Journal Article

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

Schuster, Maximilian, Bayindir‐Buchhalter, Irem, Billeter, Adrian T, Ketscher, Lars, Herzig, Stephan, Gronych, Jan, Ruas, Jorge L, Wolff, Gretchen, Spielmann, Nadine, Lerch, Sarah, Sijmonsma, Tjeerd, Müller‐Stich, Beat P, Vegiopoulos, Alexandros, Babaei, Rohollah, Heikenwalder, Mathias, Hrabe de Angelis, Martin, Krunic, Damir, Lichter, Peter

2018

Overview

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. Graphical 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.

• Publisher: Nature Publishing Group UK,EMBO Press,John Wiley and Sons Inc,Springer Nature
• Subject: adipocyte progenitors / Adipocytes / Adipose tissue / Antidiabetics / browning / Cited4 / Diabetes / Diabetes mellitus / Diabetes mellitus (non-insulin dependent) / EMBO21 / Energy expenditure / Females / glitazones / Insulin / insulin sensitivity / Metabolic syndrome / Peroxisome proliferator-activated receptors / Phenotypes / Progenitor cells / Research Article / Rodents / Rosiglitazone / Sex differences / Stem cells / Thermogenesis / Transcription