title: Sexual dimorphism in activation of placental autophagy in obese women with evidence for fetal programming from a placenta-specific mouse model.
abstract: The 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.
authors.affiliation: a Center for Pregnancy and Newborn Research , Department of Obstetrics and Gynecology , University of Texas Health Science Center , San Antonio , TX , USA.
authors.forename: Sribalasubashini
authors.initials: S
authors.lastname: Muralimanoharan
authors.affiliation: b The Metabolomics Core Facility, Institutional Mass Spectrometry Laboratory, University of Texas Health Science Center , San Antonio , TX , USA.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Gao
authors.affiliation: b The Metabolomics Core Facility, Institutional Mass Spectrometry Laboratory, University of Texas Health Science Center , San Antonio , TX , USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Weintraub
authors.affiliation: a Center for Pregnancy and Newborn Research , Department of Obstetrics and Gynecology , University of Texas Health Science Center , San Antonio , TX , USA.|c Department of Ob/Gyn , Oregon Health and Science University , Portland , OR , USA.
authors.forename: Leslie
authors.initials: L
authors.lastname: Myatt
authors.affiliation: a Center for Pregnancy and Newborn Research , Department of Obstetrics and Gynecology , University of Texas Health Science Center , San Antonio , TX , USA.|d Knight Cardiovascular Institute, Oregon Health and Science University , Portland , OR , USA.
authors.forename: Alina
authors.initials: A
authors.lastname: Maloyan
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics / Q000502:physiology*; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D005260:Female; D047109:Fetal Development / Q000235:genetics*; D006801:Humans; D018345:Mice, Knockout; D009765:Obesity / Q000150:complications* / Q000378:metabolism; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D012727:Sex Characteristics
keywords: fetal programming; high fat diet; maternal obesity; metabolomics; placental function; sex differences