Effects of maternal obesity on placental function and fetal development

Abstract

Obesity has reached epidemic proportions, and pregnancies in obese mothers have increased risk for complications including gestational diabetes, hypertensive disorders, pre-term birth and caesarian section. Children born to obese mothers are at increased risk of obesity and metabolic disease and are susceptible to develop neuropsychiatric and cognitive disorders. Changes in placental function not only play a critical role in the development of pregnancy complications but may also be involved in linking maternal obesity to long-term health risks in the infant. Maternal adipokines, i.e., interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α), leptin and adiponectin link maternal nutritional status and adipose tissue metabolism to placental function. Adipokines and metabolic hormones have direct impact on placental function by modulating placental nutrient transport. Nutrient delivery to the fetus is regulated by a complex interaction including insulin signaling, cytokine profile and insulin responsiveness, which is modulated by adiponectin and IL-1β. In addition, obese pregnant women are at risk for hypertension and preeclampsia with reduced placental vascularity and blood flow, which would restrict placental nutrient delivery to the developing fetus. These sometimes opposing signals regulating placental function may contribute to the diversity of short and long-term outcomes observed in pregnant obese women. This review focuses on the changes in adipokines and obesity-related metabolic hormones, how these factors influence placental function and fetal development to contribute to long-term metabolic and behavioral consequences of children born to obese mothers.

Figure 1

The role of adiponectin in lean and obese women to modulate fetal growth. (1A) Adiponectin influence on placental insulin response in lean mothers. Placental insulin signaling pathway in lean women where high levels of adiponectin leads to PPARα activation and ceramide synthesis to decrease placental insulin responsiveness through IRS-1 inhibition limiting amino acid transport to modulate fetal growth. (1B) Low maternal adiponectin in maternal obesity leads to fetal overgrowth. Low adiponectin in obese mothers allows for improved placental insulin sensitivity and activation of placental amino acid transport. This supports fetal overgrowth which is associated with maternal obesity

Figure 1

The role of adiponectin in lean and obese women to modulate fetal growth. (1A) Adiponectin influence on placental insulin response in lean mothers. Placental insulin signaling pathway in lean women where high levels of adiponectin leads to PPARα activation and ceramide synthesis to decrease placental insulin responsiveness through IRS-1 inhibition limiting amino acid transport to modulate fetal growth. (1B) Low maternal adiponectin in maternal obesity leads to fetal overgrowth. Low adiponectin in obese mothers allows for improved placental insulin sensitivity and activation of placental amino acid transport. This supports fetal overgrowth which is associated with maternal obesity

Figure 2

Metabolic hormones and adipokine impact on placental function leads to fetal overgrowth. Factors associated with maternal obesity play a significant role in regulating placental transport and impact fetal development. Increased levels of TNF-α observed in pregnancies complicated by obesity stimulate the p38/MAPK pathway and high maternal leptin and/or IL-6 levels stimulate Systems A/L via STAT3 activation. Placental toll-like receptor 4 expression is increased in obese women who often have high non-esterified fatty acids leading to activation of placental amino acid transport. High maternal insulin also activates mTOR-System A/L to increase amino acid transport, leading to fetal overgrowth.

Figure 3

Role of adipokines and metabolic hormones in pregnancies complicated by obesity. Diversity in cytokine profiles in obese women may contribute to variation in fetal growth outcomes. In pregnancies complicated by LGA, multiple metabolic factors, insulin, leptin, IL-6 and TNF-α and low maternal adiponectin have been found to stimulate placental nutrient transport, contributing to fetal overgrowth. In pregnancies complicated by hypertension, IL-1β and sFlt1 are up-regulated while PlGF is decreased, leading to reduced placental blood flow which will limit fetal growth. Fetal brain development and long-term neurodevelopmental programming is linked to inflammation and placental serotonin production. Interestingly both poor and accelerated fetal growth are associated with similar long-term metabolic disorders in the children