New Frontiers: Umbilical Cord Mesenchymal Stem Cells Uncover Developmental Roots and Biological Underpinnings of Obesity Susceptibility.

Purpose Of Review: To review evidence supporting human umbilical cord mesenchymal stem cells (UC-MSC) as an innovative model system advancing obesity precision medicine.

Recent Findings: Obesity prevalence is increasing rapidly and exposures during fetal development can impact individual susceptibility to obesity. UC-MSCs exhibit heterogeneous phenotypes associated with maternal exposures and predictive of child cardiometabolic outcomes.

Impact of prenatal exposure to delta 9-tetrahydrocannabinol and cannabidiol on birth size and postnatal growth trajectories.

Background: Prenatal exposure to cannabis (or more specifically, delta 9-tetrahydrocannabinol [Δ9-THC]) has been consistently linked to low birthweight. Animal models further show that Δ9-THC is associated with rapid postnatal growth. Whether this association is modified by breastfeeding is unknown.

Precision stratification of prognostic risk factors associated with outcomes in gestational diabetes mellitus: a systematic review.

Background: The objective of this systematic review is to identify prognostic factors among women and their offspring affected by gestational diabetes mellitus (GDM), focusing on endpoints of cardiovascular disease (CVD) and type 2 diabetes (T2D) for women, and cardiometabolic profile for offspring.

Methods: This review included studies published in English language from January 1st, 1990, through September 30th, 2021, that focused on the above outcomes of interest with respect to sociodemographic factors, lifestyle and behavioral characteristics, traditional clinical traits, and 'omics biomarkers in the mothers and offspring during the perinatal/postpartum periods and across the lifecourse. Studies that did not report associations of prognostic factors with outcomes of interest among GDM-exposed women or children were excluded.

In Vitro Circadian Clock Gene Expression Assessments in Mesenchymal Stem Cells from Human Infants: A Pilot Study.

Background: Exposure to intrauterine obesity can disrupt clock gene rhythmicity in animal models. The aim of this pilot study was to determine if maternal obesity alters rhythmic expression of core clock in mesenchymal stem cells (MSCs) from umbilical cords of human infants born to mothers with obesity (Ob-MSC) vs. normal weight (NW-MSC).

Prenatal exposure to per- and polyfluoroalkyl substances and early childhood adiposity and cardiometabolic health in the Healthy Start study.

Background/objectives: Observational and experimental studies have suggested that prenatal exposure to per- and polyfluoroalkyl substances (PFAS) can increase childhood adiposity and cardiometabolic disruption. However, most previous studies have used weight-based measures that cannot distinguish between fat mass and lean mass. We evaluated associations of prenatal PFAS exposure with precisely measured body composition and cardiometabolic biomarkers in early childhood.

Cord blood DNA methylation of immune and lipid metabolism genes is associated with maternal triglycerides and child adiposity.

Objective: Fetal exposures may impact offspring epigenetic signatures and adiposity. The authors hypothesized that maternal metabolic traits associate with cord blood DNA methylation, which, in turn, associates with child adiposity.

Methods: Fasting serum was obtained in 588 pregnant women (27-34 weeks' gestation), and insulin, glucose, high-density lipoprotein cholesterol, triglycerides, and free fatty acids were measured.

Adipocyte hypertrophy in mesenchymal stem cells from infants of mothers with obesity.

Objective: Fat content of adipocytes derived from infant umbilical cord mesenchymal stem cells (MSCs) predicts adiposity in children through 4 to 6 years of age. This study tested the hypothesis that MSCs from infants born to mothers with obesity (Ob-MSCs) exhibit adipocyte hypertrophy and perturbations in genes regulating adipogenesis compared with MSCs from infants of mothers with normal weight (NW-MSCs).

Methods: Adipogenesis was induced in MSCs embedded in three-dimensional hydrogel structures, and cell size and number were measured by three-dimensional imaging.

Predictors and risk factors of short-term and long-term outcomes among women with gestational diabetes mellitus (GDM) and their offspring: Moving toward precision prognosis?

As part of the American Diabetes Association Precision Medicine in Diabetes Initiative (PMDI) - a partnership with the European Association for the Study of Diabetes (EASD) - this systematic review is part of a comprehensive evidence evaluation in support of the 2 International Consensus Report on Precision Diabetes Medicine. Here, we sought to synthesize evidence from empirical research papers published through September 1 , 2021 to evaluate and identify prognostic conditions, risk factors, and biomarkers among women and children affected by gestational diabetes mellitus (GDM), focusing on clinical endpoints of cardiovascular disease (CVD) and type 2 diabetes (T2D) among women with a history of GDM; and adiposity and cardiometabolic profile among offspring exposed to GDM We identified a total of 107 observational studies and 12 randomized controlled trials testing the effect of pharmaceutical and/or lifestyle interventions. Broadly, current literature indicates that greater GDM severity, higher maternal body mass index, belonging to racial/ethnic minority group; and unhealthy lifestyle behaviors would predict a woman's risk of incident T2D and CVD, and an unfavorable cardiometabolic profile among offspring.

Fat content in infant mesenchymal stem cells prospectively associates with childhood adiposity and fasting glucose.

Objective: In human studies, new model systems are needed for improved mechanistic investigation of developmental predisposition for metabolic disease but also to serve as benchmarks in early life prevention or intervention efforts. In this regard, human infant umbilical cord-derived mesenchymal stem cells (MSCs) are an emerging tool. However, long-term clinical relevance to in vivo markers of metabolic disease is unknown.

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.

Influence of Maternal Exercise on Glucose and Lipid Metabolism in Offspring Stem Cells: ENHANCED by Mom.

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).

Maternal Diet Quality Is Associated with Placental Proteins in the Placental Insulin/Growth Factor, Environmental Stress, Inflammation, and mTOR Signaling Pathways: The Healthy Start ECHO Cohort.

Background: Maternal nutritional status affects placental function, which may underlie the intrauterine origins of obesity and diabetes. The extent to which diet quality is associated with placental signaling and which specific pathways are impacted is unknown.

Objectives: To examine sex-specific associations of maternal diet quality according to the Healthy Eating Index (HEI)-developed to align with recommendations from the Dietary Guidelines for Americans-with placental proteins involved in metabolism and mediators of environmental stress, inflammation, and growth factors.

A role for the early pregnancy maternal milieu in the intergenerational transmission of obesity.

Objective: Maternal obesity increases the risks for adverse pregnancy and offspring outcomes but with large heterogeneity. This study examined changes to the maternal metabolic milieu across pregnancy in women with obesity. It identified differences between a metabolically unhealthy obesity (MUO) phenotype and a metabolically healthy obesity (MHO) phenotype, as well as the differences in offspring adiposity between the two metabolic phenotypes.

Maternal metabolic health drives mesenchymal stem cell metabolism and infant fat mass at birth.

Exposure to maternal obesity may promote metabolic dysfunction in offspring. We used infant mesenchymal stem cells (MSCs) to experimentally examine cellular mechanisms of intergenerational health transmission. Our earlier reports show MSCs collected from infants of mothers with obesity had a dichotomous distribution in metabolic efficiency; they were either efficient (Ef-Ob) or inefficient (In-Ob) with respect to fatty acid oxidation (FAO).

Placental Insulin/IGF-1 Signaling, PGC-1α, and Inflammatory Pathways Are Associated With Metabolic Outcomes at 4-6 Years of Age: The ECHO Healthy Start Cohort.

An adverse intrauterine environment is associated with the future risk of obesity and type 2 diabetes. Changes in placental function may underpin the intrauterine origins of adult disease, but longitudinal studies linking placental function with childhood outcomes are rare. Here, we determined the abundance and phosphorylation of protein intermediates involved in insulin signaling, inflammation, cortisol metabolism, protein glycosylation, and mitochondrial biogenesis in placental villus samples from healthy mothers from the Healthy Start cohort.

Prenatal Exposure to Per- and Polyfluoroalkyl Substances, Umbilical Cord Blood DNA Methylation, and Cardio-Metabolic Indicators in Newborns: The Healthy Start Study.

Background: Per- and polyfluoroalkyl substances (PFAS) are environmentally persistent chemicals widely detected in women of reproductive age. Prenatal PFAS exposure is associated with adverse health outcomes in children. We hypothesized that DNA methylation changes may result from prenatal PFAS exposure and may be linked to offspring cardio-metabolic phenotype.

Associations between the activity of placental nutrient-sensing pathways and neonatal and postnatal metabolic health: the ECHO Healthy Start cohort.

Objective: Our hypothesis was that the activity of placental nutrient-sensing pathways is associated with adiposity and metabolic health in childhood.

Research Design And Methods: Using placental villus samples from healthy mothers from the Healthy Start Study, we measured the abundance and phosphorylation of key intermediates in the mTOR, insulin, AMPK, and ER stress signaling pathways. Using multivariate multiple regression models, we tested the association between placental proteins and offspring adiposity (%fat mass) at birth (n = 109), 4-6 months (n = 104), and 4-6 years old (n = 64), adjusted for offspring sex and age.

Maternal Fat-1 Transgene Protects Offspring from Excess Weight Gain, Oxidative Stress, and Reduced Fatty Acid Oxidation in Response to High-Fat Diet.

Overweight and obesity accompanies up to 70% of pregnancies and is a strong risk factor for offspring metabolic disease. Maternal obesity-associated inflammation and lipid profile are hypothesized as important contributors to excess offspring liver and skeletal muscle lipid deposition and oxidative stress. Here, we tested whether dams expressing the fat-1 transgene, which endogenously converts omega-6 (n-6) to omega-3 (n-3) polyunsaturated fatty acid, could protect wild-type (WT) offspring against high-fat diet induced weight gain, oxidative stress, and disrupted mitochondrial fatty acid oxidation.

Microplate Assays for Spectrophotometric Measurement of Mitochondrial Enzyme Activity.

Spectrophotometric analysis of metabolic enzyme activity from homogenized tissues is a valuable method for investigating mitochondrial content and capacity. Enzyme activity is normally measured in single cuvette spectrophotometers, requiring a large sample volume and low throughput. Here, we describe microplate assays for high-throughput analysis of mitochondrial enzymes citrate synthase, β-hydroxyacyl CoA dehydrogenase, aconitase, and mitochondrial electron transport system (ETS) complexes I, II, III, and IV.

Lipoprotein Lipase Is a Feature of Alternatively-Activated Microglia and May Facilitate Lipid Uptake in the CNS During Demyelination.

Severe demyelinating disorders of the central nervous system (CNS) such as multiple sclerosis (MS), can be devastating for many young lives. To date, the factors resulting in poor remyelination and repair are not well understood, and reparative therapies that benefit MS patients have yet to be developed. We have previously shown that the activity and abundance of Lipoprotein Lipase (LPL)-the rate-limiting enzyme in the hydrolysis of triglyceride-rich lipoproteins-is increased in Schwann cells and macrophages following nerve crush injury in the peripheral nervous system (PNS), suggesting that LPL may help scavenge myelin-derived lipids.