Cited4 is a sex‐biased mediator of the antidiabetic glitazone response in adipocyte progenitors
Abstract Most antidiabetic drugs treat disease symptoms rather than adipose tissue dysfunction as a key pathogenic cause in the metabolic syndrome and type 2 diabetes. Pharmacological targeting of adipose tissue through the nuclear receptor PPARg, as exemplified by glitazone treatments, mediates eff...
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| Format: | Article |
| Language: | English |
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Springer Nature
2018-07-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201708613 |
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| author | Irem Bayindir‐Buchhalter Gretchen Wolff Sarah Lerch Tjeerd Sijmonsma Maximilian Schuster Jan Gronych Adrian T Billeter Rohollah Babaei Damir Krunic Lars Ketscher Nadine Spielmann Martin Hrabe de Angelis Jorge L Ruas Beat P Müller‐Stich Mathias Heikenwalder Peter Lichter Stephan Herzig Alexandros Vegiopoulos |
| author_facet | Irem Bayindir‐Buchhalter Gretchen Wolff Sarah Lerch Tjeerd Sijmonsma Maximilian Schuster Jan Gronych Adrian T Billeter Rohollah Babaei Damir Krunic Lars Ketscher Nadine Spielmann Martin Hrabe de Angelis Jorge L Ruas Beat P Müller‐Stich Mathias Heikenwalder Peter Lichter Stephan Herzig Alexandros Vegiopoulos |
| author_sort | Irem Bayindir‐Buchhalter |
| collection | DOAJ |
| description | Abstract Most antidiabetic drugs treat disease symptoms rather than adipose tissue dysfunction as a key pathogenic cause in the metabolic syndrome and type 2 diabetes. Pharmacological targeting of adipose tissue through the nuclear receptor PPARg, as exemplified by glitazone treatments, mediates efficacious insulin sensitization. However, a better understanding of the context‐specific PPARg responses is required for the development of novel approaches with reduced side effects. Here, we identified the transcriptional cofactor Cited4 as a target and mediator of rosiglitazone in human and murine adipocyte progenitor cells, where it promoted specific sets of the rosiglitazone‐dependent transcriptional program. In mice, Cited4 was required for the proper induction of thermogenic expression by Rosi specifically in subcutaneous fat. This phenotype had high penetrance in females only and was not evident in beta‐adrenergically stimulated browning. Intriguingly, this specific defect was associated with reduced capacity for systemic thermogenesis and compromised insulin sensitization upon therapeutic rosiglitazone treatment in female but not male mice. Our findings on Cited4 function reveal novel unexpected aspects of the pharmacological targeting of PPARg. |
| format | Article |
| id | doaj-art-a4f7620a706d40c1b743c16d6f4e5f05 |
| institution | DOAJ |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2018-07-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-a4f7620a706d40c1b743c16d6f4e5f052025-08-20T03:05:55ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842018-07-0110811810.15252/emmm.201708613Cited4 is a sex‐biased mediator of the antidiabetic glitazone response in adipocyte progenitorsIrem Bayindir‐Buchhalter0Gretchen Wolff1Sarah Lerch2Tjeerd Sijmonsma3Maximilian Schuster4Jan Gronych5Adrian T Billeter6Rohollah Babaei7Damir Krunic8Lars Ketscher9Nadine Spielmann10Martin Hrabe de Angelis11Jorge L Ruas12Beat P Müller‐Stich13Mathias Heikenwalder14Peter Lichter15Stephan Herzig16Alexandros Vegiopoulos17DKFZ Junior Group Metabolism and Stem Cell Plasticity, German Cancer Research CenterDKFZ Junior Group Metabolism and Stem Cell Plasticity, German Cancer Research CenterDKFZ Junior Group Metabolism and Stem Cell Plasticity, German Cancer Research CenterDivision Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ)DKFZ Junior Group Metabolism and Stem Cell Plasticity, German Cancer Research CenterDivision of Molecular Genetics, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK)Department of General, Visceral, and Transplantation Surgery, University of HeidelbergDKFZ Junior Group Metabolism and Stem Cell Plasticity, German Cancer Research CenterLight Microscopy Facility, German Cancer Research Center (DKFZ)Department of Physiology and Pharmacology, Molecular and Cellular Exercise Physiology, Karolinska InstitutetGerman Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental HealthGerman Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental HealthDepartment of Physiology and Pharmacology, Molecular and Cellular Exercise Physiology, Karolinska InstitutetDepartment of General, Visceral, and Transplantation Surgery, University of HeidelbergDivision Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ)Division of Molecular Genetics, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK)Helmholtz Center Munich, Institute for Diabetes and Cancer IDCDKFZ Junior Group Metabolism and Stem Cell Plasticity, German Cancer Research CenterAbstract Most antidiabetic drugs treat disease symptoms rather than adipose tissue dysfunction as a key pathogenic cause in the metabolic syndrome and type 2 diabetes. Pharmacological targeting of adipose tissue through the nuclear receptor PPARg, as exemplified by glitazone treatments, mediates efficacious insulin sensitization. However, a better understanding of the context‐specific PPARg responses is required for the development of novel approaches with reduced side effects. Here, we identified the transcriptional cofactor Cited4 as a target and mediator of rosiglitazone in human and murine adipocyte progenitor cells, where it promoted specific sets of the rosiglitazone‐dependent transcriptional program. In mice, Cited4 was required for the proper induction of thermogenic expression by Rosi specifically in subcutaneous fat. This phenotype had high penetrance in females only and was not evident in beta‐adrenergically stimulated browning. Intriguingly, this specific defect was associated with reduced capacity for systemic thermogenesis and compromised insulin sensitization upon therapeutic rosiglitazone treatment in female but not male mice. Our findings on Cited4 function reveal novel unexpected aspects of the pharmacological targeting of PPARg.https://doi.org/10.15252/emmm.201708613adipocyte progenitorsbrowningCited4glitazonesinsulin sensitivity |
| spellingShingle | Irem Bayindir‐Buchhalter Gretchen Wolff Sarah Lerch Tjeerd Sijmonsma Maximilian Schuster Jan Gronych Adrian T Billeter Rohollah Babaei Damir Krunic Lars Ketscher Nadine Spielmann Martin Hrabe de Angelis Jorge L Ruas Beat P Müller‐Stich Mathias Heikenwalder Peter Lichter Stephan Herzig Alexandros Vegiopoulos Cited4 is a sex‐biased mediator of the antidiabetic glitazone response in adipocyte progenitors EMBO Molecular Medicine adipocyte progenitors browning Cited4 glitazones insulin sensitivity |
| title | Cited4 is a sex‐biased mediator of the antidiabetic glitazone response in adipocyte progenitors |
| title_full | Cited4 is a sex‐biased mediator of the antidiabetic glitazone response in adipocyte progenitors |
| title_fullStr | Cited4 is a sex‐biased mediator of the antidiabetic glitazone response in adipocyte progenitors |
| title_full_unstemmed | Cited4 is a sex‐biased mediator of the antidiabetic glitazone response in adipocyte progenitors |
| title_short | Cited4 is a sex‐biased mediator of the antidiabetic glitazone response in adipocyte progenitors |
| title_sort | cited4 is a sex biased mediator of the antidiabetic glitazone response in adipocyte progenitors |
| topic | adipocyte progenitors browning Cited4 glitazones insulin sensitivity |
| url | https://doi.org/10.15252/emmm.201708613 |
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