RESUMO
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. Using MANOVA, we tested the association between placental proteins and offspring adiposity (fat mass percentage) at birth (n = 109) and infancy (4-6 months, n = 104), and adiposity, skinfold thickness, triglycerides, and insulin in children (4-6 years, n = 66). Placental IGF-1 receptor protein was positively associated with serum triglycerides in children. GSK3ß phosphorylation at serine 9, a readout of insulin and growth factor signaling, and the ratio of phosphorylated to total JNK2 were both positively associated with midthigh skinfold thickness in children. Moreover, peroxisome proliferator-activated receptor γ coactivator (PGC)-1α abundance was positively associated with insulin in children. In conclusion, placental insulin/IGF-1 signaling, PGC-1α, and inflammation pathways were positively associated with metabolic outcomes in 4- to 6-year-old children, identifying a novel link between placental function and long-term metabolic outcomes.
Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 2/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Insulina/metabolismo , Proteína Quinase 9 Ativada por Mitógeno/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Placenta/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/genética , Índice de Massa Corporal , Criança , Pré-Escolar , Feminino , Humanos , Técnicas In Vitro , Lactente , Proteína Quinase 9 Ativada por Mitógeno/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Fosforilação , Gravidez , Proteínas Quinases p38 Ativadas por Mitógeno/genéticaRESUMO
Maternal obesity increases the risk for pediatric obesity; however, the molecular mechanisms in human infants remain poorly understood. We hypothesized that mesenchymal stem cells (MSCs) from infants born to obese mothers would demonstrate greater potential for adipogenesis and less potential for myogenesis, driven by differences in ß-catenin, a regulator of MSC commitment. MSCs were cultured from the umbilical cords of infants born to normal-weight (prepregnancy [pp] BMI 21.1 ± 0.3 kg/m(2); n = 15; NW-MSCs) and obese mothers (ppBMI 34.6 ± 1.0 kg/m(2); n = 14; Ob-MSCs). Upon differentiation, Ob-MSCs exhibit evidence of greater adipogenesis (+30% Oil Red O stain [ORO], +50% peroxisome proliferator-activated receptor (PPAR)-γ protein; P < 0.05) compared with NW-MSCs. In undifferentiated cells, total ß-catenin protein content was 10% lower and phosphorylated Thr41Ser45/total ß-catenin was 25% higher (P < 0.05) in Ob-MSCs versus NW-MSCs (P < 0.05). Coupled with 25% lower inhibitory phosphorylation of GSK-3ß in Ob-MSCs (P < 0.05), these data suggest greater ß-catenin degradation in Ob-MSCs. Lithium chloride inhibition of GSK-3ß increased nuclear ß-catenin content and normalized nuclear PPAR-γ in Ob-MSCs. Last, ORO in adipogenic differentiating cells was positively correlated with the percent fat mass in infants (r = 0.475; P < 0.05). These results suggest that altered GSK-3ß/ß-catenin signaling in MSCs of infants exposed to maternal obesity may have important consequences for MSC lineage commitment, fetal fat accrual, and offspring obesity risk.