Trophoblast-specific overexpression of adiponectin receptor 2 causes fetal growth restriction in pregnant mice.

Autor: Dumolt JH; Division of Reproductive Sciences, Department of Obstetrics & Gynecology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA., Rosario FJ; Division of Reproductive Sciences, Department of Obstetrics & Gynecology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA., Barentsen K; Division of Reproductive Sciences, Department of Obstetrics & Gynecology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA., Urschitz J; Division of Reproductive Sciences, Department of Obstetrics & Gynecology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.; Institute for Biogenesis Research, University of Hawaii, Honolulu, Hawaii, USA., Powell TL; Division of Reproductive Sciences, Department of Obstetrics & Gynecology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.; Section of Neonatology, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA., Jansson T; Division of Reproductive Sciences, Department of Obstetrics & Gynecology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
Jazyk: angličtina
Zdroj: FASEB journal : official publication of the Federation of American Societies for Experimental Biology [FASEB J] 2024 Oct 15; Vol. 38 (19), pp. e70100.
DOI: 10.1096/fj.202302143R
Abstrakt: Maternal obesity in pregnancy is strongly associated with complications such as fetal overgrowth and infants of obese mothers have an increased risk to develop obesity, diabetes, and cardiovascular disease later in life. However, the underlying mechanisms are not well established. Circulating levels of adiponectin are low in obese pregnant women and maternal circulating adiponectin is negatively associated with birth weight. We have reported that normalizing maternal adiponectin in obese pregnant mice prevents placental dysfunction, fetal overgrowth, and programming of offspring cardio-metabolic disease. However, the mechanistic link between maternal adiponectin, placental function, and fetal growth remains to be established. We hypothesized that trophoblast-specific overexpression of the adiponectin receptor 2 (Adipor2) in healthy pregnant mice inhibits placental mTORC1 signaling and nutrient transport, resulting in fetal growth restriction. Using lentiviral transduction of blastocysts with a mammalian gene expression lentiviral vector for up-regulation of Adipor2 (Adipor2-OX), we achieved a ~ 3-fold increase in placenta Adipor2 mRNA levels and a 2-fold increase of the ADIPOR2 protein in the trophoblast plasma membrane. Placenta-specific Adipor2-OX increased placental peroxisome proliferator-activated receptor-α phosphorylation, ceramide synthase expression and ceramide concentrations. Furthermore, Adipor2-OX inhibited placental mTORC1 signaling and reduced in vivo placental transport of glucose and amino acids. Lastly, Adipor2-OX reduced fetal weight by 11%. These data provide mechanistic evidence that placental Adipor2 signaling directly affects fetal growth. We propose that low circulating adiponectin in maternal obesity causes fetal overgrowth and programs the offspring for cardio-metabolic disease mediated by a direct effect on placental function.
(© 2024 Federation of American Societies for Experimental Biology.)
Databáze: MEDLINE
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