Regulation of Adipogenesis by Natural and Synthetic REV-ERB Ligands
| Autor: | Thomas P. Burris, Christine Crumbley, Jeffrey M. Gimble, Theodore M. Kamenecka, Keith R. Stayrook, Gargi Bhattacharyya, Yongjun Wang, Naresh Kumar, Patrick R. Griffin, Z. Elizabeth Floyd, Laura A. Solt, Pamela M. Rogers |
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| Rok vydání: | 2010 |
| Předmět: |
Chromatin Immunoprecipitation
medicine.medical_specialty Cellular differentiation Blotting Western Heme Biology Ligands Article Rosiglitazone Mice chemistry.chemical_compound Endocrinology 3T3-L1 Cells Internal medicine medicine Animals RNA Small Interfering skin and connective tissue diseases Receptor Adipogenesis Cell Differentiation ALAS1 body regions Nuclear receptor chemistry Biochemistry Nuclear Receptor Subfamily 1 Group D Member 1 Thiazolidinediones Signal transduction Corepressor 5-Aminolevulinate Synthetase |
| Zdroj: | Endocrinology. 151:3015-3025 |
| ISSN: | 1945-7170 0013-7227 |
| DOI: | 10.1210/en.2009-0800 |
| Popis: | The nuclear hormone receptor, REV-ERB, plays an essential role in adipogenesis. Rev-erbα 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-γ 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. |
| Databáze: | OpenAIRE |
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