HDAC3 is a molecular brake of the metabolic switch supporting white adipose tissue browning

Ferrari, Alessandra; Longo, Raffaella; Fiorino, Erika; Silva, Rui; Mitro, Nico; Cermenati, Gaia; Gilardi, Federica; Desvergne, Béatrice; Andolfo, Annapaola; Magagnotti, Cinzia; Caruso, Donatella; Fabiani, Emma De; Hiebert, Scott W.; Crestani, Maurizio

doi:10.1038/s41467-017-00182-7

Cited by 71 publications

(70 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A previous report has shown that HDAC3-deficient mice underwent significant re-modelling of the WAT metabolic pathway to resemble BAT (browning) without β-AR stimulation [13]. This study thus highlights a negative regulation of HDAC3 to WAT browning.…”

Section: Discussionsupporting

confidence: 59%

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

Yuliana

Jheng

Kawarasaki

et al. 2018

IJMS

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 59%

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

Yuliana

Jheng

Kawarasaki

et al. 2018

IJMS

View full text Add to dashboard Cite

show abstract

“…Exposure to the cold [16-18] or selective ADRB3 agonists [7] resulted in higher resting metabolic rate and hBAT activity in healthy individuals as measured via 18 F-FDG/PET-CT, in whom the ADRB3 pathway was considered as a dominant signaling pathway to promote the activation or differentiation of beige adipocytes [17, 19, 20]. ADRB3 belong to G protein-coupled receptors and are abundant in adipose tissue, especially in the BAT [17, 21]. Trp64Arg polymorphisms of ADRB3 genes are associated with a variety of body weight [22, 23].…”

Section: Discussionmentioning

confidence: 99%

Adipocyte ADRB3 Down-Regulated in Chinese Overweight Individuals Adipocyte ADRB3 in Overweight

et al. 2018

View full text Add to dashboard Cite

Objectives: Activation of β3-adrenoceptor (ADRB3) is essential in the process of human adipose tissue browning, but obese subjects suffered from reduced ability of brown adipose tissue activation. The present study aims to detect the adipocyte ADRB3 expression in overweight individuals and the relationship between adipocyte ADRB3 expression and adiposity in adults. Methods: Visceral adipose tissue samples were obtained from 85 subjects who underwent abdominal surgery. ADRB3 mRNA and protein expression levels in mature adipocytes and adipose tissue stromal vascular cells were examined by quantitative real-time PCR and Western blot assay, respectively. UCP-1mRNA expression levels in mature adipocytes were examined by quantitative real-time PCR. Results: The data revealed that ADRB3 mRNA (p = 0.021) and protein (p = 0.025) expression levels in mature adipocytes were significantly higher in the normal-weight than in the overweight group. Similar results were also found for ADRB3 mRNA (p = 0.041) and protein (p = 0.025) expressions of stromal vascular cells. An inverse correlation was verified between mature adipocyte ADRB3 mRNA expression and BMI (r = –0.362, p = 0.012). UCP-1 mRNA expression levels in mature adipocytes were higher in the normal-weight group compared with the overweight group (p = 0.045). Conclusion: Adipocyte ADRB3 expression levels were down-regulated before the onset of obesity, which indicated that the reduction of ADRB3 expression might be the cause of compromised adipose tissue browning and obesity rather than the result. Thus, the interference of the ADRB3 pathway in adipocytes may provide a potential treatment target for obesity.

show abstract

“…For example, HDAC1 has been shown to associate with regulatory elements of BAT-specific genes, resulting in reduced histone H3K27 acetylation and consequent transcriptional repression (38). Another class I HDAC, HDAC3, has also been linked to the regulation of BAT gene expression and thermogenesis in mice (39)(40)(41).…”

Section: Discussionmentioning

confidence: 99%

HDAC11 Suppresses the Thermogenic Program of Adipose Tissue via BRD2

Bagchi

Ferguson

Stratton

et al. 2018

Preprint

View full text Add to dashboard Cite

Little is known about the biological function of histone deacetylase 11 (HDAC11), which is the lone class IV HDAC. Here, we demonstrate that deletion of HDAC11 in mice stimulates brown adipose tissue (BAT) formation and beiging of white adipose tissue (WAT). Consequently, HDAC11-deficient mice exhibit dramatically enhanced thermogenic potential and, in response to high fat feeding, attenuated obesity, insulin resistance, and hepatic steatosis. Ex vivo and cellbased assays revealed that HDAC11 catalytic activity suppresses the BAT transcriptional program, in both the basal state and in response to -adrenergic receptor signaling, through a mechanism that is dependent on physical association with BRD2, a bromodomain and extraterminal (BET) acetyl-histone binding protein. These findings define a novel epigenetic pathway for the regulation of energy homeostasis, and suggest potential for HDAC11-selective inhibitors for the treatment of obesity and diabetes.suggest the intriguing possibility that selective HDAC11 inhibitors could be developed to increase energy expenditure for the treatment of obesity and metabolic disease.

show abstract

HDAC3 is a molecular brake of the metabolic switch supporting white adipose tissue browning

Cited by 71 publications

References 49 publications

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

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

Adipocyte ADRB3 Down-Regulated in Chinese Overweight Individuals Adipocyte ADRB3 in Overweight

HDAC11 Suppresses the Thermogenic Program of Adipose Tissue via BRD2

Contact Info

Product

Resources

About