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      Altered gene expression and metabolism in fetal umbilical cord mesenchymal stem cells correspond with differences in 5-month-old infant adiposity gain

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          Abstract

          The intrauterine period is a critical time wherein developmental exposure can influence risk for chronic disease including childhood obesity. Using umbilical cord-derived mesenchymal stem cells (uMSC) from offspring born to normal-weight and obese mothers, we tested the hypothesis that changes in infant body composition over the first 5 months of life correspond with differences in cellular metabolism and transcriptomic profiles at birth. Higher long-chain acylcarnitine concentrations, lipid transport gene expression, and indicators of oxidative stress in uMSC-adipocytes were related to higher adiposity at 5 months of age. In uMSC-myocytes, lower amino acid concentrations and global differential gene expression for myocyte growth, amino acid biosynthesis, and oxidative stress were related to lower infant percent fat-free mass at 5 months of age, particularly in offspring of obese mothers. This is the first evidence of human infant adipocyte- or myocyte-related alterations in cellular metabolic pathways that correspond with increased adiposity and lower fat-free mass in early infancy. These pathways might reflect the effects of an adverse maternal metabolic environment on the fetal metabolome and genome. Our findings suggest that programmed differences in infant stem cell metabolism correspond with differences in body composition in early life, a known contributor to obesity risk.

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          Differential metabolomics reveals ophthalmic acid as an oxidative stress biomarker indicating hepatic glutathione consumption.

          Metabolomics is an emerging tool that can be used to gain insights into cellular and physiological responses. Here we present a metabolome differential display method based on capillary electrophoresis time-of-flight mass spectrometry to profile liver metabolites following acetaminophen-induced hepatotoxicity. We globally detected 1,859 peaks in mouse liver extracts and highlighted multiple changes in metabolite levels, including an activation of the ophthalmate biosynthesis pathway. We confirmed that ophthalmate was synthesized from 2-aminobutyrate through consecutive reactions with gamma-glutamylcysteine and glutathione synthetase. Changes in ophthalmate level in mouse serum and liver extracts were closely correlated and ophthalmate levels increased significantly in conjunction with glutathione consumption. Overall, our results provide a broad picture of hepatic metabolite changes following acetaminophen treatment. In addition, we specifically found that serum ophthalmate is a sensitive indicator of hepatic GSH depletion, and may be a new biomarker for oxidative stress. Our method can thus pinpoint specific metabolite changes and provide insights into the perturbation of metabolic pathways on a large scale and serve as a powerful new tool for discovering low molecular weight biomarkers.
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            Maternal high-fat diet triggers lipotoxicity in the fetal livers of nonhuman primates.

            Maternal obesity is thought to increase the offspring's risk of juvenile obesity and metabolic diseases; however, the mechanism(s) whereby excess maternal nutrition affects fetal development remain poorly understood. Here, we investigated in nonhuman primates the effect of chronic high-fat diet (HFD) on the development of fetal metabolic systems. We found that fetal offspring from both lean and obese mothers chronically consuming a HFD had a 3-fold increase in liver triglycerides (TGs). In addition, fetal offspring from HFD-fed mothers (O-HFD) showed increased evidence of hepatic oxidative stress early in the third trimester, consistent with the development of nonalcoholic fatty liver disease (NAFLD). O-HFD animals also exhibited elevated hepatic expression of gluconeogenic enzymes and transcription factors. Furthermore, fetal glycerol levels were 2-fold higher in O-HFD animals than in control fetal offspring and correlated with maternal levels. The increased fetal hepatic TG levels persisted at P180, concurrent with a 2-fold increase in percent body fat. Importantly, reversing the maternal HFD to a low-fat diet during a subsequent pregnancy improved fetal hepatic TG levels and partially normalized gluconeogenic enzyme expression, without changing maternal body weight. These results suggest that a developing fetus is highly vulnerable to excess lipids, independent of maternal diabetes and/or obesity, and that exposure to this may increase the risk of pediatric NAFLD.
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              Increased fetal adiposity: a very sensitive marker of abnormal in utero development.

              Because offspring of women with gestational diabetes mellitus have an increased risk of obesity and diabetes mellitus as young adults, our purpose was to characterize body composition at birth in infants of women with gestational diabetes mellitus and normal glucose tolerance. One hundred ninety-five infants of women with gestational diabetes mellitus and 220 infants of women with normal glucose tolerance had anthropometric measurements and total body electrical conductivity body composition evaluations at birth. Parental demographic, anthropometric, medical and family history data, and diagnostic glucose values were used to develop a stepwise regression model that related to fetal growth and body composition. There was no significant difference in birth weight (gestational diabetes mellitus [3398+/-550 g] vs normal glucose tolerance [3337+/-549 g], P=.26) or fat-free mass (gestational diabetes mellitus [2962+/-405 g] vs normal glucose tolerance [2975+/-408 g], P=.74) between groups. However, infants of women with gestational diabetes mellitus had significantly greater skinfold measures (P=.0001) and fat mass (gestational diabetes mellitus [436+/-206 g] vs normal glucose tolerance [362+/-198 g], P=.0002) compared with infants of women with normal glucose tolerance. In the gestational diabetes mellitus group, although gestational age had the strongest correlation with birth weight and fat-free mass, fasting glucose level had the strongest correlation with neonatal adiposity. Infants of women with gestational diabetes mellitus, even when they are average weight for gestational age, have increased body fat compared with infants of women with normal glucose tolerance. Maternal fasting glucose level was the strongest predictor of fat mass in infants of women with gestational diabetes mellitus. This increase in body fat may be a significant risk factor for obesity in early childhood and possibly in later life.
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                Author and article information

                Contributors
                peter.baker@childrenscolorado.org
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                22 December 2017
                22 December 2017
                2017
                : 7
                : 18095
                Affiliations
                [1 ]ISNI 0000 0001 0703 675X, GRID grid.430503.1, Department of Pediatrics, Sections of Clinical Genetics and Metabolism, , University of Colorado Anschutz Medical Campus, ; Aurora, CO 80045 USA
                [2 ]ISNI 0000 0001 0703 675X, GRID grid.430503.1, Department of Pediatrics, Section of Nutrition, , University of Colorado Anschutz Medical Campus, ; Aurora, CO 80045 USA
                [3 ]ISNI 0000 0001 0703 675X, GRID grid.430503.1, Colorado School of Public Health, , University of Colorado Anschutz Medical Campus, ; Aurora, CO 80045 USA
                [4 ]ISNI 0000 0001 0703 675X, GRID grid.430503.1, Department of Pediatrics, Section of Neonatology, , University of Colorado Anschutz Medical Campus, ; Aurora, CO 80045 USA
                Article
                17588
                10.1038/s41598-017-17588-4
                5741772
                29273781
                20822f0d-7cf9-463c-8da3-235f040bf5cf
                © The Author(s) 2017

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 25 September 2017
                : 27 November 2017
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