Associations of maternal diet and placenta leptin methylation
Introduction
Early environment plays a critical role in modulating risk for downstream chronic disease. Developing tissues and organ systems in utero are particularly susceptible to environmental perturbations that can have long-term consequences for health and disease. Adverse prenatal circumstances, such as reduced nutrient availability, are major risk factors for the future development of metabolic, cardiovascular, neuropsychiatric, immunologic, and gastrointestinal disorders (Ravelli et al., 1999; Roseboom et al., 2001). Further, the fetal overnutrition hypothesis suggests that maternal fuels are in greater abundance in maternal obesity and gestational diabetes mellitus (GDM), predicting excessive nutrient availability after birth, with high fat and high caloric diets yielding increased adiposity and inflammation in offspring (Nicholas et al., 2016; Sullivan et al., 2015). Recent epidemiological evidence has shown that maternal hyperglycemia is associated with increased risk of abnormal glucose tolerance, obesity and elevations in blood pressure in children by the age seven––effects that were independent of maternal obesity, birth weight, and body mass index (BMI) (Tam et al., 2017).
Prenatal environments are hypothesized to influence downstream health outcomes through a number of mechanisms. Epigenetics refers to a collection of processes that allow for transient environmental influences to have long-lasting effects on DNA expression that endure across subsequent cell generations. Through various means of controlling gene transcription, epigenetic regulation allows for a wide range of phenotypes to arise from identical genomic information. The most stable epigenetic mechanism is methylation of the 5’ cytosine nucleotide within CpG islands, which serves to repress mRNA expression (Smith and Ryckman, 2015).
Leptin is a pro-inflammatory cytokine primarily produced by adipose tissue (also referred to as an adipokine), but also in other tissues, including the placenta (Ashworth et al., 2000). Leptin plays a central role in the regulation of food intake behaviors, metabolism, and inflammation (Friedman, 2011; Harris, 2014). Centrally, leptin acts as a satiety signal through suppression of orexigenic peptides at the ventromedial hypothalamus (Ahima, 2006). Peripherally, leptin serves to mobilize stored energy through lipolysis (Ahima, 2006). Leptin levels vary with energy states and adiposity––with high levels of leptin in obesity leading to central leptin insensitivity at the level of the hypothalamus (Engin, 2017). Leptin may have particular importance in the perinatal period. Leptin is produced by the placenta and circulating maternal leptin increases throughout the second trimester, producing a physiologic hyperleptinemic state with associated hypothalamic leptin insensitivity to allow for increased appetitive behaviors (Ashworth et al., 2000). Leptin injection at birth in leptin-deficient mice influenced hypothalamic connectivity, resulting in reduced food intake and attenuated weight gain over the lifetime (Bouret et al., 2004).
Dysregulated maternal metabolic states, such as pre-pregnancy obesity and GDM, are associated with changes in placenta leptin methylation. Obesity in pregnancy is associated with higher maternal circulating leptin and placenta leptin production has been shown to increase with BMI in non-obese mothers as well. Pre-pregnancy obesity is associated with broad changes in placental gene expression and in particular, reduced placenta leptin expression (Tessier et al., 2013). Pre-pregnancy obesity and GDM have both been found to have associations with changes in leptin methylation patterns (Lesseur et al., 2014a, Lesseur et al., 2014b; Lesseur and Chen, 2018; Nogues et al., 2019).
Further, maternal fasting glucose has been directly correlated with cord blood leptin (Allard et al., 2015). As the blood supply within the placenta can be divided into maternal and fetal systems of circulation, measures of leptin methylation from each side can be compared. For example, maternal glucose levels are positively correlated with maternal side placenta DNA methylation and negatively correlated with methylation in the fetal side (Bouchard et al., 2010).
In order to better understand the contribution of maternal diet to fetal metabolic programming through epigenetic changes in utero, we studied maternal diet and placenta leptin methylation in a group of mother-infant dyads in the immediate postpartum period.
Section snippets
Subjects
Subjects (N = 135) were mother-infant pairs recruited following delivery at Women and Infants Hospital in Providence Rhode Island, USA as part of the Rhode Island Child Health Study (Marsit et al., 2012). The current sample, however, is distinct from that used in a previous publication on leptin methylation that did not assess dietary intake, the main focus of the current study (Lesseur et al., 2014a, Lesseur et al., 2014b). Briefly, term infants born small for gestational age (SGA; <10th
Sample characteristics
Characteristics of the study population are listed in Table 1. In accordance with the study design, all infants were born at term. Consistent with local demographics, the majority of infants (N = 135) were born to white mothers (72.5%) who ranged between 18 and 40 years of age (M = 30 years).
Maternal diet
Table 2 displays summary values for maternal macronutrient intake. Women reported consuming an average of 283.0 g of carbohydrates daily (SD = 103.4 g; range = 125.7–660.1 g). Of these, an average of 67.2 g
Discussion
This study demonstrates that maternal intake of carbohydrates, in particular added sugar and white/refined carbohydrates, are negatively predictive of placenta leptin methylation. These findings withstood correction for other potential mediators of placenta leptin methylation, including genotype, maternal age, infant sex, gestational diabetes, and pre-pregnancy obesity. While caloric intake was similarly associated with placenta leptin methylation, this correlation did not withstand correction
Author contribution
Teresa E. Daniels: Conceptualization, Formal Analysis, Methodology, Writing – Original Draft, Reviewing and Editing Alexander Sadovnikoff: Conceptualization, Formal Analysis, Methodology, Reviewing and Editing Kathryn K. Ridout: Formal Analysis, Reviewing and Editing Corina Lesseur: Conceptualization, Methodology, Reviewing and Editing Carmen J. Marsit: Conceptualization, Funding Acquisition, Methodology, Reviewing and Editing Audrey R. Tyrka: Conceptualization, Formal Analysis, Methodology,
Declaration of competing interest
All authors have nothing to disclose. All authors report no conflict of interest.
Acknowledgments
This work was supported by NIH grants R01 HD086487 (ART), R24 ES028507 (CJM), and K99 HD097286 (CL). Dr. Daniels and Dr. Ridout received support from R25 MH101076. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
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