期刊
CELL REPORTS
卷 25, 期 6, 页码 1577-+出版社
CELL PRESS
DOI: 10.1016/j.celrep.2018.10.035
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资金
- Italian Ministry of Education, University and Research (MIUR) (Project National Operational Programme for Research and Competitiveness'' 2007-2013) [PON01_02460]
- FLAGSHIP InterOmics'' Project ASPIRE
- Italian MIUR organization, POR CAMPANIA FESR 2007/2013 TIMING Terapie Innovative di Malattie Infiammatorie croniche, metaboliche, Neoplastiche e Geriatriche''
- CNR organization, POR CAMPANIA FESR 2007/2013 TIMING Terapie Innovative di Malattie Infiammatorie croniche, metaboliche, Neoplastiche e Geriatriche''
- AIRC [IG 19001]
- Wellcome Trust [107064]
- European Foundation
Peroxisome-proliferator-activated receptorg gamma (PPAR gamma) regulates glucose and lipid homeostasis, insulin signaling, and adipocyte differentiation. Here, we report the skipping of exon 5 as a legitimate splicing event generating PPAR gamma Delta 5, a previously unidentified naturally occurring truncated isoform of PPAR gamma, which lacks the entire ligand-binding domain. PPAR gamma Delta 5 is endogenously expressed in human adipose tissue and, during adipocyte differentiation, lacks ligand-dependent transactivation ability and acts as a dominant-negative isoform reducing PPAR gamma activity. Ligand-mediated PPAR gamma activation induces exon 5 skipping in a negative feedback loop, suggesting alternative splicing as a mechanism regulating PPAR gamma activity. PPAR gamma Delta 5 overexpression modifies the PPAR gamma-induced transcriptional network, significantly impairing the differentiation ability of adipocyte precursor cells. Additionally, PPAR gamma Delta 5 expression in subcutaneous adipose tissue positively correlates with BMI in two independent cohorts of overweight or obese and type 2 diabetic patients. From a functional perspective, PPAR gamma Delta 5 mimics PPARG dominant-negative mutated receptors, possibly contributing to adipose tissue dysfunction. These findings open an unexplored scenario in PPARG regulation and PPAR gamma-related diseases.
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