title: Coregulator cell cycle and apoptosis regulator 1 (CCAR1) positively regulates adipocyte differentiation through the glucocorticoid signaling pathway.
abstract: Glucocorticoids contribute to adipocyte differentiation by cooperating with transcription factors, such as CCAAT/enhancer-binding protein β (C/EBPβ), to stimulate transcription of the gene encoding peroxisome proliferator-activated receptor (PPARγ), a master regulator of adipogenesis. However, the mechanism of PPARγ 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 PPARγ gene were responsive to glucocorticoid, and treatment of 3T3-L1 preadipocytes with glucocorticoid alone induced GR occupancy and chromatin remodeling at PPARγ GBRs, which also contain binding sites for C/EBP and PPARγ proteins. GR recruited cell cycle and apoptosis regulator 1 (CCAR1), a transcription coregulator, to the PPARγ gene GBRs. Notably, CCAR1 was required for GR occupancy and chromatin remodeling at one of the PPARγ 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 PPARγ, C/EBPα, and C/EBPδ. 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.
authors.affiliation: From the Department of Biochemistry and Molecular Biology, University of Southern California, Los Angeles, California 90089 and.
authors.forename: Chen-Yin
authors.initials: CY
authors.lastname: Ou
authors.affiliation: Department of Nutritional Science and Toxicology, University of California, Berkeley, California 94720.
authors.forename: Tzu-Chieh
authors.initials: TC
authors.lastname: Chen
authors.affiliation: Department of Nutritional Science and Toxicology, University of California, Berkeley, California 94720.
authors.forename: Joyce V
authors.initials: JV
authors.lastname: Lee
authors.affiliation: Department of Nutritional Science and Toxicology, University of California, Berkeley, California 94720 walwang@berkeley.edu.
authors.forename: Jen-Chywan
authors.initials: JC
authors.lastname: Wang
authors.affiliation: From the Department of Biochemistry and Molecular Biology, University of Southern California, Los Angeles, California 90089 and stallcup@usc.edu.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Stallcup
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000378:metabolism*; D050156:Adipogenesis; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D042002:Chromatin Assembly and Disassembly; D005938:Glucocorticoids / Q000378:metabolism; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D041681:NIH 3T3 Cells; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D051017:Apoptosis Regulatory Proteins; D022762:CCAAT-Enhancer-Binding Proteins; C540324:CCAR1 protein, mouse; D018797:Cell Cycle Proteins; D005938:Glucocorticoids; D047495:PPAR gamma; D011965:Receptors, Glucocorticoid
keywords: Adipogenesis; Cell Cycle and Apoptosis Regulator 1 (CCAR1); Chromatin Modification; Glucocorticoid Receptor; Peroxisome Proliferator-activated Receptor; Transcription Enhancer; Transcription Regulation