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EMBO Mol Med. 2018 Aug;10(8). pii: e8613. doi: 10.15252/emmm.201708613.

Cited4 is a sex-biased mediator of the antidiabetic glitazone response in adipocyte progenitors.

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DKFZ Junior Group Metabolism and Stem Cell Plasticity, German Cancer Research Center, Heidelberg, Germany.
Division Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Division of Molecular Genetics, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany.
Department of General, Visceral, and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.
Light Microscopy Facility, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Department of Physiology and Pharmacology, Molecular and Cellular Exercise Physiology, Karolinska Institutet, Stockholm, Sweden.
German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Chair of Experimental Genetics, School of Life Science Weihenstephan, Technische Universität München, Freising, Germany.
German Center for Diabetes Research (DZD), Neuherberg, Germany.
Helmholtz Center Munich, Institute for Diabetes and Cancer IDC, Neuherberg, Germany.
Joint Heidelberg-IDC Translational Diabetes Program, Heidelberg University Hospital, Heidelberg, Germany.
DKFZ Junior Group Metabolism and Stem Cell Plasticity, German Cancer Research Center, Heidelberg, Germany


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.


Cited4; adipocyte progenitors; browning; glitazones; insulin sensitivity

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