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Frendo-Cumbo, S.* ; Zareifi, D.* ; Bigay, J.* ; Dias Araújo, A.R.* ; Lapp, A.* ; Hansen, M.* ; Reindl, T.P.* ; Engelmann, B.* ; Klingelhuber, F. ; Cordeddu, L.* ; Elmastas, M.* ; Jalkanen, J.* ; Renzi, G.* ; Buvry, O.* ; Debayle, D.* ; Allos, H.* ; López Yus, M.* ; Weinbrenner, S. ; Schormair, K.* ; Jamialahmadi, O.* ; Kerr, A.G.* ; Romeo, S.* ; Rolle-Kampczyk, U.* ; von Bergen, M.* ; Massier, L. ; Krahmer, N. ; Gautier, R.* ; Antonny, B.* ; Rydén, M.* ; Mejhert, N.*

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

Nat. Commun. 17:9458 (2026)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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.
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Publication type Article: Journal article
Document type Scientific Article
ISSN (print) / ISBN 2041-1723
e-ISSN 2041-1723
Journal Nature Communications
Quellenangaben Volume: 17, Issue: 1, Pages: , Article Number: 9458 Supplement: ,
Publisher Springer
Publishing Place London
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes and Obesity (IDO)
Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG)
Grants Vetenskapsrådet (Swedish Research Council)