β-adrenergic Receptor Stimulation Revealed a Novel Regulatory Pathway via Suppressing Histone Deacetylase 3 to Induce Uncoupling Protein 1 Expression in Mice Beige Adipocyte.

Browning of adipose tissue has been prescribed as a potential way to treat obesity, marked by the upregulation of uncoupling protein 1 (). Several reports have suggested that histone deacetylase (HDAC) might regulate by remodelling chromatin structure, although the mechanism remains unclear. Herein, we investigate the effect of β-adrenergic receptor (β-AR) activation on the chromatin state of beige adipocyte. β-AR-stimulated expression via cold (in vivo) and isoproterenol (in vitro) resulted in acetylation of histone activation mark H3K27. H3K27 acetylation was also seen within promoter upon isoproterenol addition, favouring open chromatin for transcriptional activation. This result was found to be associated with the downregulation of class I HDAC mRNA, particularly and . Further investigation showed that although HDAC8 activity decreased, expression was not altered when HDAC8 was activated or inhibited. In contrast, HDAC3 mRNA and protein levels were simultaneously downregulated upon isoproterenol addition, resulting in reduced recruitment of HDAC3 to the enhancer region, causing an increased H3K27 acetylation for upregulation. The importance of HDAC3 inhibition was confirmed through the enhanced expression when the cells were treated with HDAC3 inhibitor. This study highlights the novel mechanism of HDAC3-regulated expression during β-AR stimulation.