Myogenically differentiated mesenchymal stem cell insulin sensitivity is associated with infant adiposity at 1 and 6 months of age.

OBJECTIVE: In adults, skeletal muscle insulin sensitivity (SI ) and fatty acid oxidation (FAO) are linked with a predisposition to obesity. The current study aimed to determine the effects of maternal exercise on a model of infant skeletal muscle tissue (differentiated umbilical cord mesenchymal stem cells [MSCs]) SI and FAO and analyzed for associations with infant body composition. METHODS: Females <16 weeks' gestation were randomized to either 150 min/wk of moderate-intensity aerobic, resistance, or combination exercise or a nonexercising control. At delivery, MSCs were isolated from umbilical cords and myogenically differentiated, and SI and FAO were measured using radiolabeled substrates. Infant body fat percentage (BF%) and fat-free mass were calculated using standard equations at 1 and 6 months of age. RESULTS: MSCs from infants of all exercisers had significantly (p < 0.05) higher SI . MSC SI was inversely associated with infant BF% at 1 (r = -0.38, p < 0.05) and 6 (r = -0.65, p < 0.01) months of age. Infants with high SI had lower BF% at 1 (p = 0.06) and 6 (p < 0.01) months of age. MSCs in the high SI group had higher (p < 0.05) FAO. CONCLUSIONS: Exposure to any type of exercise in utero improves offspring SI and could reduce adiposity in early infancy.

Greater reliance on glycolysis is associated with lower mitochondrial substrate oxidation and insulin sensitivity in infant myogenic MSCs.

Individuals with insulin resistance and obesity display higher skeletal muscle production of nonoxidized glycolytic products (i.e., lactate), and lower complete mitochondrial substrate oxidation to CO2. These findings have also been observed in individuals without obesity and are associated with an increased risk for metabolic disease. The purpose of this study was to determine if substrate preference is evident at the earliest stage of life (birth) and to provide a clinical blood marker (lactate) that could be indicative of a predisposition for metabolic disease later. We used radiolabeled tracers to assess substrate oxidation and insulin sensitivity of myogenically differentiated mesenchymal stem cells (MSCs), a proxy of infant skeletal muscle tissue, derived from umbilical cords of full-term infants. We found that greater production of nonoxidized glycolytic products (lactate, pyruvate, alanine) is directly proportional to lower substrate oxidation and insulin sensitivity in MSCs. In addition, we found an inverse relationship between the ratio of complete glucose oxidation to CO2 and infant blood lactate at 1 mo of age. Collectively, considering that higher lactate was associated with lower MSC glucose oxidation and has been shown to be implicated with metabolic disease, it may be an early indicator of infant skeletal muscle phenotype.NEW & NOTEWORTHY In infant myogenically differentiated mesenchymal stem cells, greater production of nonoxidized glycolytic products was directly proportional to lower substrate oxidation and insulin resistance. Glucose oxidation was inversely correlated with infant blood lactate. This suggests that innate differences in infant substrate oxidation exist at birth and could be associated with the development of metabolic disease later in life. Clinical assessment of infant blood lactate could be used as an early indicator of skeletal muscle phenotype.

Maternal and Neonatal Outcomes of Pregnancy within 7 years after Roux-Y Gastric Bypass or Sleeve Gastrectomy Surgery.

PURPOSE: Few studies examine whether maternal and neonatal outcomes differ by time from metabolic and bariatric surgery (MBS) to conception. We describe maternal and neonatal outcomes among women with pregnancy after Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) overall and by whether conception occurred during the period when pregnancy is not recommended (< 18 months postoperative) versus later. MATERIALS AND METHODS: A prospective cohort study enrolled 135 US adult women (median age, 30 years, body mass index [BMI], 47.2 kg/m2) who underwent RYGB or SG (2006-2009) and subsequently reported ≥ 1 pregnancy within 7 years. Participants self-reported pregnancy-related information annually. Differences in prevalence of maternal and neonatal outcomes by postoperative conception timeframe (< 18 versus ≥ 18 months) were assessed. RESULTS: Thirty-one women reported ≥ 2 postoperative pregnancies. At time of postoperative conception (median 26 [IQR:22-52] months postoperative) median BMI was 31 (IQR:27-36) kg/m2. Excessive gestational weight gain (55%), cesarean section (42%) and preterm labor or rupture of membranes (40%) were the most common maternal outcomes. Forty percent of neonates had a composite outcome of still birth (1%), preterm birth (26%), small for gestational age (11%), or neonatal intensive care unit admission (8%). Prevalence of outcomes did not statistically significantly differ by timeframe. CONCLUSION: In US women who conceived ≤ 7 years following RYGB or SG, 40% of neonates had the composite neonatal outcome. The prevalence of maternal and neonatal outcomes post-MBS were not statistically significant by conception timeframe.

Differences in substrate metabolism between African American and Caucasian infants: evidence from mesenchymal stem cells.

Type 2 diabetes is more prevalent in African American (AA) than Caucasian (C) adults. Furthermore, differential substrate utilization has been observed between AA and C adults, but data regarding metabolic differences between races at birth remains scarce. The purpose of the present study was to determine if there are racial differences in substrate metabolism evident at birth using a mesenchymal stem cells (MSCs) collected from offspring umbilical cords. Using radio-labeled tracers, MSCs from offspring of AA and C mothers were tested for glucose and fatty acid metabolism in the undifferentiated state and while undergoing myogenesis in vitro. Undifferentiated MSCs from AA exhibited greater partitioning of glucose toward nonoxidized glucose metabolites. In the myogenic state, AA displayed higher glucose oxidation, but similar fatty acid oxidation rates. In the presence of both glucose and palmitate, but not palmitate only, AA exhibit a higher rate of incomplete fatty acid oxidation evident by a greater production of acid-soluble metabolites. Myogenic differentiation of MSCs elicits an increase in glucose oxidation in AA, but not in C. Together, these data suggest that metabolic differences between AA and C races exist at birth.NEW & NOTEWORTHY African Americans, when compared with Caucasians, display greater insulin resistance in skeletal muscle. Differences in substrate utilization have been proposed as a factor for this health disparity; however, it remains unknown how early these differences manifest. Using infant umbilical cord-derived mesenchymal stem cells, we tested for in vitro glucose and fatty acid oxidation differences. Myogenically differentiated MSCs from African American offspring display higher rates of glucose oxidation and incomplete fatty acid oxidation.

Effects of Maternal Exercise Modes on Glucose and Lipid Metabolism in Offspring Stem Cells.

CONTEXT: Maternal exercise positively influences pregnancy outcomes and metabolic health in progeny; however, data regarding the effects of different modes of prenatal exercise on offspring metabolic phenotype is lacking. OBJECTIVE: To elucidate the effects of different modes of maternal exercise on offspring umbilical cord derived mesenchymal stem cell (MSC) metabolism. DESIGN: Randomized controlled trial. SETTING: Clinical research facility. PATIENTS: Healthy females between 18 and 35 years of age and <16 weeks' gestation. INTERVENTION: Women were randomized to either 150 minutes of moderate intensity aerobic, resistance (RE), or combination exercise per week or to a non-exercising control. MAIN OUTCOME MEASURES: At delivery, MSCs were isolated from the umbilical cords. MSC glucose and fatty acid(s) metabolism was assessed using radiolabeled substrates. RESULTS: MSCs from offspring of all the exercising women demonstrated greater partitioning of oleate (P ≤ 0.05) and palmitate (P ≤ 0.05) toward complete oxidation relative to non-exercisers. MSCs from offspring of all exercising mothers also had lower rates of incomplete fatty acid oxidation (P ≤ 0.05), which was related to infant adiposity at 1 month of age. MSCs from all exercising groups exhibited higher insulin-stimulated glycogen synthesis rates (P ≤ 0.05), with RE having the largest effect (P ≤ 0.05). RE also had the greatest effect on MSC glucose oxidation rates (P ≤ 0.05) and partitioning toward complete oxidation (P ≤ 0.05). CONCLUSION: Our data demonstrates that maternal exercise enhances glucose and lipid metabolism of offspring MSCs. Improvements in MSC glucose metabolism seem to be the greatest with maternal RE. Clinical Trial: ClinicalTrials.gov Identifier: NCT03838146.

Infant Mesenchymal Stem Cell Insulin Action Is Associated With Maternal Plasma Free Fatty Acids, Independent of Obesity Status: The Healthy Start Study.

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.

Hybrid fiber alterations in exercising seniors suggest contribution to fast-to-slow muscle fiber shift.

BACKGROUND: Human skeletal muscle is composed of a functional and metabolic continuum of slow (Type I) and fast fibers (IIa and IIx). Hybrid fibers co-expressing different myosin heavy chains are also present and seem to be more prominent in aging muscle. Their role is debated; hybrid fibers were reported either in a transitional state, between slow and fast fibers, or as fixed individual entities. This study examined the fate of hybrid fibers with an endurance exercise intervention in an elderly sedentary population. METHODS: Twenty-two sedentary healthy elderly men and women underwent a 16-week supervised endurance exercise intervention. Eighteen endurance-trained age- and gender-matched volunteers served as controls. Fiber type distribution was determined by immunohistochemistry on vastus lateralis muscle biopsies pre-intervention and post-intervention. RESULTS: A total of 13840 fibers were analyzed. At baseline, a Type II dominant fiber profile was observed compared with the control group, with more Type IIa (P = 0.0301) and Type IIx fibers (P = 0.0328). Hybrid fibers represented almost 5% of total muscle fibers in both groups. There was no significant difference between groups (I-IIa, P = 0.6719 and IIa-IIx, P = 0.0998). Intervention triggered qualitative dynamics towards an increase in Type I, and decrease in Type II fibers, paralleled by an increase in I-IIa hybrids (P = 0.0301). CONCLUSIONS: The present study is, to our knowledge, the first to examine hybrid muscle fiber type adaptations to an endurance exercise intervention in the elderly. Hybrid fiber proportions did not differ between chronic sedentary state and chronic endurance-trained state. Exercise intervention increased Type I-IIa hybrid fibers along with shift dynamics in other fiber types suggesting the contribution of hybrid fiber to a fast-to-slow fiber type transition, eventually serving as intermediate reservoir from one monomorphic myosin heavy chain expressing fiber type to another. This finding favours the transitional theory regarding hybrid muscle fibers and exercise, crucial to understanding reversible mechanisms of sarcopenia and development of prevention measures.

Assessing Energy Requirements in Women With Polycystic Ovary Syndrome: A Comparison Against Doubly Labeled Water.

Context: Weight loss is prescribed to offset the deleterious consequences of polycystic ovary syndrome (PCOS), but a successful intervention requires an accurate assessment of energy requirements. Objective: Describe energy requirements in women with PCOS and evaluate common prediction equations compared with doubly labeled water (DLW). Design: Cross-sectional study. Setting: Academic research center. Participants: Twenty-eight weight-stable women with PCOS completed a 14-day DLW study along with measures of body composition and resting metabolic rate and assessment of physical activity by accelerometry. Main Outcome: Total daily energy expenditure (TDEE) determined by DLW. Results: TDEE was 2661 ± 373 kcal/d. TDEE estimated from four commonly used equations was within 4% to 6% of the TDEE measured by DLW. Hyperinsulinemia (fasting insulin and homeostatic model assessment of insulin resistance) was associated with TDEE estimates from all prediction equations (both r = 0.45; P = 0.02) but was not a significant covariate in a model that predicts TDEE. Similarly, hyperandrogenemia (total testosterone, free androgen index, and dehydroepiandrosterone sulfate) was not associated with TDEE. In weight-stable women with PCOS, the following equation derived from DLW can be used to determine energy requirements: TDEE (kcal/d) = 438 - [1.6 * Fat Mass (kg)] + [35.1 * Fat-Free Mass (kg)] + [16.2 * Age (y)]; R2 = 0.41; P = 0.005. Conclusions: Established equations using weight, height, and age performed well for predicting energy requirements in weight-stable women with PCOS, but more precise estimates require an accurate assessment of physical activity. Our equation derived from DLW data, which incorporates habitual physical activity, can also be used in women with PCOS; however, additional studies are needed for model validation.