PPARγΔ5, a Naturally Occurring Dominant-Negative Splice Isoform, Impairs PPARγ Function and Adipocyte Differentiation

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.