Impact of Obesity and Hyperglycemia on Placental Mitochondria

Abstract

A lipotoxic placental environment is recognized in maternal obesity, with increased inflammation and oxidative stress. These changes might alter mitochondrial function, with excessive production of reactive oxygen species, in a vicious cycle leading to placental dysfunction and impaired pregnancy outcomes. Here, we hypothesize that maternal pregestational body mass index (BMI) and glycemic levels can alter placental mitochondria. We measured mitochondrial DNA (mtDNA, real-time PCR) and morphology (electron microscopy) in placentas of forty-seven singleton pregnancies at elective cesarean section. Thirty-seven women were normoglycemic: twenty-one normal-weight women, NW, and sixteen obese women, OB/GDM(−). Ten obese women had gestational diabetes mellitus, OB/GDM(+). OB/GDM(−) presented higher mtDNA levels versus NW, suggesting increased mitochondrial biogenesis in the normoglycemic obese group. These mitochondria showed similar morphology to NW. On the contrary, in OB/GDM(+), mtDNA was not significantly increased versus NW. Nevertheless, mitochondria showed morphological abnormalities, indicating impaired functionality. The metabolic response of the placenta to impairment in obese pregnancies can possibly vary depending on several parameters, resulting in opposite strains acting when insulin resistance of GDM occurs in the obese environment, characterized by inflammation and oxidative stress. Therefore, mitochondrial alterations represent a feature of obese pregnancies with changes in placental energetics that possibly can affect pregnancy outcomes.

Increased placental mitochondrial fusion in gestational diabetes mellitus: an adaptive mechanism to optimize feto-placental metabolic homeostasis?

“…Taking into account that increased placental OPA1 levels were observed also in the D-GDM patients (ie, mostly normal weight women, with no insulin treatment, assumably milder hyperinsulinemia, and newborns displaying the lowest mean birth weight), it cannot be excluded that GDM diet treatment might also influence placental mitochondrial dynamics. Considering our result of lower placental OPA1 levels in obese versus non-obese GDM patients, it is possible that this compensatory capacity is exceeded in maternal obesity, due to factors such as oxidative stress, inflammation, hyperlipidemia and lipotoxicity, which are detrimental to proper mitochondrial function 28…”

“…Since maternal obesity associates with placental mitochondrial alterations28 and GWG outside recommended ranges with adverse perinatal outcomes,29 we examined placental pDRP1 and OPA1 levels also in GDM subjects categorized based on maternal BMI and GWG. Interestingly, the median (IQR) placental OPA1 fold change, normalized to ACTB, was higher in GDM women with BMI <30 kg/m 2 (1.29 (0.99/1.72), n=13) as compared with those with BMI ≥30 kg/m 2 (0.75 (0.60/1.03), n=6), p=0.029.…”

“…Similarly, in pregnancies complicated by pre-existing diabetes, suppressed placental mitochondrial respiratory chain enzyme activity has been shown 40. Interestingly, in obese women without GDM, contrasting findings such as heightened mtDNA content in the placenta28 and peripheral blood,41 suggesting increased mitochondrial biogenesis, have been reported. Collectively, these data point toward reduced placental mitochondrial biogenesis and/or respiratory capacity in diabetic pregnancies.…”

Fetal circulating human resistin increases in diabetes during pregnancy and impairs placental mitochondrial biogenesis

“…Our study begins to examine potential functions of resistin in the fetus, suggesting involvement in regulation of placental mitochondrial abundance and function. Mitochondria play a key role in placental function, and defects in placental mitochondrial function and content are associated with impaired placental energetics and increased oxidative stress, which lead to adverse pregnancy outcomes (30)(31)(32). We previously demonstrated a decrease in PGC-1α/TFAM/mitochondrial biogenesis signaling in placenta of women with diabetes during pregnancy (23).…”

Fetal circulating human resistin increases in diabetes during pregnancy and impairs placental mitochondrial biogenesis

“…Our study begins to examine the potential functions of resistin in the fetus, suggesting involvement in regulation of placental mitochondrial abundance and function. Mitochondria play a key role in placental function, and defects in placental mitochondrial function and content are associated with impaired placental energetics and increased oxidative stress, leading to adverse pregnancy outcomes (28)(29)(30). We previously demonstrated a decrease in PGC-1α/TFAM/mitochondrial biogenesis signaling in placenta of women with diabetes during pregnancy (22).…”