PPAR gamma Delta 5, a Naturally Occurring Dominant-Negative Splice Isoform, Impairs PPAR gamma Function and Adipocyte Differentiation

Peroxisome-proliferator-activated receptor ? (PPAR?) 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??5, a previously unidentified naturally occurring truncated isoform of PPAR?, which lacks the entire ligand-binding domain. PPAR??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? activity. Ligand-mediated PPAR? activation induces exon 5 skipping in a negative feedback loop, suggesting alternative splicing as a mechanism regulating PPAR? activity. PPAR??5 overexpression modifies the 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 overweight or obese and type 2 diabetic patients. From a functional perspective, PPAR??5 mimics PPARG dominant-negative mutated receptors, possibly contributing to adipose tissue dysfunction. These findings open an unexplored scenario in PPARG regulation and PPAR?-related diseases.