Mechanisms Regulating Adipocyte Expression of Resistin

Resistin, also known as AdipocyteSecreted Factor (ADSF) and Found inInflammatory Zone 3 (FIZZ3), is a mouse protein with potential roles in insulin resistance and adipocyte differentiation. The resistin gene is expressed almost exclusively in adipocytes. Here we show that a proximal 264-base pair fragment of the mouse resistin promoter is sufficient for expression in adipocytes. Ectopic expression of the adipogenic transcription factor CCAAT/enhancer-binding protein (C/EBPα) was sufficient for expression in non-adipogenic cells. C/EBPα binds specifically to a site that is essential for expression of the resistin promoter. Chromatin immunoprecipitation studies of the endogenous gene demonstrated adipocyte-specific association of C/EBPα with the proximal resistin promoter in adipocytes but not preadipocytes. C/EBPα binding was associated with the recruitment of coactivators p300 and CREB-binding protein and a dramatic increase in histone acetylation in the vicinity of the resistin promoter. The antidiabetic thiazolidinedione (TZD) drug rosiglitazone reduced resistin expression with an ED50 similar to its Kdfor binding to peroxisome proliferator activated receptor γ (PPARγ). Other TZD- and non-TZD PPARγ ligands also down-regulated resistin expression. However, no functional PPARγ binding site was found within 6.2 kb of the transcriptional start site, suggesting that if PPARγ is involved, it is either acting at a long distance from the start site, in an intron, or indirectly. Nevertheless, rosiglitazone treatment selectively decreased histone acetylation at the resistin promoter without a change in occupation by C/EBPα, CREB-binding protein, or p300. Thus, adipocyte specificity of resistin gene expression is because of C/EBPα binding, leading to the recruitment of transcriptional coactivators and histone acetylation that is characteristic of an active chromatin environment. TZD reduces resistin gene expression at least in part by reducing histone acetylation associated with the binding of C/EBPα in mature adipocytes.