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In the present study, we identified PLD1 as a negative regulator of adipogenic differentiation. We showed that PLD activity was downregulated by both 3-Isobutyl-1-methylxanthine (IBMX) and insulin upon induction of differentiation in 3T3-L1 adipogenic cells. In line with this observation, PLD activity decreased in both high fat diet (HFD)-fed mice and ob\/ob mice. We also found that differentiation of 3T3-L1 preadipocytes was enhanced by the depletion of PLD1 levels or inhibition of PLD1 activity by VU0155069, a PLD1-specific inhibitor. Conversely, treatment with phosphatidic acid (PA), a PLD product, and overexpression of PLD1 both caused a decrease in adipogenic differentiation. Moreover, the elevated differentiation in PLD1-knockdown 3T3-L1 cells was reduced by either PA treatment or PLD1 expression, confirming negative roles of PLD1 and PA in adipogenic differentiation. Further investigation revealed that PA displaces DEP domain-containing mTOR-interacting protein (DEPTOR) from mTORC1, which subsequently phosphorylates insulin receptor substrate-1 (IRS-1) at serine 636\/639 in 3T3-L1 cells. Taken together, our findings provide convincing evidence for a direct role of PLD1 in adipogenic differentiation by regulating IRS-1 phosphorylation at serine 636\/639 through DEPTOR displacement and mTOR activation.<\/jats:p>","DOI":"10.1038\/srep36968","type":"journal-article","created":{"date-parts":[[2016,11,22]],"date-time":"2016-11-22T09:57:35Z","timestamp":1479808655000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["PLD1 regulates adipogenic differentiation through mTOR - IRS-1 phosphorylation at serine 636\/639"],"prefix":"10.1038","volume":"6","author":[{"given":"Hae-In","family":"Song","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mee-Sup","family":"Yoon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,11,22]]},"reference":[{"key":"BFsrep36968_CR1","doi-asserted-by":"publisher","first-page":"555","DOI":"10.1093\/ajcn\/81.3.555","volume":"81","author":"Y Wang","year":"2005","unstructured":"Wang, Y., Rimm, E. 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