TY  - JOUR
AU  - Bayindir-Buchhalter, Irem
AU  - Wolff, Gretchen
AU  - Lerch, Sarah
AU  - Sijmonsma, Tjeerd
AU  - Schuster, Maximilian
AU  - Gronych, Jan
AU  - Billeter, Adrian T
AU  - Babaei, Rohollah
AU  - Krunic, Damir
AU  - Ketscher, Lars
AU  - Spielmann, Nadine
AU  - Hrabe de Angelis, Martin
AU  - Ruas, Jorge L
AU  - Müller-Stich, Beat P
AU  - Heikenwalder, Mathias
AU  - Lichter, Peter
AU  - Herzig, Stephan
AU  - Vegiopoulos, Alexandros
TI  - Cited4 is a sex-biased mediator of the antidiabetic glitazone response in adipocyte progenitors.
JO  - EMBO molecular medicine
VL  - 10
IS  - 8
SN  - 1757-4684
CY  - Weinheim
PB  - Wiley-VCH
M1  - DKFZ-2018-01285
SP  - e8613
PY  - 2018
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:29973382
C2  - pmc:PMC6079535
DO  - DOI:10.15252/emmm.201708613
UR  - https://inrepo02.dkfz.de/record/136847
ER  -