Maternal obesity alters brain derived neurotrophic factor (BDNF) signaling in the placenta in a sexually dimorphic manner

Abstract

Introduction Obesity is a major clinical problem in obstetrics being associated with adverse pregnancy outcomes and fetal programming. Brain derived neurotrophic factor (BDNF), a validated miR-210 target, is necessary for placental development, fetal growth, glucose metabolism, and energy homeostasis. Plasma BDNF levels are reduced in obese individuals; however, placental BDNF has yet to be studied in the context of maternal obesity. In this study, we investigated the effect of maternal obesity and sexual dimorphism on placental BDNF signaling. Methods BDNF signaling was measured in placentas from lean (pre-pregnancy BMI < 25) and obese (pre-pregnancy BMI>30) women at term without medical complications that delivered via cesarean section without labor. MiRNA-210, BDNF mRNA, proBDNF, and mature BDNF were measured by RT – PCR, ELISA, and Western blot. Downstream signaling via TRKB (BDNF receptor) was measured using Western blot. Results Maternal obesity was associated with increased miRNA-210 and decreased BDNF mRNA in placentas from female fetuses, and decreased proBDNF in placentas from male fetuses. We also identified decreased mature BDNF in placentas from male fetuses when compared to female fetuses. Mir-210 expression was negatively correlated with mature BDNF protein. TRKB phosphorylated at tyrosine 817, not tyrosine 515, was increased in placentas from obese women. Maternal obesity was associated with increased phosphorylation of MAPK p38 in placentas from male fetuses, but not phosphorylation of ERK p42/44. Discussion BDNF regulation is complex and highly regulated. Pre-pregnancy/early maternal obesity adversely affects BDNF/TRKB signaling in the placenta in a sexually dimorphic manner. These data collectively suggest that induction of placental TRKB signaling could ameliorate the placental OB phenotype, thus improving perinatal outcome.

Epigenetic signatures associated with maternal body mass index or gestational weight gain: a systematic review

“…59 Prince et al also found a negative correlation between mature Brain derived neurotrophic factor (BDNF) protein and miR-210 expression (n = 52). 52 Two independent research groups examined placentas and found increased expression of miR-210 in placentas from pregnancies association with high ppBMI, yet only in pregnancies with female fetuses in female fetuses was found by two independent research groups. 51,52 In contrast, Tsamou et al (n = 215) 53 reported an inverse relationship between miR-210 and ppBMI, and their sample size was larger (n = 215).…”

Association between maternal overweight or obesity and cerebral palsy in children: A meta-analysis

“…Brain-derived neurotrophic factor (BDNF) is necessary for placental development and fetal growth. An additional study[ 48 ] found that pre-pregnancy/early maternal obesity adversely affects BDNF signaling and affects placental function and fetal growth. A study by Hatanaka et al[ 49 ] showed that maternal obesity leads to the abnormal development of the neuronal circuitry and the loss of synapses.…”

Sex and gender differences in developmental programming of metabolism

“…Furthermore, genome wide changes in methylation pattern have been observed in individuals who were in utero during the Dutch Hunger Winter, and the majority of these are sex specific, and could therefore explain the sexually dimorphic occurrence of obesity and other diseases in this cohort [111] . Further human studies have shown that maternal obesity alters the expression of miRNA210 in the placenta of female offspring specifically [112] , [113] . Due to the widespread changes seen in global DNA methylation state as a result of changes in early life nutrition, several groups have examined the potential of methyl donor supplementation in the maternal diet during obese or nutrient-restricted pregnancies as an intervention strategy.…”