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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\u2010metabolic disease. However, the mechanistic link between maternal adiponectin, placental function, and fetal growth remains to be established. We hypothesized that trophoblast\u2010specific overexpression of the adiponectin receptor 2 (\n                    <jats:italic>Adipor2)<\/jats:italic>\n                    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\u2010regulation of\n                    <jats:italic>Adipor2<\/jats:italic>\n                    (\n                    <jats:italic>Adipor2<\/jats:italic>\n                    \u2010OX), we achieved a\u2009~\u20093\u2010fold increase in placenta\n                    <jats:italic>Adipor2 mRNA levels<\/jats:italic>\n                    and a 2\u2010fold increase of the ADIPOR2 protein in the trophoblast plasma membrane. Placenta\u2010specific\n                    <jats:italic>Adipor2<\/jats:italic>\n                    \u2010OX increased placental peroxisome proliferator\u2010activated receptor\u2010\u03b1 phosphorylation, ceramide synthase expression and ceramide concentrations. Furthermore,\n                    <jats:italic>Adipor2\u2010<\/jats:italic>\n                    OX inhibited placental mTORC1 signaling and reduced in\u00a0vivo placental transport of glucose and amino acids. Lastly,\n                    <jats:italic>Adipor2<\/jats:italic>\n                    \u2010OX reduced fetal weight by 11%. These data provide mechanistic evidence that placental\n                    <jats:italic>Adipor2<\/jats:italic>\n                    signaling directly affects fetal growth. We propose that low circulating adiponectin in maternal obesity causes fetal overgrowth and programs the offspring for cardio\u2010metabolic disease mediated by a direct effect on placental function.\n                  <\/jats:p>","DOI":"10.1096\/fj.202302143r","type":"journal-article","created":{"date-parts":[[2024,10,10]],"date-time":"2024-10-10T10:53:00Z","timestamp":1728557580000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Trophoblast\u2010specific overexpression of adiponectin receptor 2 causes fetal growth restriction in pregnant mice"],"prefix":"10.1096","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7974-3418","authenticated-orcid":false,"given":"Jerad H.","family":"Dumolt","sequence":"first","affiliation":[{"name":"Division of Reproductive Sciences, Department of Obstetrics &amp; Gynecology University of Colorado Anschutz Medical Campus  Aurora Colorado 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