Role of histone deacetylase 9 in regulating adipogenic differentiation and high fat diet-induced metabolic disease

Chatterjee, Tapan K.; Basford, Joshua E.; Yiew, Kan Hui; Stepp, David W.; Hui, David Y.; Weintraub, Neal L.

doi:10.4161/adip.28814

Cited by 35 publications

(21 citation statements)

References 51 publications

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“…The increased understanding of adipogenesis provides a promising new avenue for the treatment of metabolic disease in obesity (9,44). Both HDAC9 and ABCG1 have been proposed as therapeutic targets for patients with obesity in separate previous studies (34,41), however, our data support a mechanistic pathway linking them to metabolic diseases.…”

Section: Discussionsupporting

confidence: 42%

“…These findings are of particular significance in light of several studies that demonstrated the key role of HDAC9 in adipocytes function: overexpression of Hdac9 in 3T3-L1 preadipocyte mouse cell lines suppressed adipogenesis and inversely, preadipocytes isolated from Hdac9 knockout mice had an accelerated adipocyte differentiation (33). Furthermore, Hdac9 knockout mice showed improved metabolic homeostasis and were protected from adipose tissue dysfunction in mice fed on a high fat feeding (34). These studies clearly indicate the deleterious role of HDAC9 in maintaining adipocytes homeostasis both in vitro and in vivo .…”

Section: Discussionmentioning

confidence: 99%

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Histone deacetylase 9 promoter hypomethylation associated with adipocyte dysfunction is a statin-related metabolic effect

Khamis

Boutry

Canouil

et al. 2019

Preprint

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AbstractBackgroundAdipogenesis, the process whereby preadipocytes differentiate into mature adipocytes, is crucial for maintaining metabolic homeostasis. Cholesterol lowering statins increase type 2 diabetes (T2D) risk possibly by affecting adipogenesis and insulin resistance but the (epi)genetic mechanisms involved are unknown. Here, we characterised the effects of statin treatment on adipocyte differentiation using in vitro human preadipocytes cell model to identify putative effective genes.ResultsStatin treatment during adipocyte differentiation caused a reduction in key genes involved in adipogenesis, such as ADIPOQ, GLUT4 and ABCG1. Using Illumina’s Infinium ‘850K’ Methylation EPIC array, we found a significant hypomethylation of cg14566882, located in the promoter of the histone deacetylase 9 (HDAC9) gene, in response to two types of statins (atorvastatin and mevastatin), which correlates with an increased HDAC9 mRNA expression. HDAC9 is a transcriptional repressor of the cholesterol efflux ABCG1 gene expression, which is epigenetically modified in obesity and prediabetic states. Thus, we assessed the putative impact of ABCG1 knockdown in mimicking the effect of statin in adipogenesis. ABCG1 KD reduced the expression of key genes involved in adipocyte differentiation and decreased insulin signalling and glucose uptake. In human blood cells from two cohorts, ABCG1 expression was impaired in response to statins, confirming that ABCG1 is in vivo targeted by these drugs.ConclusionsWe identified an epigenetic link between adipogenesis and adipose tissue insulin resistance in the context of T2D risk associated with statin use, which has important implications as HDAC9 and ABCG1 are considered potential therapeutic targets for obesity and metabolic diseases.

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Section: Discussionsupporting

confidence: 42%

Section: Discussionmentioning

confidence: 99%

Histone deacetylase 9 promoter hypomethylation associated with adipocyte dysfunction is a statin-related metabolic effect

Khamis

Boutry

Canouil

et al. 2019

Preprint

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“…In this regard, there is a clear difference between the total loss of HDACs, as occurs in genetic models, and pharmacological inhibitors of HDACs, which only reduce activity and maintain the key ability of HDACs to form complexes with other proteins. Pharmacological inhibitors of HDACs increase the expression of GLUT4 in skeletal muscle [118], and HDAC inhibitors have shown promise in models of obesity and diabetes, preventing insulin resistance and reducing circulating triglycerides and cholesterol [119, 120], although these effects may be due to the roles of HDACs in liver and adipose tissue [121–123]. …”

Section: The Role Of Histone Deacetylases In Skeletal Muscle Developmmentioning

confidence: 99%

Emerging roles for histone deacetylases in age-related muscle atrophy

Walsh

Remmen

2016

Nutrition and Healthy Aging

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BACKGROUND: Skeletal muscle atrophy during aging, a process known as sarcopenia, is associated with muscle weakness, frailty, and the loss of independence in older adults. The mechanisms contributing to sarcopenia are not totally understood, but muscle fiber loss due to apoptosis, reduced stimulation of anabolic pathways, activation of catabolic pathways, denervation, and altered metabolism have been observed in muscle from old rodents and humans.OBJECTIVE: Recently, histone deacetylases (HDACs) have been implicated in muscle atrophy and dysfunction due to denervation, muscular dystrophy, and disuse, and HDACs play key roles in regulating metabolism in skeletal muscle. In this review, we will discuss the role of HDACs in muscle atrophy and the potential of HDAC inhibitors for the treatment of sarcopenia.CONCLUSIONS: Several HDAC isoforms are potential targets for intervention in sarcopenia. Inhibition of HDAC1 prevents muscle atrophy due to nutrient deprivation. HDAC3 regulates metabolism in skeletal muscle and may inhibit oxidative metabolism during aging. HDAC4 and HDAC5 have been implicated in muscle atrophy due to denervation, a process implicated in sarcopenia. HDAC inhibitors are already in use in the clinic, and there is promise in targeting HDACs for the treatment of sarcopenia.

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“…The class II HDAC, HDAC9, has been demonstrated to repress adipogenesis, and deletion of HDAC9 in mice is sufficient to promote beiging and increase energy expenditure and adaptive thermogenesis in the context of high fat feeding (42)(43)(44). However, unlike HDAC1 and HDAC3, HDAC9-mediated regulation of adipogenic gene expression is not dependent on its deacetylase domain, and instead is mediated by the amino-terminal co-factor interaction module of the protein (42).…”

Section: Discussionmentioning

confidence: 99%

HDAC11 Suppresses the Thermogenic Program of Adipose Tissue via BRD2

Bagchi

Ferguson

Stratton

et al. 2018

Preprint

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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.

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Role of histone deacetylase 9 in regulating adipogenic differentiation and high fat diet-induced metabolic disease

Cited by 35 publications

References 51 publications

Histone deacetylase 9 promoter hypomethylation associated with adipocyte dysfunction is a statin-related metabolic effect

Histone deacetylase 9 promoter hypomethylation associated with adipocyte dysfunction is a statin-related metabolic effect

Emerging roles for histone deacetylases in age-related muscle atrophy

HDAC11 Suppresses the Thermogenic Program of Adipose Tissue via BRD2

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