Sexual dimorphism in activation of placental autophagy in obese women with evidence for fetal programming from a placenta-specific mouse model

Abstract

(2016) Sexual dimorphism in activation of placental autophagy in obese women with evidence for fetal programming from a placenta-specific mouse model, Autophagy, 12:5, 752-769, DOI: 10.1080/15548627.2016 ABSTRACTThe incidence of maternal obesity and its co-morbidities (diabetes, cardiovascular disease) continues to increase at an alarming rate, with major public health implications. In utero exposure to maternal obesity has been associated with development of cardiovascular and metabolic diseases in the offspring as a result of developmental programming. The placenta regulates maternal-fetal metabolism and shows significant changes in its function with maternal obesity. Autophagy is a cell-survival process, which is responsible for the degradation of damaged organelles and misfolded proteins. Here we show an activation of autophagosomal formation and autophagosome-lysosome fusion in placentas of males but not females from overweight (OW) and obese (OB) women vs. normal weight (NW) women. However, total autophagic activity in these placentas appeared to be decreased as it showed an increase in SQSTM1/p62 and a decrease in lysosomal biogenesis. A mouse model with a targeted deletion of the essential autophagy gene Atg7 in placental tissue showed significant placental abnormalities comparable to those seen in human placenta with maternal obesity. These included a decrease in expression of mitochondrial genes and antioxidants, and decreased lysosomal biogenesis. Strikingly, the knockout mice were developmentally programmed as they showed an increased sensitivity to high-fat diet-induced obesity, hyperglycemia, hyperinsulinemia, increased adiposity, and cardiac remodeling. In summary, our results indicate a sexual dimorphism in placental autophagy in response to maternal obesity. We also show that autophagy plays an important role in placental function and that inhibition of placental autophagy programs the offspring to obesity, and to metabolic and cardiovascular diseases.

Sexual dimorphism in the effect of maternal obesity on antioxidant defense mechanisms in the human placenta

“…We continue to demonstrate sexual dimorphism in the placenta as previously reported [18, 36]. Sexual dimorphism of antioxidants and markers of oxidative and nitrative stress has also been demonstrated in the human placenta in response to glucocorticoid exposure in preterm deliveries [37] where male placentas had a higher pro-oxidant state (increased protein carbonyls, lipid hydroperoxides, and nitrotyrosine), but lower glutathione peroxidase activity when compared to female placentas [37].…”

Sexual dimorphism in the fetal cardiac response to maternal nutrient restriction

“…Differences in gene expression between males and females have been previously reported in liver[88] and brain[89]. Our team have recently shown sex differences in expression of genes associated with autophagy and lysosomal function in the placenta [90]. Interestingly, a study in the mouse implicates HNF4α as transcription factor responsible for regulating genes that are preferentially expressed in each sex[91].…”

Role of autophagy in oocytogenesis, embryogenesis, implantation, and pathophysiology of pre‐eclampsia

“…These results suggested that sera from women with pre‐eclampsia do not activate autophagy. Pups delivered from placenta‐specific Atg7 knockout mice, which lacked Atg7 in the syncytiotrophoblast layer, were significantly smaller than those from wild types . Taken together, autophagy inhibition plays an important role in preventing pre‐eclampsia.…”