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Epidemiology and Population Health

Associations between the activity of placental nutrient-sensing pathways and neonatal and postnatal metabolic health: the ECHO Healthy Start cohort

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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.

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Fig. 1: Nutrient-sensing pathways investigated in this experiment.
Fig. 2: RPS6 and S6K1 phosphorylation are positively associated with offspring adiposity while 4EBP1 phosphorylation is negatively associated, and PKCα is associated with higher systolic blood pressure at age 4–6.
Fig. 3: Placental AMPK activation associated with offspring body composition.

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Acknowledgements

The authors thank M. Martinez (the Healthy Start Study project coordinator, Colorado School of Public Health, University of Colorado) and the Healthy Start team for their hard work and dedication to this study.

Funding

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. The funders had no influence on the results of the study.

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Authors and Affiliations

  1. Section of Nutrition, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

    Madeline Rose Keleher & Kristen E. Boyle

  2. The Lifecourse Epidemiology of Adiposity and Diabetes (LEAD) Center, Aurora, CO, USA

    Madeline Rose Keleher, Katerina Kechris, Ivana V. Yang, Dana Dabelea & Kristen E. Boyle

  3. Department of Obstetrics and Gynecology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

    Kathryn Erickson & Thomas Jansson

  4. Department of Biostatistics & Informatics, Colorado School of Public Health, Aurora, CO, USA

    Katerina Kechris

  5. Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA

    Ivana V. Yang

  6. Department of Epidemiology, Colorado School of Public Health, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

    Dana Dabelea

  7. Department of Pediatrics, Section of Neonatology, University of Colorado School of Medicine, Aurora, CO, USA

    Jacob E. Friedman

  8. Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Jacob E. Friedman

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  1. Madeline Rose Keleher
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Contributions

TJ contributed to the conception of the article. MRK, KE, KEB, DD, JEF, and TJ contributed to data collection. MRK, KE, and KK contributed to the statistical analysis. TJ, MRK, IVY, DD, and KEB contributed to the interpretation of the results. MRK, KEB, and TJ drafted the manuscript. All authors approved the final version of the manuscript. TJ is the guarantor of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

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Correspondence to Madeline Rose Keleher.

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Keleher, M.R., Erickson, K., Kechris, K. et al. Associations between the activity of placental nutrient-sensing pathways and neonatal and postnatal metabolic health: the ECHO Healthy Start cohort. Int J Obes 44, 2203–2212 (2020). https://doi.org/10.1038/s41366-020-0574-y

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