Attenuation of diet-induced obesity and induction of white fat browning with a chemical inhibitor of histone deacetylases

Ferrari, Alessandra; Fiorino, Erika; Longo, Raffaella; Barilla, Serena; Mitro, Nico; Cermenati, Gaia; Giudici, Marco; Caruso, Donatella; Mai, Antonello; Guerrini, Uliano; Fabiani, Emma De; Crestani, Maurizio

doi:10.1038/ijo.2016.191

Cited by 43 publications

(36 citation statements)

References 43 publications

(24 reference statements)

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“…However, which factors regulate behind this phenomenon is still unclear. The potential of HDAC, as one of the main regulators of histone acetylation, to regulate browning in adipose tissue has been suggested by several studies that tested HDAC inhibitory compounds in both BAT and WAT [11,20,24]. Moreover, many HDIs have shown to be beneficial in alleviating obesity and various diseases [20,21,22,23,29,30,31,32,33].…”

Section: Discussionmentioning

confidence: 99%

“…HDAC3 might also specifically regulate Ucp1 expression, because the treatment of HDAC3 inhibitor barely altered the mRNA expression of other browning markers such as Adrb3 , Pgc1α , Pparα , and Pparγ . On the other hand, pan-HDAC inhibitor [20] or class I HDAC inhibitor MS275 (Figure S2) [24] was shown to upregulate not only Ucp1 , but also Adrb3 mRNA expression and other browning-related markers.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, there is accumulating evidence that HDAC inhibitor (HDI) can stimulate browning of adipose tissue in BAT and WAT [11,12,19,20,21,22,23,24] which suggest the inhibition of HDAC might be closely related to browning. However, the detailed mechanism is still unclear and how β-AR stimulation might regulate HDAC activity is unknown.…”

Section: Introductionmentioning

confidence: 99%

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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

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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

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“…MS-275 is a class I HDACi known for its inhibitory properties against HDAC1 and HDAC3, while SAHA is a pan-HDACi (119,(130)(131)(132) (Figure 7A). When C2C12 myotubes were treated with these inhibitors, mitochondrial biogenesis, and oxidative metabolism were stimulated (130).…”

Section: Ms-275 Saha and Tsamentioning

confidence: 99%

Regulation of Thermogenic Adipocyte Differentiation and Adaptive Thermogenesis Through Histone Acetylation

et al. 2020

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Over the past decade, the increasing prevalence of obesity and its associated metabolic disorders constitutes one of the most concerning healthcare issues for countries worldwide. In an effort to curb the increased mortality and morbidity derived from the obesity epidemic, various therapeutic strategies have been developed by researchers. In the recent years, advances in the field of adipocyte biology have revealed that the thermogenic adipose tissue holds great potential in ameliorating metabolic disorders. Additionally, epigenetic research has shed light on the effects of histone acetylation on adipogenesis and thermogenesis, thereby establishing the essential roles which histone acetyltransferases (HATs) and histone deacetylases (HDACs) play in metabolism and systemic energy homeostasis. In regard to the therapeutic potential of thermogenic adipocytes for the treatment of metabolic diseases, herein, we describe the current state of knowledge of the regulation of thermogenic adipocyte differentiation and adaptive thermogenesis through histone acetylation. Furthermore, we highlight how different HATs and HDACs maintain the epigenetic transcriptional network to mediate the pathogenesis of various metabolic comorbidities. Finally, we provide insights into recent advances of the potential therapeutic applications and development of HAT and HDAC inhibitors to alleviate these pathological conditions.

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“…HDAC3 inhibition, however, improves glycemia and insulin secretion in obese diabetic rats (5). Treatment of mice with MS-275, an HDAC1/HDAC3 inhibitor, stimulates the functionality and oxidative potential of adipose tissue, improves glucose tolerance and ameliorates the 5 metabolic profile in diet-induced obese mice (6). In a contrasting study, inhibition of HDAC8 causes insulin resistance (7).…”

Section: Introductionmentioning

confidence: 99%

HDAC11 Deficiency Prevents High-Fat Diet-Induced Obesity and Metabolic Syndrome

Sun

Evsikova²,

Bian

et al. 2018

Preprint

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Significance StatementObesity is a serious and widespread health problem which has become a growing concern in many societies. Most currently available weight-loss medications do not work for everyone, and the effects decline over time. Thus, there is an urgent need to identify new molecular targets to improve drug development for the treatment of obesity and obesity-related diseases. In this study, we discovered that the histone deacetylase 11 (HDAC11) enzyme is a key regulator of metabolism and obesity, and the absence of HDAC11 prevents obesity in mice. Our findings will facilitate the development of novel therapeutics to treat obesity by targeting HDAC11.3 AbstractObesity and its associated metabolic syndromes are the consequence of susceptible genes and obesogenic environments. We report here that histone deacetylase 11 (HDAC11) plays a critical role in the development of obesity and in metabolic homeostasis. HDAC11 knockout mice display resistance to high-fat diet-induced obesity and associated syndromes by enhancing glucose tolerance and insulin sensitivity, attenuating hypercholesterolemia and hyperinsulinemia, and blocking hepatosteatosis and liver damage. Mechanistically, HDAC11 deficiency boosts energy expenditure through promoting thermogenic capacity, which attributes to the elevation of uncoupling protein 1 (UCP1) expression and activity in brown adipose tissue.Moreover, loss of HDAC11 stimulates mitochondrial oxidation, elevates plasma adiponectin, and activates the adiponectin-AdipoR-AMPK pathway in the liver, which may contribute to a reversal in hepatosteatosis. These findings establish HDAC11 as a key regulator of metabolism and indicate that HDAC11 inhibitors may hold promise for treating overweight and obesityrelated diseases.

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Attenuation of diet-induced obesity and induction of white fat browning with a chemical inhibitor of histone deacetylases

Cited by 43 publications

References 43 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

Regulation of Thermogenic Adipocyte Differentiation and Adaptive Thermogenesis Through Histone Acetylation

HDAC11 Deficiency Prevents High-Fat Diet-Induced Obesity and Metabolic Syndrome

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