Cited4 is a sex‐biased mediator of the antidiabetic glitazone response in adipocyte progenitors. Issue 8 (4th July 2018)

• Record Type: Journal Article
• Authors: Bayindir‐Buchhalter, Irem; Wolff, Gretchen; Lerch, Sarah; Sijmonsma, Tjeerd; Schuster, Maximilian; Gronych, Jan; Billeter, Adrian T; Babaei, Rohollah; Krunic, Damir; Ketscher, Lars; Spielmann, Nadine; Hrabe de Angelis, Martin; Ruas, Jorge L; Müller‐Stich, Beat P; Heikenwalder, Mathias; Lichter, Peter; Herzig, Stephan; Vegiopoulos, Alexandros
• Is Part Of: EMBO molecular medicine. Volume 10:Issue 8(2018)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2018-07-04
• Subjects: adipocyte progenitors -- browning -- Cited4 -- glitazones -- insulin sensitivity; Molecular biology -- Periodicals; Medical genetics -- Periodicals; Pathology, Molecular -- Periodicals; 616.04205
• DOI: 10.15252/emmm.201708613
• Languages: English
• ISSNs: 1757-4676

Abstract

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. Synopsis: The identification of the Cited4 cofactor as a sex‐, tissue‐ and signal‐specific mediator of transcriptional responses to glitazones in adipocyte progenitors reveals unexpected aspects of therapeutic PPARg targeting for insulin sensitization in type 2 diabetes and prediabetes. Cited4 is a glitazone target in human and murine adipocyte progenitors promoting the induction of beige adipocyte differentiation. Cited4 is required for rosiglitazone‐mediated but not beta‐adrenergic induction of thermogenic expression in subcutaneous fat in a sex‐biased manner. Systemic energy expenditure and maximal beta‐adrenergic adipocyte respiration are reduced in Cited4‐deficient female mice under rosiglitazone treatment. Reduced thermogenic expression in subcutaneous fat is associated with compromised insulin sensitization upon therapeutic rosiglitazone treatment specifically in female mice. Abstract : The identification of the Cited4 cofactor as a sex‐, tissue‐ and signal‐specific mediator of transcriptional responses to glitazones in adipocyte progenitors reveals unexpected aspects of therapeutic PPARg targeting for insulin sensitization in type 2 diabetes and prediabetes.