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Mechanisms regulating adipocyte expression of resistin
Helen B Hartman1, Xiao Hu, Keala X Tyler
1Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine and Genetics and The Penn Diabetes Center, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
The Journal of Biological Chemistry
|March 20, 2002
Summary
Resistin gene expression in adipocytes is driven by C/EBPalpha binding, promoting an active chromatin state. Rosiglitazone reduces resistin by decreasing histone acetylation at the promoter.
Area of Science:
- Molecular Biology
- Genetics
- Endocrinology
Background:
- Resistin, a protein hormone, is implicated in insulin resistance and adipocyte differentiation.
- Its gene expression is largely restricted to mature adipocytes.
Purpose of the Study:
- To elucidate the molecular mechanisms regulating resistin gene expression in adipocytes.
- To investigate the role of CCAAT/enhancer-binding protein alpha (C/EBPalpha) and peroxisome proliferator-activated receptor gamma (PPARgamma) in resistin regulation.
Main Methods:
- Analysis of the mouse resistin promoter activity using a 264-base pair fragment.
- Chromatin immunoprecipitation (ChIP) to assess C/EBPalpha binding and histone modifications.
- Treatment with thiazolidinedione (TZD) drugs, including rosiglitazone, to evaluate effects on resistin expression.
Main Results:
- A 264-bp resistin promoter fragment conferred adipocyte-specific expression.
- C/EBPalpha directly binds to a critical site on the resistin promoter, recruiting coactivators and increasing histone acetylation.
- Rosiglitazone and other PPARgamma ligands down-regulated resistin expression, primarily by reducing histone acetylation at the promoter without altering C/EBPalpha or coactivator binding.
Conclusions:
- Adipocyte-specific resistin expression is mediated by C/EBPalpha-driven transcriptional activation and chromatin remodeling.
- TZDs, like rosiglitazone, suppress resistin expression through decreased histone acetylation, suggesting a novel regulatory pathway independent of direct PPARgamma binding to the promoter.