Tropomyosin Receptor Kinase B Agonist, 7, 8-Dihydroxyflavone, Improves Mitochondrial Respiration in Placentas From Obese Women. (March 2018)

• Record Type: Journal Article
• Authors: Prince, Calais S.; Maloyan, Alina; Myatt, Leslie
• Is Part Of: Reproductive sciences. Volume 25:Number 3(2018:Mar.)
• Page Start: 452
• Page End: 462
• Publication Date: 2018-03
• Subjects: mitochondrial respiration -- neurotrophin -- obesity -- placenta; Reproductive health -- Periodicals; Reproduction -- Periodicals; 612.6
• DOI: 10.1177/1933719117716776
• Languages: English
• ISSNs: 1933-7191

Abstract

Maternal obesity negatively impacts the placenta, being associated with increased inflammation, decreased mitochondrial respiration, decreased expression of brain-derived neurotrophic factor (BDNF), and its receptor, tropomyosin receptor kinase B (TRKB). TRKB induction by 7, 8-dihydroxyflavone (7, 8-DHF) improves energy expenditure in an obesity animal model. We hypothesized that TRKB activation would improve mitochondrial respiration in trophoblasts from placentas of obese women. Placentas were collected from lean (pre-pregnancy BMI < 25) and obese (pre-pregnancy BMI > 30) women at term following cesarean section delivery without labor. Cytotrophoblasts were isolated and plated, permitting syncytialization. At 72 hours, syncytiotrophoblasts (STs) were treated for 1 hour with 7, 8-DHF (10 nM–10 M), TRKB antagonists (ANA-12 (10 nM–1 M), Cyclotraxin B (1 nM–1M)), or vehicle. Mitochondrial respiration was measured using the XF24 Extracellular Flux Analyzer. TRKB, MAPK, and PGC1α were measured using Western blotting. Maternal obesity was associated with decreased mitochondrial respiration in STs; however, 7, 8-DHF increased basal, ATP-coupled, maximal, spare capacity, and nonmitochondrial respiration. A 10 μM dose of 7, 8-DHF reduced spare capacity in STs from lean women, with no effect on other respiration parameters. 7, 8-DHF had no effect on TRKB phosphorylation; however, there was a concentration-dependent decrease of p38 MAPK phosphorylation and increase of PGC1α in STs from obese, but not in lean women. TRKB antagonism attenuated ATP-coupled respiration, maximal respiration, and spare capacity in STs from lean and obese women. 7, 8-DHF improves mitochondrial respiration in STs from obese women, suggesting that the obese phenotype in the placenta can be rescued by TRKB activation.