{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T09:14:44Z","timestamp":1780391684500,"version":"3.54.1"},"reference-count":59,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2021,12,24]],"date-time":"2021-12-24T00:00:00Z","timestamp":1640304000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003407","name":"Ministero dell\u2019Istruzione, dell\u2019Universit\u00e0 e della Ricerca","doi-asserted-by":"publisher","award":["PON Ricerca e Innovazione 2014\u20132020, PON Ars01_01270 \u201cInnovative Device For SHAping the Risk of Diabetes\u201d (IDF SHARID)"],"award-info":[{"award-number":["PON Ricerca e Innovazione 2014\u20132020, PON Ars01_01270 \u201cInnovative Device For SHAping the Risk of Diabetes\u201d (IDF SHARID)"]}],"id":[{"id":"10.13039\/501100003407","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001648","name":"European Foundation for the Study of Diabetes","doi-asserted-by":"publisher","award":["Boehringer Ingelheim European Research Programme in Microvascular Complications of Diabetes"],"award-info":[{"award-number":["Boehringer Ingelheim European Research Programme in Microvascular Complications of Diabetes"]}],"id":[{"id":"10.13039\/501100001648","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Low-grade chronic inflammation and reduced differentiation capacity are hallmarks of hypertrophic adipose tissue (AT) and key contributors of insulin resistance. We identified PPARG\u03945 as a dominant-negative splicing isoform overexpressed in the AT of obese\/diabetic patients able to impair adipocyte differentiation and PPAR\u03b3 activity in hypertrophic adipocytes. Herein, we investigate the impact of macrophage-secreted pro-inflammatory factors on PPARG splicing, focusing on PPARG\u03945. We report that the epididymal AT of LPS-treated mice displays increased Pparg\u03945\/cPparg ratio and reduced expression of Pparg-regulated genes. Interestingly, pro-inflammatory factors secreted from murine and human pro-inflammatory macrophages enhance the PPARG\u03945\/cPPARG ratio in exposed adipogenic precursors. TNF\u03b1 is identified herein as factor able to alter PPARG splicing\u2014increasing PPARG\u03945\/cPPARG ratio\u2014through PI3K\/Akt signaling and SRp40 splicing factor. In line with in vitro data, TNFA expression is higher in the SAT of obese (vs. lean) patients and positively correlates with PPARG\u03945 levels. In conclusion, our results indicate that inflammatory factors secreted by metabolically-activated macrophages are potent stimuli that modulate the expression and splicing of PPARG. The resulting imbalance between canonical and dominant negative isoforms may crucially contribute to impair PPAR\u03b3 activity in hypertrophic AT, exacerbating the defective adipogenic capacity of precursor cells.<\/jats:p>","DOI":"10.3390\/cells11010042","type":"journal-article","created":{"date-parts":[[2021,12,24]],"date-time":"2021-12-24T08:38:46Z","timestamp":1640335126000},"page":"42","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["TNF\u03b1 Mediates Inflammation-Induced Effects on PPARG Splicing in Adipose Tissue and Mesenchymal Precursor Cells"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6113-5812","authenticated-orcid":false,"given":"Simona","family":"Cataldi","sequence":"first","affiliation":[{"name":"Institute of Genetics and Biophysics \u2018\u2018Adriano Buzzati-Traverso\u2019\u2019, CNR, Via P. Castellino 111, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7055-4306","authenticated-orcid":false,"given":"Marianna","family":"Aprile","sequence":"additional","affiliation":[{"name":"Institute of Genetics and Biophysics \u2018\u2018Adriano Buzzati-Traverso\u2019\u2019, CNR, Via P. Castellino 111, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Melillo","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Cell Biology, CNR, Via P. Castellino 111, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"In\u00e8s","family":"Mucel","sequence":"additional","affiliation":[{"name":"Universit\u00e9 C\u00f4te d\u2019Azur, Inserm UMR1065, C3M, Team Cellular and Molecular Pathophysiology of Obesity, 06204 Nice, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Giorgetti-Peraldi","sequence":"additional","affiliation":[{"name":"Universit\u00e9 C\u00f4te d\u2019Azur, Inserm UMR1065, C3M, Team Cellular and Molecular Pathophysiology of Obesity, 06204 Nice, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mireille","family":"Cormont","sequence":"additional","affiliation":[{"name":"Universit\u00e9 C\u00f4te d\u2019Azur, Inserm UMR1065, C3M, Team Cellular and Molecular Pathophysiology of Obesity, 06204 Nice, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9830-2733","authenticated-orcid":false,"given":"Paola","family":"Italiani","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Cell Biology, CNR, Via P. Castellino 111, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0208-2065","authenticated-orcid":false,"given":"Matthias","family":"Bl\u00fcher","sequence":"additional","affiliation":[{"name":"Medical Department III-Endocrinology, Nephrology and Rheumatology, University of Leipzig, 04103 Leipzig, Germany"},{"name":"Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum M\u00fcnchen at the University of Leipzig and University Hospital Leipzig, Philipp-Rosenthal-Str. 27, 04103 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1782-1318","authenticated-orcid":false,"given":"Jean-Fran\u00e7ois","family":"Tanti","sequence":"additional","affiliation":[{"name":"Universit\u00e9 C\u00f4te d\u2019Azur, Inserm UMR1065, C3M, Team Cellular and Molecular Pathophysiology of Obesity, 06204 Nice, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9924-1482","authenticated-orcid":false,"given":"Alfredo","family":"Ciccodicola","sequence":"additional","affiliation":[{"name":"Institute of Genetics and Biophysics \u2018\u2018Adriano Buzzati-Traverso\u2019\u2019, CNR, Via P. Castellino 111, 80131 Naples, Italy"},{"name":"Department of Science and Technology, University of Naples \u2018\u2018Parthenope\u2019\u2019, 80143 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7294-6933","authenticated-orcid":false,"given":"Valerio","family":"Costa","sequence":"additional","affiliation":[{"name":"Institute of Genetics and Biophysics \u2018\u2018Adriano Buzzati-Traverso\u2019\u2019, CNR, Via P. Castellino 111, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,24]]},"reference":[{"key":"ref_1","first-page":"405","article-title":"Metabolically Healthy Obesity","volume":"41","year":"2020","journal-title":"Endocr. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1111\/obr.12551","article-title":"Obesity: A chronic relapsing progressive disease process. 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