Placental Insulin/IGF-1 Signaling, PGC1α, and Inflammatory Pathways are Associated With Metabolic Outcomes at 4-6 years of Age: The ECHO Healthy Start Cohort

Abstract

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 (percent fat mass) at birth (n=109) and infancy (4-6mo, n=104), and adiposity, skinfold thickness, triglycerides, and insulin in children (4-6y, n=66). Placental IGF-1 receptor protein was positively associated with serum triglycerides in children. GSK3β 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, 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 4-6-year-old children, identifying a novel link between placental function and long-term metabolic outcomes.

The Update of Fetal Growth Restriction Associated with Biomarkers

“…66,100 Cord and maternal sera in pregnancies that produced small neonates share dysfunctional lipoproteins with proatherogenic properties, providing evidence for Barker's hypothesis 101 : oxidized low-density lipoproteins in cord blood from neonates with FGR 19 and maternal serum and umbilical cord blood leptin concentrations with FGR. [102][103][104] One recent study shows placental IGF1 receptor protein positively associated with serum triglycerides in children, 67 which emphasize the adverse intrauterine environment is associated with the potential risk of obesity and type 2 diabetes.…”

“…More research is needed to elucidate these markers in pregnancy in general; however, we hypothesize these biomarkers would be enriched in cases of FGR, PE, and preterm, which are conditions associated with an adverse intrauterine environment. For example, one recent study showed placental IGF1 receptor protein positively associated with serum triglycerides in children, 67 which emphasized that adverse intrauterine environment is associated with the potential risk of obesity and type 2 diabetes. Abnormal biomarkers may suggest abnormal organ growth (ie, liver) in the fetus, which may ultimately decrease the important reserves (eg, cell number and growth) that are important to face and resist environmental insults later in life.…”