Scott Frendo-Cumbo, Danae Zareifi, Joëlle Bigay, Ana Rita Dias Araújo, Alina Lapp, Mattias Hansen, Teresa P Reindl, Beatrice Engelmann, Felix Klingelhuber, Lina Cordeddu, Merve Elmastas, Jutta Jalkanen, Gianluca Renzi, Océane Buvry, Delphine Debayle, Hanin Allos, Marta López Yus, Sophie Weinbrenner, Katharina Schormair, Oveis Jamialahmadi, Alastair G Kerr, Stefano Romeo, Ulrike Rolle-Kampczyk, Martin von Bergen, Lucas Massier, Natalie Krahmer, Romain Gautier, Bruno Antonny, Mikael Rydén, Niklas Mejhert
Insulin-driven gene regulation is central to adipocyte function, but the roles of many of these genes in lipid metabolism remain unclear. Here, we integrate three transcriptomic datasets to identify insulin-responsive genes and define their functions in human adipocytes using a multiparametric lipid turnover screen. Our results reveal four major clusters involved in metabolic regulation, transcription, stress responses, and lipid metabolism. Among lipid-related hits, phospholipase C X domain-containing protein-1 (PLCXD1) emerges as a regulator of insulin-stimulated lipogenesis, without affecting lipolysis or adipogenesis. PLCXD1 is induced by insulin via sterol regulatory element-binding proteins, a response attenuated in insulin-resistant states. This atypical phospholipase is genetically associated with fat mass-related traits, localizes to early endosomes and catalyzes phosphatidylinositol conversion into diacylglycerol. Through structure-function analyses, we show that PLCXD1 catalytic activity is required for insulin-stimulated lipogenesis. Altogether, our results uncover PLCXD1 as an insulin-regulated enzyme linking endosomal phosphoinositide metabolism to lipid storage in adipocytes.