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

Abstract

Browning of adipose tissue has been prescribed as a potential way to treat obesity, marked by the upregulation of uncoupling protein 1 (Ucp1). Several reports have suggested that histone deacetylase (HDAC) might regulate Ucp1 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 Ucp1 expression via cold (in vivo) and isoproterenol (in vitro) resulted in acetylation of histone activation mark H3K27. H3K27 acetylation was also seen within Ucp1 promoter upon isoproterenol addition, favouring open chromatin for Ucp1 transcriptional activation. This result was found to be associated with the downregulation of class I HDAC mRNA, particularly Hdac3 and Hdac8. Further investigation showed that although HDAC8 activity decreased, Ucp1 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 Ucp1 enhancer region, causing an increased H3K27 acetylation for Ucp1 upregulation. The importance of HDAC3 inhibition was confirmed through the enhanced Ucp1 expression when the cells were treated with HDAC3 inhibitor. This study highlights the novel mechanism of HDAC3-regulated Ucp1 expression during β-AR stimulation.

ACE2 exerts anti-obesity effect via stimulating brown adipose tissue and induction of browning in white adipose tissue

“…Selective ablation of HDAC3 in WAT promotes browning of WAT via enhancers in Ppar␥ and Ucp1 genes, and increased acetylation of H3K27 in the putative regulatory region of Ppar␣ gene (7,9). Furthermore, Ucp1 expression in WAT increases H3K27 acetylation in the Ucp1 promoter lesion through ␤ 3 -AR by both cold and isoproterenol stimulation (27). These results suggest that browning of WAT is related to the downregulation of HDAC3 via the ␤ 3 -AR.…”

Adaptor protein APPL1 coordinates HDAC3 to modulate brown adipose tissue thermogenesis in mice

“…Concisely, in brown adipocytes, APPL1 is an endogenous HDAC inhibitor that could modulate thermogenic gene expression. Acetylation of histone 3 lysine 27 (H3K27ac) is known as a potent activation mark for browning-related genes, such as UCP1 [41,42]. H3K27ac distinguish active enhancers which favors transcriptional activation.…”

Endoplasmic Reticulum Stress Impaired Uncoupling Protein 1 Expression via the Suppression of Peroxisome Proliferator-Activated Receptor γ Binding Activity in Mice Beige Adipocytes

“…RNA was extracted as described previously [50]. Total RNA was collected from cultured cells or tissues using Sepasol-RNA I Super G (Nacalai Tesque, Kyoto, Japan) or QIAzol Lysis Reagent (Qiagen, Hilden, Germany), respectively.…”

“…Western blotting was performed as previously described [50]. The protein concentration was measured using the DC protein assay (Bio-Rad, Hercules, CA, USA).…”

“…The ChIP assay was performed as described previously [50]. The cells were subjected to overnight immunoprecipitation with 8 μg Pparγ antibody (Perseus Proteomics, Tokyo, Japan), or rabbit IgG isotype control (Novus Biological, Littleton, CO, USA) as a mock control and analyzed by real-time PCR.…”