Functional annotation of insulin-responsive genes in human adipocytes reveals PLCXD1 as a lipid storage regulator
- 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
2026-09-03
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.