ena-STUDY-NATIONAL RESEARCH COUNCIL (CNR)-27-09-2018-12:31:57:152-684
PPAR??5, a new naturally occurring dominant negative splice isoform impairs PPAR? function and adipocyte differentiation
PPAR? regulates glucose and lipid homeostasis, insulin signaling and adipocyte differentiation. Here we report the skipping of exon 5 as legitimate splicing event generating PPAR??5, a new truncated isoform lacking the ligand binding domain. PPAR??5 is endogenously expressed in human adipose tissue and during adipocyte differentiation, lacks the ligand-dependent transactivation ability and acts as dominant negative reducing PPAR? activity. Ligand-mediated PPAR? activation induces exon 5 skipping in a negative feedback loop, suggesting alternative splicing as a new mechanism regulating PPAR? activity. PPAR??5 over-expression modifies PPAR?-induced transcriptional network, significantly impairing the differentiation ability of adipocyte precursor cells. Additionally, PPAR??5 expression in subcutaneous adipose tissue positively correlates with BMI in two independent cohorts of obese and diabetic patients. From a functional perspective PPAR??5 mimics PPARG dominant negative mutated receptors, possibly contributing to adipose tissue dysfunctions. These findings open unexplored scenario in PPARG regulation and PPAR?-related diseases
PPAR? regulates glucose and lipid homeostasis, insulin signaling and adipocyte differentiation. Here we report the skipping of exon 5 as legitimate splicing event generating PPAR??5, a new truncated isoform lacking the ligand binding domain. PPAR??5 is endogenously expressed in human adipose tissue and during adipocyte differentiation, lacks the ligand-dependent transactivation ability and acts as dominant negative reducing PPAR? activity. Ligand-mediated PPAR? activation induces exon 5 skipping in a negative feedback loop, suggesting alternative splicing as a new mechanism regulating PPAR? activity. PPAR??5 over-expression modifies PPAR?-induced transcriptional network, significantly impairing the differentiation ability of adipocyte precursor cells. Additionally, PPAR??5 expression in subcutaneous adipose tissue positively correlates with BMI in two independent cohorts of obese and diabetic patients. From a functional perspective PPAR??5 mimics PPARG dominant negative mutated receptors, possibly contributing to adipose tissue dysfunctions. These findings open unexplored scenario in PPARG regulation and PPAR?-related diseases