Mesenchymal Stem Cells From Infants Born to Obese Mothers Exhibit Greater Potential for Adipogenesis: The Healthy Start BabyBUMP Project

Boyle, Kristen E.; Patinkin, Zachary W; Shapiro, Allison; Baker, Peter R.; Dabelea, Dana; Friedman, Jacob E.

doi:10.2337/db15-0849

Cited by 89 publications

(126 citation statements)

References 39 publications

(50 reference statements)

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“…Although mechanisms underlying this pathophysiology are poorly understood, studies of stem cells from babies born to mothers with obesity have provided insight. These cells have increased adipogenic capacity 16 , and changes in amino acid and fatty acid oxidation metabolites in lipidexposed, adipocytedifferentiated stem cells were predictive of rapid increases in adiposity from birth to 5 months of age 24 . Notably, biomarkers of mitochondrial dysfunction are elevated in plasma at 48 h of life in neonates born to mothers who are obese 25 .…”

Section: Developmental Programming Of Nafldmentioning

confidence: 99%

“…Data published in 2016 indicate that maternal obesity in humans promotes umbilical cord mesenchymal stem cells from newborn babies to preferentially differentiate into adipocytes rather than myocytes, correlating with an increase in neonate adiposity measured within 72 h of birth 16 . Furthermore, MRI and magnetic resonance spectroscopy in babies born to mothers with GDM who are obese showed a 70% increase in liver fat, with no statistically significant increase in subcutaneous or intraabdominal fat 17 , suggesting that fetal exposures during gestation (that is, obesity, GDM or raised levels of fatty acids) increase NAFLD risk in the human neonate.…”

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confidence: 99%

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Developmental origins of NAFLD: a womb with a clue

Wesolowski

Kasmi

Jonscher

et al. 2016

Nat Rev Gastroenterol Hepatol

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Changes in the maternal environment leading to an altered intrauterine milieu can result in subtle insults to the fetus, promoting increased lifetime disease risk and/or disease acceleration in childhood and later in life. Particularly worrisome is that the prevalence of NAFLD is rapidly increasing among children and adults, and is being diagnosed at increasingly younger ages, pointing towards an early-life origin. A wealth of evidence, in humans and non-human primates, suggests that maternal nutrition affects the placenta and fetal tissues, leading to persistent changes in hepatic metabolism, mitochondrial function, the intestinal microbiota, liver macrophage activation and susceptibility to NASH postnatally. Deleterious exposures in utero include fetal hypoxia, increased nutrient supply, inflammation and altered gut microbiota that might produce metabolic clues, including fatty acids, metabolites, endotoxins, bile acids and cytokines, which prime the infant liver for NAFLD in a persistent manner and increase susceptibility to NASH. Mechanistic links to early disease pathways might involve shifts in lipid metabolism, mitochondrial dysfunction, pioneering gut microorganisms, macrophage programming and epigenetic changes that alter the liver microenvironment, favouring liver injury. In this Review, we discuss how maternal, fetal, neonatal and infant exposures provide developmental clues and mechanisms to help explain NAFLD acceleration and increased disease prevalence. Mechanisms identified in clinical and preclinical models suggest important opportunities for prevention and intervention that could slow down the growing epidemic of NAFLD in the next generation.NAFLD is a general term used to describe a broad spectrum of liver abnormalities, ranging from simple, uncomplicated hepatic steatosis to NASH, accompanied by different degrees of Correspondence to J.E.F. jed.friedman@ucdenver.edu. Author contributionsAll authors researched data for the article, provided a substantial contribution to discussion of content, wrote the article, and reviewed and edited the manuscript before submission. Competing interests statementThe authors declare no competing interests. HHS Public AccessAuthor manuscript Nat Rev Gastroenterol Hepatol. Author manuscript; available in PMC 2017 December 12. Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript inflammation and fibrosis. NAFLD is increasing in prevalence, especially in adolescents 1 , despite the levellingoff of the obesity epidemic from 2003-2004 to 2013-2014 in children and adolescents aged 2-19 years (REF.2). The most common chronic liver disease worldwide, NAFLD increases the risk of cardiovascular events eightfold and type 2 diabetes mellitus (T2DM) threefold 3 , and is a strong risk factor for hepatocellular carcinoma (HCC) 4 . At the time of paediatric NAFLD diagnosis, 25-50% of children have NASH and 10-25% have advanced fibrosis 5 . For many decades, it was thought that NAFLD was predominantly driven by obesity in the setting of genetic suscep...

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Section: Developmental Programming Of Nafldmentioning

confidence: 99%

mentioning

confidence: 99%

Developmental origins of NAFLD: a womb with a clue

Wesolowski

Kasmi

Jonscher

et al. 2016

Nat Rev Gastroenterol Hepatol

Self Cite

169

167

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“…Our methods in growth and differentiation of uMSC have been described previously for myocytes and adipocytes (27). Undifferentiated uMSC were grown to confluence and then exposed to lipid enriched (oleate [C18:1, 133 μM], palmitate [C16:0, 67 μM], and carnitine [1 mM]) myocyte and adipocyte differentiation media.…”

Section: Methodsmentioning

confidence: 99%

“…To investigate the Biology of intraUterine Metabolic Programming (BUMP), umbilical cord tissue was obtained at birth from a convenience sample of 165 Healthy Start infants and used to culture uMSC as an ancillary part of the Healthy Start Study (Baby BUMP Project). In a subsample of these infants, we have recently shown that differentiating uMSC myocytes and adipocytes were physiologically distinct (as demonstrated by differential expression of PAX7, myogenin, myosin heavy chain, FABP4, CEBPa, and PPARγ), despite coming from the same original precursor (27). Differentiating uMSC adipocytes from offspring of OB women, compared with normal weight (NW) matched controls, had greater adipogenic potential (higher PPARγ), and uMSC lipid accumulation in the adipogenic condition was correlated with adiposity in the neonate (27).…”

Section: Introductionmentioning

confidence: 99%

“…In a subsample of these infants, we have recently shown that differentiating uMSC myocytes and adipocytes were physiologically distinct (as demonstrated by differential expression of PAX7, myogenin, myosin heavy chain, FABP4, CEBPa, and PPARγ), despite coming from the same original precursor (27). Differentiating uMSC adipocytes from offspring of OB women, compared with normal weight (NW) matched controls, had greater adipogenic potential (higher PPARγ), and uMSC lipid accumulation in the adipogenic condition was correlated with adiposity in the neonate (27). However, data demonstrating altered metabolic networks in the infant with increased obesity risk based on maternal phenotype have yet to be defined.…”

Section: Introductionmentioning

confidence: 99%

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Maternal obesity and increased neonatal adiposity correspond with altered infant mesenchymal stem cell metabolism

et al. 2017

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Novel Metabolic Subtypes in Pregnant Women and Risk of Early Childhood Obesity in Offspring

Francis¹,

Kechris

Jansson

et al. 2023

JAMA Netw Open

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ImportanceThe in utero metabolic milieu is associated with offspring adiposity. Standard definitions of maternal obesity (according to prepregnancy body mass index [BMI]) and gestational diabetes (GDM) may not be adequate to capture subtle yet important differences in the intrauterine environment that could be involved in programming.ObjectivesTo identify maternal metabolic subgroups during pregnancy and to examine associations of subgroup classification with adiposity traits in their children.Design, Setting, and ParticipantsThis cohort study included mother-offspring pairs in the Healthy Start prebirth cohort (enrollment: 2010-2014) recruited from University of Colorado Hospital obstetrics clinics in Aurora, Colorado. Follow-up of women and children is ongoing. Data were analyzed from March to December 2022.ExposuresMetabolic subtypes of pregnant women ascertained by applying k-means clustering on 7 biomarkers and 2 biomarker indices measured at approximately 17 gestational weeks: glucose, insulin, Homeostatic Model Assessment for Insulin Resistance, total cholesterol, high-density lipoprotein cholesterol (HDL-C), triglycerides, free fatty acids (FFA), HDL-C:triglycerides ratio, and tumor necrosis factor α.Main Outcomes and MeasuresOffspring birthweight z score and neonatal fat mass percentage (FM%). In childhood at approximately 5 years of age, offspring BMI percentile, FM%, BMI in the 95th percentile or higher, and FM% in the 95th percentile or higher.ResultsA total of 1325 pregnant women (mean [SD] age, 27.8 [6.2 years]; 322 [24.3%] Hispanic, 207 non-Hispanic Black [15.6%], and 713 [53.8%] non-Hispanic White), and 727 offspring with anthropometric data measured in childhood (mean [SD] age 4.81 [0.72] years, 48% female) were included. We identified the following 5 maternal metabolic subgroups: reference (438 participants), high HDL-C (355 participants), dyslipidemic–high triglycerides (182 participants), dyslipidemic–high FFA (234 participants), and insulin resistant (IR)–hyperglycemic (116 participants). Compared with the reference subgroup, women in the IR-hyperglycemic and dyslipidemic–high FFA subgroups had offspring with 4.27% (95% CI, 1.94-6.59) and 1.96% (95% CI, 0.45-3.47) greater FM% during childhood, respectively. There was a higher risk of high FM% among offspring of the IR-hyperglycemic (relative risk, 8.7; 95% CI, 2.7-27.8) and dyslipidemic–high FFA (relative risk, 3.4; 95% CI, 1.0-11.3) subgroups; this risk was of greater magnitude compared with prepregnancy obesity alone, GDM alone, or both conditions.Conclusions and RelevanceIn this cohort study, an unsupervised clustering approach revealed distinct metabolic subgroups of pregnant women. These subgroups exhibited differences in risk of offspring adiposity in early childhood. Such approaches have the potential to refine understanding of the in utero metabolic milieu, with utility for capturing variation in sociocultural, anthropometric, and biochemical risk factors for offspring adiposity.

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Mesenchymal Stem Cells From Infants Born to Obese Mothers Exhibit Greater Potential for Adipogenesis: The Healthy Start BabyBUMP Project

Cited by 89 publications

References 39 publications

Developmental origins of NAFLD: a womb with a clue

Developmental origins of NAFLD: a womb with a clue

Maternal obesity and increased neonatal adiposity correspond with altered infant mesenchymal stem cell metabolism

Novel Metabolic Subtypes in Pregnant Women and Risk of Early Childhood Obesity in Offspring

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