Coregulator Cell Cycle and Apoptosis Regulator 1 (CCAR1) Positively Regulates Adipocyte Differentiation through the Glucocorticoid Signaling Pathway

Glucocorticoids contribute to adipocyte differentiation by cooperating with transcription factors, such as CCAAT/enhancer-binding protein beta (C/EBP beta), to stimulate transcription of the gene encoding peroxisome proliferator-activated receptor (PPAR gamma), a master regulator of adipogenesis. However, the mechanism of PPAR gamma gene regulation by glucocorticoids, the glucocorticoid receptor (GR), and its coregulators is poorly understood. Here we show that two GR binding regions (GBRs) in the mouse PPAR gamma gene were responsive to glucocorticoid, and treatment of 3T3-L1 preadipocytes with glucocorticoid alone induced GR occupancy and chromatin remodeling at PPAR gamma GBRs, which also contain binding sites for C/EBP and PPAR gamma proteins. GR recruited cell cycle and apoptosis regulator 1 (CCAR1), a transcription coregulator, to the PPAR gamma gene GBRs. Notably, CCAR1 was required for GR occupancy and chromatin remodeling at one of the PPAR gamma gene GBRs. Moreover, depletion of CCAR1 markedly suppressed differentiation of mouse mesenchymal stem cells and 3T3-L1 preadipocytes to mature adipocytes and decreased induction of PPAR gamma, C/EBP alpha, and C/EBP delta. Although CCAR1 was required for stimulation of several GR-regulated adipogenic genes in 3T3-L1 preadipocytes by glucocorticoid, it was not required for GR-activated transcription of certain anti-inflammatory genes in human A549 lung epithelial cells. Overall, our results highlighted the novel and specific roles of GR and CCAR1 in adipogenesis.