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 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.

Diet-dependent function of the extracellular matrix proteoglycan Lumican in obesity and glucose homeostasis

“…Liver and muscle triglycerides were extracted as previously described [24] and determined with the Serum Triglyceride Determination Kit (TR0100, Sigma Aldrich, Munich Germany) and the Mithras Microplate Reader (Berthold Technologies GmbH & Co, Germany). Insulin tolerance test (ITT) and glucose tolerance test (GTT) were performed as previously described [25].…”

“…To isolate progenitor cells for seeding or sorting [25], gWAT was dissected and digested as described previously [29], [30]. The Lin-Sca1+ fraction cells were counted using a hemocytometer and seeded on laminin-coated 24-well plates.…”

CD_99 G1 neutrophils modulate osteogenic differentiation of mesenchymal stem cells in the pathological process of ankylosing spondylitis

“…The cells in this subcluster demonstrated strong chemokine secretion and the ability to recruit neutrophils. Additionally, we identified CITED4, EPAS1 and PPARG as genes that were more highly expressed in the Adipo-CAR subcluster, which were all closely involved in regulating adipose production 53–56. According to our results, cluster 3 was closely associated with the multidirectional differentiation function of MSCs and increased MSC-C2 was the most stemmed transcription factor cluster (figure 2E).…”

Protein Arginine Methyltransferase PRMT5 Regulates Fatty Acid Metabolism and Lipid Droplet Biogenesis in White Adipose Tissues

“…[ 37 ] Depot, age, and gender specific effects of various other genes has also been reported, for example Cited4 has distinct roles in regulating thermogenic gene expression in female and male mice, and different fat depots. [ 38 ] Previous in vitro studies showed that knockdown of Prmt5 in 3T3‐L1 cells inhibits adipogenic differentiation and adipogenic gene expression, [ 17 ] through a mechanism involving Prmt5 facilitated enhancer–promoter looping to promote expression of Ppar γ 2. [ 18 ] However, we did not observe a very significant decrease in Pparγ expression in Prmt5 ‐null adipocytes.…”