Madeline Rose Keleher1,2, Kathryn Erickson3, Katerina Kechris4,5, Ivana V Yang4,6, Dana Dabelea4,7, Jacob E Friedman8,9, Kristen E Boyle10,4, Thomas Jansson3. 1. Section of Nutrition, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. madeline.keleher@ucdenver.edu. 2. The Lifecourse Epidemiology of Adiposity and Diabetes (LEAD) Center, Aurora, CO, USA. madeline.keleher@ucdenver.edu. 3. Department of Obstetrics and Gynecology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. 4. The Lifecourse Epidemiology of Adiposity and Diabetes (LEAD) Center, Aurora, CO, USA. 5. Department of Biostatistics & Informatics, Colorado School of Public Health, Aurora, CO, USA. 6. Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA. 7. Department of Epidemiology, Colorado School of Public Health, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. 8. Department of Pediatrics, Section of Neonatology, University of Colorado School of Medicine, Aurora, CO, USA. 9. Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. 10. Section of Nutrition, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Abstract
OBJECTIVE: Our hypothesis was that the activity of placental nutrient-sensing pathways is associated with adiposity and metabolic health in childhood. RESEARCH DESIGN AND METHODS: Using placental villus samples from healthy mothers from the Healthy Start Study, we measured the abundance and phosphorylation of key intermediates in the mTOR, insulin, AMPK, and ER stress signaling pathways. Using multivariate multiple regression models, we tested the association between placental proteins and offspring adiposity (%fat mass) at birth (n = 109), 4-6 months (n = 104), and 4-6 years old (n = 64), adjusted for offspring sex and age. RESULTS: Placental mTORC1 phosphorylation was positively associated with adiposity at birth (R2 = 0.13, P = 0.009) and 4-6 years (R2 = 0.15, P = 0.046). The mTORC2 target PKCα was positively associated with systolic blood pressure at 4-6 years (β = 2.90, P = 0.005). AMPK phosphorylation was positively associated with adiposity at birth (β = 2.32, P = 0.023), but the ratio of phosphorylated to total AMPK was negatively associated with skinfold thickness (β = -2.37, P = 0.022) and body weight (β = -2.92, P = 0.005) at 4-6 years. CONCLUSIONS: This is the first report of associations between key placental protein activity measures and longitudinal child outcomes at various life stages. Our data indicate that AMPK and mTOR signaling are linked to cardiometabolic measures at birth and 4-6 years, providing novel insight into potential mechanisms underpinning how metabolic signaling in the placenta is associated with future risk of cardiovascular disease.
OBJECTIVE: Our hypothesis was that the activity of placental nutrient-sensing pathways is associated with adiposity and metabolic health in childhood. RESEARCH DESIGN AND METHODS: Using placental villus samples from healthy mothers from the Healthy Start Study, we measured the abundance and phosphorylation of key intermediates in the mTOR, insulin, AMPK, and ER stress signaling pathways. Using multivariate multiple regression models, we tested the association between placental proteins and offspring adiposity (%fat mass) at birth (n = 109), 4-6 months (n = 104), and 4-6 years old (n = 64), adjusted for offspring sex and age. RESULTS: Placental mTORC1 phosphorylation was positively associated with adiposity at birth (R2 = 0.13, P = 0.009) and 4-6 years (R2 = 0.15, P = 0.046). The mTORC2 target PKCα was positively associated with systolic blood pressure at 4-6 years (β = 2.90, P = 0.005). AMPK phosphorylation was positively associated with adiposity at birth (β = 2.32, P = 0.023), but the ratio of phosphorylated to total AMPK was negatively associated with skinfold thickness (β = -2.37, P = 0.022) and body weight (β = -2.92, P = 0.005) at 4-6 years. CONCLUSIONS: This is the first report of associations between key placental protein activity measures and longitudinal child outcomes at various life stages. Our data indicate that AMPK and mTOR signaling are linked to cardiometabolic measures at birth and 4-6 years, providing novel insight into potential mechanisms underpinning how metabolic signaling in the placenta is associated with future risk of cardiovascular disease.
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