal obesity induced metabolic derangements and has the capacity to increase offspring resilience against future metabolic challenges. Further, offspring metabolic adaptations (**Figure 1**) as a result of maternal exercise seem to be independent of body composition alterations. These adaptations include improvements in offspring glucose and fatty acid metabolism across two major metabolically active tissues, the liver and SkM. In part, these adaptations are linked to mitochondrial structure remodeling, enhanced bioenergetic function, and greater redox capacity. Finally, it is imperative to keep in mind that cellular metabolic programing precedes improvements detected at the whole-body level making *in vitro* assessments indispensable for the understanding of maternal exercise-induced fetal programing.

**Figure 1.**

*Maternal exercise enhances offspring metabolism across two major metabolically active tissues, the liver and SkM. Offspring from exercising mothers have lower body weight (BW) and body fat (BF%) gain with age and exhibit enhanced whole body glucose tolerance. Additionally, maternal exercise leads to greater insulin sensitivity, mitochondrial remodeling, and improved bioenergetic function and substrate metabolism in peripheral tissue. Abbreviations: BW, body weight; BF%, body fat percentage; and OXPHOS, oxidative phosphorylation.*
