Increased Death of Adipose Cells, a Path to Release Cell‐Free DNA Into Systemic Circulation of Obese Women

Abstract

Remodeling of adipose tissue is required to support the expansion of adipose mass. In obesity, an increased death of adipocytes contributes to the accelerated cellular turnover. We have shown that obesity in pregnancy is associated with metabolic and immune alterations in the adipose tissue. In this study we characterized the mechanisms responsible for increased death of adipose cells of pregnant obese women and its functional consequences. We postulated that a higher turnover of dead cells in white adipose tissue of obese women would translate into release of cell free DNA (cfDNA) into their systemic circulation. Increase in adipose mass of obese compared to lean women results from a lesser number of hypertrophic adipocytes and an accumulation of macrophages in the stromal vascular fraction (SVF). The adipocytes of obese displayed enhanced necrosis with a loss of perilipin staining at the plasma membrane. Apoptosis was prominent in SVF cells with an increased expression of caspase 9 and caspase 3 and a higher rate of TUNEL positive CD68 macrophages in obese vs lean. Whereas circulating fetal cfDNA concentrations were not changed, there was a 2-fold increase in circulating GAPDH cfDNA and adipose tissue GAPDH mRNA in obese women. The maternal systemic GAPDH cfDNA was positively correlated with BMI and gestational weight gain. These data suggest that the active remodeling of adipose tissue of obese pregnant women results in an increased release of cfDNA of maternal origin into the circulation.

Maternal Plasma Cell-Free Fetal and Maternal DNA at 11-13 Weeks' Gestation: Relation to Fetal and Maternal Characteristics and Pregnancy Outcomes

“…The decrease in fetal cfDNA with maternal weight is compatible with the plasma concentration of other fetoplacental products and can be attributed to a dilutional effect [22]. In contrast, maternal cfDNA levels increase with weight and recent evidence suggests that with increased weight there is active remodeling of adipose tissue with accelerated turnover of adipocytes [34]. …”

Prenatal Detection of Fetal Triploidy from Cell-Free DNA Testing in Maternal Blood

“…This is also true for other fetoplacental products, including free β-hCG and PAPP-A. A contributing factor to the decrease in fetal fraction with increasing maternal weight is the increase in maternal cfDNA levels because with increased weight there is active remodeling of adipose tissue with accelerated turnover of adipocytes [22,23]. In terms of the association of fetal fraction with serum-free β-hCG and PAPP-A, these metabolites are produced by the placenta and inevitably their maternal serum concentration provides an indirect measure of placental mass.…”

A single center’s experience with noninvasive prenatal testing

“…Maternal obesity is associated with an increased amount of total cell-free DNA, resulting from adipocyte necrosis. 22 Fetal fraction is the percentage of cell-free fetal DNA as compared with total cell-free DNA; thus, an increase in total cell-free DNA would result in a decreased fetal fraction. 23 Prior studies have demonstrated that the fetal fraction is positively correlated with gestational age and negatively correlated with maternal weight.…”