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Abstract Maternal exercise (ME) has been established as a useful non‐pharmacological intervention to improve infant metabolic health; however, mechanistic insight behind these adaptations remains mostly confined to animal models. Infant mesenchymal stem cells (MSCs) give rise to infant tissues (e.g., skeletal muscle), and remain involved in mature tissue maintenance. Importantly, these cells maintain metabolic characteristics of an offspring donor and provide a model for the investigation of mechanisms behind infant metabolic health improvements. We used undifferentiated MSC to investigate if ME affects infant MSC mitochondrial function and insulin action, and if these adaptations are associated with lower infant adiposity. We found that infants from exercising mothers have improvements in MSC insulin signaling related to higher MSC respiration and fat oxidation, and expression and activation of energy‐sensing and redox‐sensitive proteins. Further, we found that infants exposed to exercise in utero were leaner at 1 month of age, with a significant inverse correlation between infant MSC respiration and infant adiposity at 6 months of age. These data suggest that infants from exercising mothers are relatively leaner, and this is associated with higher infant MSC mitochondrial respiration, fat use, and insulin action.

Besides the well-recognized influence of maternal health on fetal in utero development, recent epidemiological studies appoint paternal preconception metabolic health as a significant factor in shaping fetal metabolic programming and subsequently offspring metabolic health; however, mechanisms behind these adaptations remain confined to animal models. To elucidate the effects of paternal obesity (P-OB) on infant metabolism in humans, we examined mesenchymal stem cells (MSCs), which give rise to infant tissue, remain involved in mature tissue maintenance, and resemble the phenotype of the offspring donor. Here, we assessed mitochondrial functional capacity, content, and insulin action in MSC from infants of fathers with overweight [body mass index (BMI: 25–30 kg/m2); paternal overweight (P-OW)] or obesity (BMI ≥ 30 kg/m2; P-OB) while controlling for maternal intrauterine environment. Compared with P-OW, infant MSCs in the P-OB group had lower intact cell respiration, OXPHOS, and electron transport system capacity, independent of any changes in mitochondrial content. Furthermore, glucose handling, insulin action, lipid content, and oxidation were similar between groups. Importantly, infants in the P-OB group had a greater weight-to-length ratio, which could be in part due to changes in MSC metabolic functioning, which precedes and, therefore, influences infant growth trajectories. These data suggest that P-OB negatively influences infant MSC mitochondria. ClinicalTrials.gov Identifier: NCT03838146. NEW & NOTEWORTHY: Paternal obesity decreases infant mesenchymal stem cell (MSC) basal and maximal respiration. Lower OXPHOS and electron transport system capacity could be explained by lower complex I and IV respiratory capacity but not changes in OXPHOS expression in infant MSC from fathers with obesity. Paternal obesity and altered MSC mitochondrial functional capacity are associated with a greater infant weight-to-length ratio at birth. [ABSTRACT FROM AUTHOR]

Maternal exercise (ME) has been established as a useful non‐pharmacological intervention to improve infant metabolic health; however, mechanistic insight behind these adaptations remains mostly confined to animal models. Infant mesenchymal stem cells (MSCs) give rise to infant tissues (e.g., skeletal muscle), and remain involved in mature tissue maintenance. Importantly, these cells maintain metabolic characteristics of an offspring donor and provide a model for the investigation of mechanisms behind infant metabolic health improvements. We used undifferentiated MSC to investigate if ME affects infant MSC mitochondrial function and insulin action, and if these adaptations are associated with lower infant adiposity. We found that infants from exercising mothers have improvements in MSC insulin signaling related to higher MSC respiration and fat oxidation, and expression and activation of energy‐sensing and redox‐sensitive proteins. Further, we found that infants exposed to exercise in utero were leaner at 1 month of age, with a significant inverse correlation between infant MSC respiration and infant adiposity at 6 months of age. These data suggest that infants from exercising mothers are relatively leaner, and this is associated with higher infant MSC mitochondrial respiration, fat use, and insulin action. [ABSTRACT FROM AUTHOR]

Context: Recent preclinical data suggest exercise during pregnancy can improve the metabolic phenotype not only of the mother, but of the developing offspring as well. However, investigations in human offspring are lacking. Objective: To characterize the effect of maternal aerobic exercise on the metabolic phenotype of the offspring’s mesenchymal stem cells (MSCs). Design: Randomized controlled trial. Setting: Clinical research facility. Patients: Healthy female adults between 18 and 35 years of age and ≤ 16 weeks’ gestation. Intervention: Mothers were randomized into 1 of 2 groups: aerobic exercise (AE, n = 10) or nonexercise control (CTRL, n = 10). The AE group completed 150 minutes of weekly moderate-intensity exercise, according to American College of Sports Medicine guidelines, during pregnancy, whereas controls attended stretching sessions. Main Outcome Measures: Following delivery, MSCs were isolated from the umbilical cord of the offspring and metabolic tracer and immunoblotting experiments were completed in the undifferentiated (D0) or myogenically differentiated (D21) state. Results: AE-MSCs at D0 had an elevated fold-change over basal in insulin-stimulated glycogen synthesis and reduced nonoxidized glucose metabolite (NOGM) production (P ≤ 0.05). At D21, AE-MSCs had a significant elevation in glucose partitioning toward oxidation (oxidation/NOGM ratio) compared with CTRL (P ≤ 0.05). Immunoblot analysis revealed elevated complex I expression in the AE-MSCs at D21 (P ≤ 0.05). Basal and palmitate-stimulated lipid metabolism was similar between groups at D0 and D21. Conclusions: These data provide evidence of a programmed metabolic phenotype in human offspring with maternal AE during pregnancy. [ABSTRACT FROM AUTHOR]

Preclinical rodent and nonhuman primate models investigating maternal obesity have highlighted the importance of the intrauterine environment in the development of insulin resistance in offspring; however, it remains unclear if these findings can be translated to humans. To investigate possible intrauterine effects in humans, we isolated mesenchymal stem cells (MSCs) from the umbilical cord tissue of infants born to mothers of normal weight or mothers with obesity. Insulin-stimulated glycogen storage was determined in MSCs undergoing myogenesis in vitro. There was no difference in insulin action based on maternal obesity. However, maternal free fatty acid (FFA) concentration, cord leptin, and intracellular triglyceride content were positively correlated with insulin action. Furthermore, MSCs from offspring born to mothers with elevated FFAs displayed elevated activation of the mTOR signaling pathway. Taken together, these data suggest that infants born to mothers with elevated lipid availability have greater insulin action in MSCs, which may indicate upregulation of growth and lipid storage pathways during periods of maternal overnutrition. [ABSTRACT FROM AUTHOR]