PPARγΔ5, a Naturally Occurring Dominant-Negative Splice Isoform, Impairs PPARγ Function and Adipocyte Differentiation
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 i...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2018-11-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124718316115 |
| _version_ | 1818947102823153664 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Marianna Aprile |
| collection | DOAJ |
| description | 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 |
| first_indexed | 2024-12-20T08:25:34Z |
| format | Article |
| id | doaj.art-02e891669fc44191935cad2f537773c1 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-20T08:25:34Z |
| publishDate | 2018-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-02e891669fc44191935cad2f537773c12022-12-21T19:46:51ZengElsevierCell Reports2211-12472018-11-0125615771592.e6PPARγΔ5, a Naturally Occurring Dominant-Negative Splice Isoform, Impairs PPARγ Function and Adipocyte DifferentiationMarianna Aprile0Simona Cataldi1Maria Rosaria Ambrosio2Vittoria D’Esposito3Koini Lim4Arne Dietrich5Matthias Blüher6David Bousfield Savage7Pietro Formisano8Alfredo Ciccodicola9Valerio Costa10Institute of Genetics and Biophysics “Adriano Buzzati-Traverso,” CNR, Via P. Castellino 111, 80131 Naples, ItalyInstitute of Genetics and Biophysics “Adriano Buzzati-Traverso,” CNR, Via P. Castellino 111, 80131 Naples, ItalyDepartment of Translational Medicine, University of Naples “Federico II” & URT “Genomic of Diabetes,” Institute of Experimental Endocrinology and Oncology “G. Salvatore,” CNR, Naples, ItalyDepartment of Translational Medicine, University of Naples “Federico II” & URT “Genomic of Diabetes,” Institute of Experimental Endocrinology and Oncology “G. Salvatore,” CNR, Naples, ItalyUniversity of Cambridge Metabolic Research Laboratories, Wellcome Trust–Medical Research Council Institute of Metabolic Science, Cambridge, UKDepartment of Surgery, University of Leipzig, Leipzig, GermanyDepartment of Medicine, University of Leipzig, Leipzig, GermanyUniversity of Cambridge Metabolic Research Laboratories, Wellcome Trust–Medical Research Council Institute of Metabolic Science, Cambridge, UKDepartment of Translational Medicine, University of Naples “Federico II” & URT “Genomic of Diabetes,” Institute of Experimental Endocrinology and Oncology “G. Salvatore,” CNR, Naples, ItalyInstitute 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, ItalyInstitute of Genetics and Biophysics “Adriano Buzzati-Traverso,” CNR, Via P. Castellino 111, 80131 Naples, Italy; Corresponding authorSummary: 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 isoformhttp://www.sciencedirect.com/science/article/pii/S2211124718316115 |
| spellingShingle | 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 PPARγΔ5, a Naturally Occurring Dominant-Negative Splice Isoform, Impairs PPARγ Function and Adipocyte Differentiation Cell Reports |
| title | PPARγΔ5, a Naturally Occurring Dominant-Negative Splice Isoform, Impairs PPARγ Function and Adipocyte Differentiation |
| title_full | PPARγΔ5, a Naturally Occurring Dominant-Negative Splice Isoform, Impairs PPARγ Function and Adipocyte Differentiation |
| title_fullStr | PPARγΔ5, a Naturally Occurring Dominant-Negative Splice Isoform, Impairs PPARγ Function and Adipocyte Differentiation |
| title_full_unstemmed | PPARγΔ5, a Naturally Occurring Dominant-Negative Splice Isoform, Impairs PPARγ Function and Adipocyte Differentiation |
| title_short | PPARγΔ5, a Naturally Occurring Dominant-Negative Splice Isoform, Impairs PPARγ Function and Adipocyte Differentiation |
| title_sort | pparγδ5 a naturally occurring dominant negative splice isoform impairs pparγ function and adipocyte differentiation |
| url | http://www.sciencedirect.com/science/article/pii/S2211124718316115 |
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