PPARγΔ5, a new naturally occurring dominant negative splice isoform impairs PPARγ function and adipocyte differentiation. Identification of a new PPARG isoform

PPARγ regulates glucose and lipid homeostasis, insulin signaling and adipocyte differentiation. Here we report the skipping of exon 5 as legitimate splicing event generating PPARγΔ5, a new truncated isoform lacking the ligand binding domain. PPARγΔ5 is endogenously expressed in human adipose tissue and during adipocyte differentiation, lacks the ligand-dependent transactivation ability and acts as dominant negative reducing PPARγ activity. Ligand-mediated PPARγ activation induces exon 5 skipping in a negative feedback loop, suggesting alternative splicing as a new mechanism regulating PPARγ activity. PPARγΔ5 over-expression modifies PPARγ-induced transcriptional network, significantly impairing the differentiation ability of adipocyte precursor cells. Additionally, PPARγΔ5 expression in subcutaneous adipose tissue positively correlates with BMI in two independent cohorts of obese and diabetic patients. From a functional perspective PPARγΔ5 mimics PPARG dominant negative mutated receptors, possibly contributing to adipose tissue dysfunctions. These findings open unexplored scenario in PPARG regulation and PPARγ-related diseases