Chen_2025_Sci.Adv_11_eads5963

Adipocyte lipolysis controls systemic energy levels and metabolic homeostasis. Lipolysis is regulated by posttranslational modifications of key lipolytic enzymes. However, less is known about the transcriptional mechanisms that regulate lipolysis. Here, we identify interferon regulatory factor-2 binding protein 2 (IRF2BP2) as a transcriptional repressor of adipocyte lipolysis. Deletion of IRF2BP2 in human adipocytes increases lipolysis without affecting glucose uptake, whereas IRF2BP2 overexpression decreases lipolysis. RNA sequencing, and chromatin immunoprecipitation sequencing analyses show that IRF2BP2 represses lipolysis-related genes, including LIPE, which encodes hormone sensitive lipase, the rate-limiting enzyme in lipolysis. Adipocyte-selective deletion of Irf2bp2 in mice increases Lipe expression and free fatty acid levels, resulting in adipose tissue inflammation and glucose intolerance. Together, these findings demonstrate that IRF2BP2 restrains adipocyte lipolysis and opens avenues to target lipolysis for the treatment of metabolic disease.