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Circulating irisin concentration increases throughout human pregnancy. In pregnancy disorders such as preeclampsia and gestational diabetes mellitus, circulating irisin levels are reduced compared to healthy controls. To date, there are no data on the role and molecular function of irisin in the human placenta or its contribution to pathophysiology. Aberrant trophoblast differentiation is involved in the pathophysiology of preeclampsia. The current study aimed to assess the molecular effects of irisin on trophoblast differentiation and function. First\u2010trimester placental explants were cultured and treated with low (10\u2009nM) and high (50\u2009nM) physiological doses of irisin. Treatment with irisin dose\u2010dependently increased both in vitro placental outgrowth (on Matrigel\u2122) and trophoblast cell\u2010cell fusion. Adenosine monophosphate\u2010activated protein kinase (AMPK) signaling, an important regulator of cellular energy homeostasis that is involved in trophoblast differentiation and pathology, was subsequently investigated. Here, irisin exposure induced placental AMPK activation. To determine the effects of irisin on trophoblast differentiation, two trophoblast\u2010like cell lines, HTR\u20108\/SVneo and BeWo, were treated with irisin and\/or a specific AMPK inhibitor (Compound C). Irisin\u2010induced AMPK phosphorylation in HTR\u20108\/SVneo cells. Additionally, as part of the differentiation process, integrin switching from \u03b16 to \u03b11 occurred as well as increased invasiveness. Overall, irisin promoted differentiation in villous and extravillous cell\u2010based models via AMPK pathway activation. These findings provide evidence that exposure to irisin promotes differentiation and improves trophoblast functions in the human placenta that are affected in abnormal placentation.<\/jats:p>","DOI":"10.1002\/jcp.29613","type":"journal-article","created":{"date-parts":[[2020,2,5]],"date-time":"2020-02-05T10:40:08Z","timestamp":1580899208000},"page":"7146-7158","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["Irisin induces trophoblast differentiation via AMPK activation in the human placenta"],"prefix":"10.1002","volume":"235","author":[{"given":"Sascha","family":"Drewlo","sequence":"first","affiliation":[{"name":"Department of Obstetrics, Gynecology and Reproductive Biology, College of Human Medicine Michigan State University Grand Rapids Michigan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugenia","family":"Johnson","sequence":"additional","affiliation":[{"name":"Department of Obstetrics, 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