Functional annotation of insulin-responsive genes in human adipocytes reveals PLCXD1 as a lipid storage regulator
Abstract
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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BibTeX
@article{frendocumbo2026functional,
title = {{Functional annotation of insulin-responsive genes in human adipocytes reveals PLCXD1 as a lipid storage regulator}},
author = {Scott Frendo-Cumbo and Danae Zareifi and Joëlle Bigay and Ana Rita Dias Araújo and Alina Lapp and Mattias Hansen and Teresa P Reindl and Beatrice Engelmann and Felix Klingelhuber and Lina Cordeddu and Merve Elmastas and Jutta Jalkanen and Gianluca Renzi and Océane Buvry and Delphine Debayle and Hanin Allos and Marta López Yus and Sophie Weinbrenner and Katharina Schormair and Oveis Jamialahmadi and Alastair G Kerr and Stefano Romeo and Ulrike Rolle-Kampczyk and Martin von Bergen and Lucas Massier and Natalie Krahmer and Romain Gautier and Bruno Antonny and Mikael Rydén and Niklas Mejhert},
journal = {Nature Communications},
year = {2026},
month = sep,
doi = {10.1038/s41467-026-77280-y},
url = {https://hal.science/hal-05762903v1},
note = {CC BY},
}
RIS
TY - JOUR
TI - Functional annotation of insulin-responsive genes in human adipocytes reveals PLCXD1 as a lipid storage regulator
AU - Scott Frendo-Cumbo
AU - Danae Zareifi
AU - Joëlle Bigay
AU - Ana Rita Dias Araújo
AU - Alina Lapp
AU - Mattias Hansen
AU - Teresa P Reindl
AU - Beatrice Engelmann
AU - Felix Klingelhuber
AU - Lina Cordeddu
AU - Merve Elmastas
AU - Jutta Jalkanen
AU - Gianluca Renzi
AU - Océane Buvry
AU - Delphine Debayle
AU - Hanin Allos
AU - Marta López Yus
AU - Sophie Weinbrenner
AU - Katharina Schormair
AU - Oveis Jamialahmadi
AU - Alastair G Kerr
AU - Stefano Romeo
AU - Ulrike Rolle-Kampczyk
AU - Martin von Bergen
AU - Lucas Massier
AU - Natalie Krahmer
AU - Romain Gautier
AU - Bruno Antonny
AU - Mikael Rydén
AU - Niklas Mejhert
PY - 2026
DA - 2026/09/03
JO - Nature Communications
DO - 10.1038/s41467-026-77280-y
UR - https://hal.science/hal-05762903v1
AB - 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.
SN - 2041-1723
SN - 2041-1723
ER -