In a groundbreaking study published in the International Journal of Obesity, researchers have unveiled compelling new insights into the intricate relationship between maternal pre-pregnancy body mass index (BMI) and the expression of serotonin-regulating genes in the placenta. This research not only broadens our understanding of the molecular mechanisms linking maternal metabolic status to fetal development but also introduces the potential moderating role of glucose tolerance status, a factor often overlooked in previous investigations.
Serotonin, a key neurotransmitter widely recognized for its role in mood regulation, has long been studied for its influence beyond the central nervous system. In the context of pregnancy, serotonin pathways within the placenta are critical for fetal growth and development. However, despite the recognized importance of serotonin metabolism in gestation, the specific impact of maternal obesity and overweight conditions on placental serotonin gene expression remained inadequately defined until now. This study bridges that gap by specifically examining genes responsible for serotonin metabolism, transport, and receptor function within term placental tissue.
The investigation centered on the placenta’s expression of genes encoding key serotonin-regulating components, including metabolic enzymes that synthesize and degrade serotonin, transmembrane transporters like the serotonin transporter (SERT), and the array of receptors that mediate serotonin’s biological effects. By analyzing these genes, the researchers aimed to elucidate how maternal BMI before pregnancy might influence the placental serotonergic environment, potentially affecting neonatal outcomes.
A pivotal aspect of this study was the consideration of maternal glucose tolerance status—specifically distinguishing between normal glucose tolerance (NGT) and gestational diabetes mellitus (GDM). Prior research has established GDM as a significant pregnancy complication that alters both maternal and fetal metabolism; however, its potential role in modulating placental gene expression related to serotonin remained poorly understood. The researchers hypothesized that glucose intolerance might interact with maternal BMI to influence placental serotonin-related gene expression in a synergistic or moderating manner.
Methodologically, the team collected term placentas from a cohort of pregnant women stratified by BMI categories and glucose tolerance status. Through quantitative gene expression analyses, they meticulously assessed the expression levels of serotonin transporters, metabolic enzymes, and receptor genes in placental tissue. This robust approach enabled the precise quantification of molecular changes associated with maternal metabolic parameters.
One of the most striking findings was the observed downregulation of SERT gene expression in placentas derived from mothers classified as overweight or obese prior to pregnancy. SERT plays a crucial role in controlling serotonin availability by facilitating its reuptake from the synaptic cleft or extracellular space, and alterations in its expression could significantly impact the local serotonergic milieu. The downregulation of SERT suggests that higher maternal BMI may disrupt serotonin homeostasis within the placental environment, which could have downstream effects on nutrient transport and fetal neurodevelopment.
Furthermore, the study indicated that glucose tolerance status exerts a moderating effect on the relationship between maternal BMI and serotonin gene expression. Notably, in the subset of mothers with GDM, the expression patterns of serotonin-regulating genes differed significantly from those with normal glucose tolerance, suggesting a complex interplay between hyperglycemia, maternal adiposity, and placental serotonergic signaling.
Beyond gene expression data, the researchers extended their analysis to consider neonatal anthropometry—parameters such as birth weight, length, and head circumference—to investigate potential clinical implications. They found significant associations between altered placental serotonin gene expression and neonatal body measurements, pointing toward a link between maternal metabolic status, placental serotonergic regulation, and fetal growth outcomes.
These findings hold profound implications for the field of obstetrics and developmental biology. By delineating the molecular mechanisms through which maternal overweight and obesity influence placental function, especially in the context of glucose dysregulation, the study opens avenues for targeted interventions aimed at optimizing fetal development and mitigating risks associated with maternal metabolic disorders.
The identification of SERT as a key mediator in this context is particularly exciting given the transporter’s well-characterized role in neuropsychiatric disorders. This raises the intriguing possibility that maternal metabolic conditions could predispose offspring to neurodevelopmental challenges by modulating placental serotonin regulation—a hypothesis warranting further longitudinal studies.
Furthermore, the nuanced understanding of how gestational diabetes may exacerbate or alter the impact of maternal BMI on placental function underscores the importance of comprehensive metabolic screening and management in pregnancy. It suggests that interventions tailored to both glucose control and weight management could synergistically improve placental health and fetal outcomes.
This study’s rigorous design and comprehensive approach set a new standard for placental research. The inclusion of multiple classes of serotonin-regulating genes spanning metabolic enzymes, transporters, and receptors allowed for a holistic assessment of the serotonergic system’s status within the placenta, rather than a narrow focus on isolated components.
Moreover, the translational potential of these findings extends beyond obstetrics to public health. With global rates of maternal overweight and obesity continuing to rise, understanding the biological pathways through which these conditions affect fetal development is paramount. This could lead to novel biomarker development for early detection of placental dysfunction and improved prenatal care protocols.
The interplay between serotonin signaling and metabolic pathways revealed by this study also prompts a reevaluation of existing therapeutic strategies for managing gestational obesity and diabetes. Pharmacological or nutritional modulation of placental serotonin pathways may emerge as a novel strategy to optimize fetal growth and neurodevelopmental outcomes.
The integration of neonatal anthropometric data adds an important clinical dimension, linking molecular perturbations in the placenta to tangible, measurable outcomes in the newborn. This strengthens the argument for considering placental serotonin transporter expression as a potential biomarker for predicting neonatal risk profiles related to maternal metabolic health.
Critically, this study invites further exploration into the mechanisms whereby altered placental serotonin dynamics influence fetal organogenesis, particularly of the brain, liver, and pancreas—organs highly sensitive to serotonergic signaling during development. Subsequent research could elucidate whether these gene expression changes translate into functional deficits or long-term health consequences for the child.
In summary, this seminal work by Perić and colleagues provides compelling evidence that maternal pre-pregnancy BMI, in conjunction with glucose tolerance status, significantly influences placental expression of serotonin-regulating genes. These molecular alterations correlate with variations in neonatal anthropometry, indicating a potential pathway through which maternal metabolic health shapes fetal development. The findings not only enhance our understanding of placental biology but also underscore the intricate connections between maternal physiology, placental function, and offspring health, with broad implications for clinical practice and public health policy.
Subject of Research:
Maternal pre-pregnancy body mass index (BMI), glucose tolerance status, and placental expression of serotonin-regulating genes.
Article Title:
Placental expression of the serotonin transporter (SERT) gene: associations with maternal overweight/obesity and neonatal anthropometry.
Article References:
Perić, M., Horvatiček, M., Kesić, M. et al. Placental expression of the serotonin transporter (SERT) gene: associations with maternal overweight/obesity and neonatal anthropometry. Int J Obes (2025). https://doi.org/10.1038/s41366-025-01918-y
Image Credits:
AI Generated
DOI:
https://doi.org/10.1038/s41366-025-01918-y
Tags: glucose tolerance and pregnancy outcomesmaternal BMI impact on fetal developmentmaternal health and child developmentmaternal metabolic health and newborn sizematernal obesity and serotonin gene expressionmolecular mechanisms of fetal growthneurotransmitters in gestationobesity effects on placental functionplacental serotonin transporter SERTprenatal nutrition and fetal growthserotonin metabolism in placental tissueserotonin pathways during pregnancy
