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Open AccessArticle

In-Vitro-Generated Hypertrophic-Like Adipocytes Displaying PPARG Isoforms Unbalance Recapitulate Adipocyte Dysfunctions In Vivo

1
Institute of Genetics and Biophysics “Adriano Buzzati-Traverso,” CNR, Via P. Castellino 111, 80131 Naples, Italy
2
Department of Translational Medicine, University of Naples “Federico II” & URT “Genomic of Diabetes,” Institute of Experimental Endocrinology and Oncology “G. Salvatore,” CNR, Via Pansini 5, 80131 Naples, Italy
3
Institute of Biochemistry and Cell Biology CNR, Via P. Castellino 111, 80131 Naples, Italy
4
Department of Medicine, University of Leipzig, 4289 Leipzig, Germany
5
Department of Science and Technology, University of Naples “Parthenope,” 80131 Naples, Italy
*
Authors to whom correspondence should be addressed.
Co-first authors.
Lead Contacts.
Cells 2020, 9(5), 1284; https://doi.org/10.3390/cells9051284
Received: 30 April 2020 / Revised: 18 May 2020 / Accepted: 19 May 2020 / Published: 21 May 2020
(This article belongs to the Special Issue The Role of PPARs in Disease)
Reduced neo-adipogenesis and dysfunctional lipid-overloaded adipocytes are hallmarks of hypertrophic obesity linked to insulin resistance. Identifying molecular features of hypertrophic adipocytes requires appropriate in vitro models. We describe the generation of a model of human hypertrophic-like adipocytes directly comparable to normal adipose cells and the pathologic evolution toward hypertrophic state. We generate in vitro hypertrophic cells from mature adipocytes, differentiated from human mesenchymal stem cells. Combining optical, confocal, and transmission electron microscopy with mRNA/protein quantification, we characterize this cellular model, confirming specific alterations also in subcutaneous adipose tissue. Specifically, we report the generation and morphological/molecular characterization of human normal and hypertrophic-like adipocytes. The latter displays altered morphology and unbalance between canonical and dominant negative (PPARGΔ5) transcripts of PPARG, paralleled by reduced expression of PPARγ targets, including GLUT4. Furthermore, the unbalance of PPARγ isoforms associates with GLUT4 down-regulation in subcutaneous adipose tissue of individuals with overweight/obesity or impaired glucose tolerance/type 2 diabetes, but not with normal weight or glucose tolerance. In conclusion, the hypertrophic-like cells described herein are an innovative tool for studying molecular dysfunctions in hypertrophic obesity and the unbalance between PPARγ isoforms associates with down-regulation of GLUT4 and other PPARγ targets, representing a new hallmark of hypertrophic adipocytes.
Keywords: hypertrophic adipocytes; PPARG isoforms; PPARG splicing; dominant-negative isoform; in vitro adipocytes; adipogenesis; hypertrophic obesity; insulin-resistance hypertrophic adipocytes; PPARG isoforms; PPARG splicing; dominant-negative isoform; in vitro adipocytes; adipogenesis; hypertrophic obesity; insulin-resistance
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MDPI and ACS Style

Aprile, M.; Cataldi, S.; Perfetto, C.; Ambrosio, M.R.; Italiani, P.; Tatè, R.; Blüher, M.; Ciccodicola, A.; Costa, V. In-Vitro-Generated Hypertrophic-Like Adipocytes Displaying PPARG Isoforms Unbalance Recapitulate Adipocyte Dysfunctions In Vivo. Cells 2020, 9, 1284.

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