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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

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posted on 07.01.2021, 22:14 by Madeline Rose Keleher, Kathryn Erickson, Harry A. Smith, Katerina J. Kechris, Ivana V. Yang, Dana Dabelea, Jacob E. Friedman, Kristen E. Boyle, Thomas Jansson
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.


This work was supported by UG3OD023248-03 (to DD). The Healthy Start BabyBUMP Project is supported by grants from the American Heart Association (predoctoral fellowship 14PRE18230008) and by the parent Healthy Start Study (to DD). The Healthy Start Study was supported by the National Institute of Health (R01 DK076648 to DD) and the Colorado Clinical and Translational Sciences Institute (UL1 TR001082) for maternal visits and collection of birth measures.