PPARγΔ5, a Naturally Occurring Dominant-Negative Splice Isoform, Impairs PPARγ Function and Adipocyte Differentiation
Marianna Aprile,
Simona Cataldi,
Maria Rosaria Ambrosio,
Vittoria D’Esposito,
Koini Lim,
Arne Dietrich,
Matthias Blüher,
David Bousfield Savage,
Pietro Formisano,
Alfredo Ciccodicola,
Valerio Costa
Affiliations
Marianna Aprile
Institute of Genetics and Biophysics “Adriano Buzzati-Traverso,” CNR, Via P. Castellino 111, 80131 Naples, Italy
Simona Cataldi
Institute of Genetics and Biophysics “Adriano Buzzati-Traverso,” CNR, Via P. Castellino 111, 80131 Naples, Italy
Maria Rosaria Ambrosio
Department of Translational Medicine, University of Naples “Federico II” & URT “Genomic of Diabetes,” Institute of Experimental Endocrinology and Oncology “G. Salvatore,” CNR, Naples, Italy
Vittoria D’Esposito
Department of Translational Medicine, University of Naples “Federico II” & URT “Genomic of Diabetes,” Institute of Experimental Endocrinology and Oncology “G. Salvatore,” CNR, Naples, Italy
Koini Lim
University of Cambridge Metabolic Research Laboratories, Wellcome Trust–Medical Research Council Institute of Metabolic Science, Cambridge, UK
Arne Dietrich
Department of Surgery, University of Leipzig, Leipzig, Germany
Matthias Blüher
Department of Medicine, University of Leipzig, Leipzig, Germany
David Bousfield Savage
University of Cambridge Metabolic Research Laboratories, Wellcome Trust–Medical Research Council Institute of Metabolic Science, Cambridge, UK
Pietro Formisano
Department of Translational Medicine, University of Naples “Federico II” & URT “Genomic of Diabetes,” Institute of Experimental Endocrinology and Oncology “G. Salvatore,” CNR, Naples, Italy
Alfredo Ciccodicola
Institute of Genetics and Biophysics “Adriano Buzzati-Traverso,” CNR, Via P. Castellino 111, 80131 Naples, Italy; Department of Science and Technology, University of Naples “Parthenope,” Naples, Italy
Valerio Costa
Institute of Genetics and Biophysics “Adriano Buzzati-Traverso,” CNR, Via P. Castellino 111, 80131 Naples, Italy; Corresponding author
Summary: Peroxisome-proliferator-activated receptor γ (PPARγ) regulates glucose and lipid homeostasis, insulin signaling, and adipocyte differentiation. Here, we report the skipping of exon 5 as a legitimate splicing event generating PPARγΔ5, a previously unidentified naturally occurring truncated isoform of PPARγ, which lacks the entire ligand-binding domain. PPARγΔ5 is endogenously expressed in human adipose tissue and, during adipocyte differentiation, lacks ligand-dependent transactivation ability and acts as a dominant-negative isoform reducing PPARγ activity. Ligand-mediated PPARγ activation induces exon 5 skipping in a negative feedback loop, suggesting alternative splicing as a mechanism regulating PPARγ activity. PPARγΔ5 overexpression modifies the 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 overweight or obese and type 2 diabetic patients. From a functional perspective, PPARγΔ5 mimics PPARG dominant-negative mutated receptors, possibly contributing to adipose tissue dysfunction. These findings open an unexplored scenario in PPARG regulation and PPARγ-related diseases. : Aprile et al. report the identification of PPARγΔ5, a naturally occurring splicing isoform of PPARγ lacking the ligand-binding domain. PPARγΔ5 reduces the adipogenic potential of precursor cells through dominant-negative inhibition of PPARγ transactivation. PPARγΔ5 is highly expressed in adipose tissue and positively correlates with BMI in obese and diabetic patients. Keywords: PPARγ, alternative splicing, adipocyte differentiation, adipose tissue, obesity, insulin resistance, dominant-negative isoform