Regulation of Adipogenesis by Natural and Synthetic REV-ERB Ligands

被引:105
作者
Kumar, Naresh
Solt, Laura A.
Wang, Yongjun
Rogers, Pamela M. [2 ]
Bhattacharyya, Gargi
Kamenecka, Theodore M.
Stayrook, Keith R. [3 ]
Crumbley, Christine
Floyd, Z. Elizabeth [2 ]
Gimble, Jeffrey M. [2 ]
Griffin, Patrick R. [1 ]
Burris, Thomas P. [1 ]
机构
[1] Scripps Res Inst, Mol Screening Ctr, Jupiter, FL 33458 USA
[2] Louisiana State Univ Syst, Pennington Biomed Res Ctr, Baton Rouge, LA 70808 USA
[3] Lilly Corp Ctr, Lilly Res Labs, Indianapolis, IN 46258 USA
基金
美国国家卫生研究院;
关键词
ADIPOCYTE DIFFERENTIATION; HEME-BIOSYNTHESIS; HORMONE-RECEPTORS; CIRCADIAN CLOCK; ALPHA; EXPRESSION; PROTEASOME; GENE; BETA; 3-AMINO-1,2,4-TRIAZOLE;
D O I
10.1210/en.2009-0800
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
The nuclear hormone receptor, REV-ERB, plays an essential role in adipogenesis. Rev-erb alpha expression is induced in 3T3-L1 cells during adipogenesis, and overexpression of this receptor leads to expression of adipogenic genes. We recently demonstrated that the porphyrin heme functions as a ligand for REV-ERB, and binding of heme is required for the receptor's activity. We therefore hypothesized that REV-ERB ligands may play a role in regulation of adipogenesis. We detected an increase intracellular heme levels during 3T3-L1 adipogenesis that correlated with induction of aminolevulinic acid synthase 1 (Alas1) expression, the rate-limiting enzyme in heme biosynthesis. If the increase in Alas1 expression was blocked, adipogenesis was severely attenuated, indicating that induction of expression of Alas1 and the increase in heme synthesis is critical for differentiation. Inhibition of heme synthesis during adipogenesis leads to decreased recruitment of nuclear receptor corepressor to the promoter of a REV-ERB target gene, suggesting alteration of REV-ERB activity. Treatment of 3T3-L1 cells with a synthetic REV-ERB ligand, SR6452, resulted in induction of adipocyte differentiation to a similar extent as treatment with the peroxisomal proliferator-activated receptor-gamma agonist, rosiglitazone. Combination of SR6452 and rosiglitazone had an additive effect on stimulation of adipocyte differentiation. These results suggest that heme, functioning as a REV-ERB ligand, is an important signaling molecule for induction of adipogenesis. Moreover, synthetic small molecule ligands for REV-ERB are effective modulators of adipogenesis and may be useful for treatment of metabolic diseases. (Endocrinology 151: 3015-3025, 2010)
引用
收藏
页码:3015 / 3025
页数:11
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