The Experts below are selected from a list of 38709 Experts worldwide ranked by ideXlab platform
Tapan K. Chatterjee - One of the best experts on this subject based on the ideXlab platform.
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role of Histone Deacetylase 9 in regulating adipogenic differentiation and high fat diet induced metabolic disease
Adipocyte, 2014Co-Authors: Tapan K. Chatterjee, Joshua E Basford, Kan Hui Yiew, David W Stepp, David Y Hui, Neal L WeintraubAbstract:Adipose tissue serves as both a storage site for excess calories and as an endocrine organ, secreting hormones such as adiponectin that promote metabolic homeostasis. In obesity, adipose tissue expands primarily by hypertrophy (enlargement of existing adipocytes) rather than hyperplasia (generation of new adipocytes via adipogenic differentiation of preadipocytes). Progressive adipocyte hypertrophy leads to inflammation, insulin resistance, dyslipidemia, and ectopic lipid deposition, the hallmark characteristics of metabolic disease. We demonstrate that during chronic high fat feeding in mice, adipogenic differentiation is impaired due to the actions of Histone Deacetylase 9 (HDAC9), a member of the class II family of HDACs. Mechanistically, upregulated HDAC9 expression blocks the adipogenic differentiation program during chronic high fat feeding, leading to accumulation of improperly differentiated adipocytes with diminished expression of adiponectin. These adipocytes are inefficient at storing lipid, resulting in ectopic lipid deposition in the liver. HDAC9 gene deletion prevents the detrimental effects of chronic high fat feeding on adipogenic differentiation, increases adiponectin expression, and enhances energy expenditure by promoting beige adipogenesis, thus leading to reduced body mass and improved metabolic homeostasis. HDAC9 is therefore emerging as a critical regulator of adipose tissue health and a novel therapeutic target for obesity-related disease.
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hdac9 knockout mice are protected from adipose tissue dysfunction and systemic metabolic disease during high fat feeding
Diabetes, 2014Co-Authors: Tapan K. Chatterjee, Víctor M. Blanco, Andra L. Blomkalns, Steven M. Rudich, Joshua E Basford, David Y Hui, Ellen Knoll, Wilson Tong, Alex B Lentsch, Neal L WeintraubAbstract:During chronic caloric excess, adipose tissue expands primarily by enlargement of individual adipocytes, which become stressed with lipid overloading, thereby contributing to obesity-related disease. Although adipose tissue contains numerous preadipocytes, differentiation into functionally competent adipocytes is insufficient to accommodate the chronic caloric excess and prevent adipocyte overloading. We report for the first time that a chronic high-fat diet (HFD) impairs adipogenic differentiation, leading to accumulation of inefficiently differentiated adipocytes with blunted expression of adipogenic differentiation-specific genes. Preadipocytes from these mice likewise exhibit impaired adipogenic differentiation, and this phenotype persists during in vitro cell culture. HFD-induced impaired adipogenic differentiation is associated with elevated expression of Histone Deacetylase 9 (HDAC9), an endogenous negative regulator of adipogenic differentiation. Genetic ablation of HDAC9 improves adipogenic differentiation and systemic metabolic state during an HFD, resulting in diminished weight gain, improved glucose tolerance and insulin sensitivity, and reduced hepatosteatosis. Moreover, compared with wild-type mice, HDAC9 knockout mice exhibit upregulated expression of beige adipocyte marker genes, particularly during an HFD, in association with increased energy expenditure and adaptive thermogenesis. These results suggest that targeting HDAC9 may be an effective strategy for combating obesity-related metabolic disease.
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abstract 61 Histone Deacetylase 9 hdac9 dysregulation precipitates high fat diet induced adipose tissue dysfunction and systemic metabolic disorders
Arteriosclerosis Thrombosis and Vascular Biology, 2012Co-Authors: Tapan K. Chatterjee, Andra L. Blomkalns, Joshua E Basford, David Y Hui, Ellen Knoll, Wilson Tong, Neal L WeintraubAbstract:During chronic overfeeding, adipose tissue expansion contributes to adipose inflammation, insulin resistance and obesity-related diabetes. Consequently, identifying mechanisms that promote “healthy” growth of adipose tissues could potentially improve obesity-related disease. We previously demonstrated that endogenous HDAC9 negatively regulates adipogenic differentiation in isolated preadipocytes. Here, we investigated the role of HDAC9 in regulating adipose tissue function and glucose intolerance in high fat fed mice. High fat feeding upregulated HDAC9 expression in adipose tissues, isolated preadipocytes and adipocytes, in conjunction with reduced expression of adipocyte differentiation-specific genes C/EBPα, PPARγ, FABP4, and adiponectin. HDAC9 gene knockout completely prevented these effects of high fat feeding on adipocyte differentiation-specific gene expression and adipogenic differentiation in vitro. HDAC9 knockout mice also gained less weight and exhibited less visceral adiposity, despite similar food intake, as compared to wild type mice during high fat feeding. In addition, HDAC9 gene deletion blunted elevations of plasma pro-inflammatory adipokines leptin and resistin, and resulted in improved systemic glucose tolerance, in the setting of high fat diet. Adipocytes were smaller in HDAC9 knockout mice, while ectopic lipid accumulation, as revealed by hepatosteatosis, following high fat feeding was completely prevented by HDAC9 gene knockout. Interestingly, adipose tissues of high fat fed HDAC9 knockout mice accumulated more anti-inflammatory M2 polarized macrophages and Treg cells, consistent with reduced adipose tissue inflammation. These findings suggest that HDAC9 disrupts adipose tissue function in high fat feeding, leading thereby to adipose tissue inflammation and glucose intolerance. Thus, HDAC9 could be a novel therapeutic target in the treatment of disorders associated with diet-induced obesity.
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Histone Deacetylase 9 Is a Negative Regulator of Adipogenic Differentiation
The Journal of biological chemistry, 2011Co-Authors: Tapan K. Chatterjee, Gila Idelman, Víctor M. Blanco, Andra L. Blomkalns, Mark Piegore, Daniel S. Weintraub, Santosh Kumar, Srinivas Rajsheker, David Manka, Steven M. RudichAbstract:Differentiation of preadipocytes into mature adipocytes capable of efficiently storing lipids is an important regulatory mechanism in obesity. Here, we examined the involvement of Histone Deacetylases (HDACs) and Histone acetyltransferases (HATs) in the regulation of adipogenesis. We find that among the various members of the HDAC and HAT families, only HDAC9 exhibited dramatic down-regulation preceding adipogenic differentiation. Preadipocytes from HDAC9 gene knock-out mice exhibited accelerated adipogenic differentiation, whereas HDAC9 overexpression in 3T3-L1 preadipocytes suppressed adipogenic differentiation, demonstrating its direct role as a negative regulator of adipogenesis. HDAC9 expression was higher in visceral as compared with subcutaneous preadipocytes, negatively correlating with their potential to undergo adipogenic differentiation in vitro. HDAC9 localized in the nucleus, and its negative regulation of adipogenesis segregates with the N-terminal nuclear targeting domain, whereas the C-terminal Deacetylase domain is dispensable for this function. HDAC9 co-precipitates with USF1 and is recruited with USF1 at the E-box region of the C/EBPα gene promoter in preadipocytes. Upon induction of adipogenic differentiation, HDAC9 is down-regulated, leading to its dissociation from the USF1 complex, whereas p300 HAT is up-regulated to allow its association with USF1 and accumulation at the E-box site of the C/EBPα promoter in differentiated adipocytes. This reciprocal regulation of HDAC9 and p300 HAT in the USF1 complex is associated with increased C/EBPα expression, a master regulator of adipogenic differentiation. These findings provide new insights into mechanisms of adipogenic differentiation and document a critical regulatory role for HDAC9 in adipogenic differentiation through a Deacetylase-independent mechanism.
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abstract 15527 Histone Deacetylase 9 hdac9 is an endogenous inhibitor of adipocyte differentiation role in diet induced obesity
Circulation, 2010Co-Authors: Tapan K. Chatterjee, Gila Idelman, Víctor M. Blanco, Andra L. Blomkalns, Mark Piegore, Daniel S. Weintraub, Santosh Kumar, Srinivas Rajsheker, David Manka, Yao Liang TangAbstract:Failure of adipocytes to efficiently differentiate and store energy in obesity is associated with adipose tissue inflammation, ectopic lipid deposition, insulin resistance, and increased cardiovasc...
Neal L Weintraub - One of the best experts on this subject based on the ideXlab platform.
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role of Histone Deacetylase 9 in regulating adipogenic differentiation and high fat diet induced metabolic disease
Adipocyte, 2014Co-Authors: Tapan K. Chatterjee, Joshua E Basford, Kan Hui Yiew, David W Stepp, David Y Hui, Neal L WeintraubAbstract:Adipose tissue serves as both a storage site for excess calories and as an endocrine organ, secreting hormones such as adiponectin that promote metabolic homeostasis. In obesity, adipose tissue expands primarily by hypertrophy (enlargement of existing adipocytes) rather than hyperplasia (generation of new adipocytes via adipogenic differentiation of preadipocytes). Progressive adipocyte hypertrophy leads to inflammation, insulin resistance, dyslipidemia, and ectopic lipid deposition, the hallmark characteristics of metabolic disease. We demonstrate that during chronic high fat feeding in mice, adipogenic differentiation is impaired due to the actions of Histone Deacetylase 9 (HDAC9), a member of the class II family of HDACs. Mechanistically, upregulated HDAC9 expression blocks the adipogenic differentiation program during chronic high fat feeding, leading to accumulation of improperly differentiated adipocytes with diminished expression of adiponectin. These adipocytes are inefficient at storing lipid, resulting in ectopic lipid deposition in the liver. HDAC9 gene deletion prevents the detrimental effects of chronic high fat feeding on adipogenic differentiation, increases adiponectin expression, and enhances energy expenditure by promoting beige adipogenesis, thus leading to reduced body mass and improved metabolic homeostasis. HDAC9 is therefore emerging as a critical regulator of adipose tissue health and a novel therapeutic target for obesity-related disease.
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hdac9 knockout mice are protected from adipose tissue dysfunction and systemic metabolic disease during high fat feeding
Diabetes, 2014Co-Authors: Tapan K. Chatterjee, Víctor M. Blanco, Andra L. Blomkalns, Steven M. Rudich, Joshua E Basford, David Y Hui, Ellen Knoll, Wilson Tong, Alex B Lentsch, Neal L WeintraubAbstract:During chronic caloric excess, adipose tissue expands primarily by enlargement of individual adipocytes, which become stressed with lipid overloading, thereby contributing to obesity-related disease. Although adipose tissue contains numerous preadipocytes, differentiation into functionally competent adipocytes is insufficient to accommodate the chronic caloric excess and prevent adipocyte overloading. We report for the first time that a chronic high-fat diet (HFD) impairs adipogenic differentiation, leading to accumulation of inefficiently differentiated adipocytes with blunted expression of adipogenic differentiation-specific genes. Preadipocytes from these mice likewise exhibit impaired adipogenic differentiation, and this phenotype persists during in vitro cell culture. HFD-induced impaired adipogenic differentiation is associated with elevated expression of Histone Deacetylase 9 (HDAC9), an endogenous negative regulator of adipogenic differentiation. Genetic ablation of HDAC9 improves adipogenic differentiation and systemic metabolic state during an HFD, resulting in diminished weight gain, improved glucose tolerance and insulin sensitivity, and reduced hepatosteatosis. Moreover, compared with wild-type mice, HDAC9 knockout mice exhibit upregulated expression of beige adipocyte marker genes, particularly during an HFD, in association with increased energy expenditure and adaptive thermogenesis. These results suggest that targeting HDAC9 may be an effective strategy for combating obesity-related metabolic disease.
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abstract 61 Histone Deacetylase 9 hdac9 dysregulation precipitates high fat diet induced adipose tissue dysfunction and systemic metabolic disorders
Arteriosclerosis Thrombosis and Vascular Biology, 2012Co-Authors: Tapan K. Chatterjee, Andra L. Blomkalns, Joshua E Basford, David Y Hui, Ellen Knoll, Wilson Tong, Neal L WeintraubAbstract:During chronic overfeeding, adipose tissue expansion contributes to adipose inflammation, insulin resistance and obesity-related diabetes. Consequently, identifying mechanisms that promote “healthy” growth of adipose tissues could potentially improve obesity-related disease. We previously demonstrated that endogenous HDAC9 negatively regulates adipogenic differentiation in isolated preadipocytes. Here, we investigated the role of HDAC9 in regulating adipose tissue function and glucose intolerance in high fat fed mice. High fat feeding upregulated HDAC9 expression in adipose tissues, isolated preadipocytes and adipocytes, in conjunction with reduced expression of adipocyte differentiation-specific genes C/EBPα, PPARγ, FABP4, and adiponectin. HDAC9 gene knockout completely prevented these effects of high fat feeding on adipocyte differentiation-specific gene expression and adipogenic differentiation in vitro. HDAC9 knockout mice also gained less weight and exhibited less visceral adiposity, despite similar food intake, as compared to wild type mice during high fat feeding. In addition, HDAC9 gene deletion blunted elevations of plasma pro-inflammatory adipokines leptin and resistin, and resulted in improved systemic glucose tolerance, in the setting of high fat diet. Adipocytes were smaller in HDAC9 knockout mice, while ectopic lipid accumulation, as revealed by hepatosteatosis, following high fat feeding was completely prevented by HDAC9 gene knockout. Interestingly, adipose tissues of high fat fed HDAC9 knockout mice accumulated more anti-inflammatory M2 polarized macrophages and Treg cells, consistent with reduced adipose tissue inflammation. These findings suggest that HDAC9 disrupts adipose tissue function in high fat feeding, leading thereby to adipose tissue inflammation and glucose intolerance. Thus, HDAC9 could be a novel therapeutic target in the treatment of disorders associated with diet-induced obesity.
Jiyoung Lee - One of the best experts on this subject based on the ideXlab platform.
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Histone Deacetylase 9 its role in the pathogenesis of diabetes and other chronic diseases
Diabetes & Metabolism Journal, 2020Co-Authors: Eun Hee Cho, Jiyoung LeeAbstract:As a member of the class IIa Histone Deacetylases (HDACs), HDAC9 catalyzes the deacetylation of Histones and transcription factors, commonly leading to the suppression of gene transcription. The activity of HDAC9 is regulated transcriptionally and post-translationally. HDAC9 is known to play an essential role in regulating myocyte and adipocyte differentiation and cardiac muscle development. Also, recent studies have suggested that HDAC9 is involved in the pathogenesis of chronic diseases, including cardiovascular diseases, osteoporosis, autoimmune disease, cancer, obesity, insulin resistance, and liver fibrosis. HDAC9 modulates the expression of genes related to the pathogenesis of chronic diseases by altering chromatin structure in their promotor region or reducing the transcriptional activity of their respective transcription factors. This review summarizes the current knowledge of the regulation of HDAC9 expression and activity. Also, the roles of HDAC9 in the pathogenesis of chronic diseases are discussed, along with potential underlying mechanisms.
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Histone Deacetylase 9 plays a role in the antifibrogenic effect of astaxanthin in hepatic stellate cells
Journal of Nutritional Biochemistry, 2017Co-Authors: Yue Yang, Minkyung Bae, Youngki Park, Yoojin Lee, Tho X Pham, Swetha Rudraiah, Jose E Manautou, Sung I Koo, Jiyoung LeeAbstract:Activation of hepatic stellate cells (HSCs) is critical for liver fibrosis development. Previously, we showed that astaxanthin (ASTX), a xanthophyll carotenoid, has antifibrogenic effects in LX-2 cells, a human HSC cell line. We sought to determine the effect of ASTX on HSC activation, and to identify molecular mediators that are critically involved in the processes. ASTX prevented the activation of mouse primary HSCs, as evidenced by attenuated induction of procollagen type I α1. In human primary HSCs, ASTX also inhibited transforming growth factor β1 (TGFβ1)-induced fibrogenic gene expression. Among 11 classical Histone Deacetylases (HDACs), difference in HDAC9 mRNA levels between quiescent and activated HSCs was most evident while ASTX significantly decreased the expression of HDAC9 and its transcriptional regulator myocyte enhancer factor 2 (MEF2). ASTX decreased HDAC9 protein as well. In the activated HSCs, ASTX significantly reduced mRNA of HDAC9 and MEF2. Human primary biliary cirrhosis livers showed significantly higher HDAC9 mRNA and protein levels than normal livers, and other liver pathologies also exhibited induced HDAC9 expression. HDAC9 knockdown in LX-2 cells decreased TGFβ1-induced fibrogenic gene expression. In conclusion, ASTX inhibits HSC activation and facilitates HSC inactivation, which is attributable to its inhibitory action on HDAC9 expression.
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astaxanthin prevented and reversed the activation of mouse primary hepatic stellate cells by inhibiting the myocyte enhancer factor 2 dependent expression of Histone Deacetylase 9
The FASEB Journal, 2015Co-Authors: Yue Yang, Minkyung Bae, Youngki Park, Swetha Rudraiah, Jose E Manautou, Sung I Koo, Bohkyung Kim, Jiyoung LeeAbstract:Dysregulated activation of hepatic stellate cells (HSCs) is a critical event in the development of liver fibrosis/cirrhosis. We previously reported that astaxanthin (ASTX), a xanthophyll carotenoid...
Nilamadhab Mishra - One of the best experts on this subject based on the ideXlab platform.
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Histone Deacetylase 9 represses cholesterol efflux and alternatively activated macrophages in atherosclerosis development
Arteriosclerosis Thrombosis and Vascular Biology, 2014Co-Authors: Qiang Cao, Shunxing Rong, Joyce J Repa, Richard W St Clair, John S Parks, Nilamadhab MishraAbstract:Objective— Recent genome-wide association studies revealed that a genetic variant in the loci corresponding to Histone Deacetylase 9 (HDAC9) is associated with large vessel stroke. HDAC9 expression was upregulated in human atherosclerotic plaques in different arteries. The molecular mechanisms how HDAC9 might increase atherosclerosis is not clear. Approach and Results— In this study, we show that systemic and bone marrow cell deletion of HDAC9 decreased atherosclerosis in LDLr −/− mice with minimal effect on plasma lipid concentrations. HDAC9 deletion resulted upregulation of lipid homeostatic genes, downregulation of inflammatory genes, and polarization toward an M2 phenotype via increased accumulation of total acetylated H3 and H3K9 at the promoters of ABCA1, ABCG1, and PPAR-γ in macrophages. Conclusions— We conclude that macrophage HDAC9 upregulation is atherogenic via suppression of cholesterol efflux and generation of alternatively activated macrophages in atherosclerosis.
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Histone Deacetylase 9 deficiency protects against effector T cell-mediated systemic autoimmunity*
The Journal of biological chemistry, 2011Co-Authors: Kailin Yan, Qiang Cao, Christopher M. Reilly, Nicolas L. Young, Benjamin A. Garcia, Nilamadhab MishraAbstract:Co-repressor Histone Deacetylase 9 (HDAC9) plays a key role in the development and differentiation of many types of cells, including regulatory T cells. However, the biological function of HDAC9 in T effector cells is unknown. Systemic autoimmune diseases like lupus, diabetes, and rheumatoid arthritis have dysfunctional effector T cells. To determine the role of HDAC9 in systemic autoimmunity, we created MRL/lpr mice with HDAC9 deficiency that have aberrant effector T cell function. HDAC9 deficiency led to decreased lympho-proliferation, inflammation, autoantibody production, and increased survival in MRL/lpr mice. HDAC9-deficient mice manifested Th2 polarization, decreased T effector follicular cells positive for inducible co-stimulator, and activated T cells in vivo compared with HDAC9-intact MRL/lpr mice. HDAC9 deficiency also resulted in increased GATA3 and roquin and decreased BCL6 gene expression. HDAC9 deficiency was associated with increased site-specific lysine Histone acetylation at H3 (H3K9, H3K14, and H3K18) globally that was localized to IL-4, roquin, and peroxisome proliferator-activated receptor-γ promoters with increased gene expression, respectively. In kidney and spleen, HDAC9 deficiency decreased inflammation and cytokine and chemokine production due to peroxisome proliferator-activated receptor γ overexpression. These findings suggest that HDAC9 acts as an epigenetic switch in effector T cell-mediated systemic autoimmunity.
Andra L. Blomkalns - One of the best experts on this subject based on the ideXlab platform.
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hdac9 knockout mice are protected from adipose tissue dysfunction and systemic metabolic disease during high fat feeding
Diabetes, 2014Co-Authors: Tapan K. Chatterjee, Víctor M. Blanco, Andra L. Blomkalns, Steven M. Rudich, Joshua E Basford, David Y Hui, Ellen Knoll, Wilson Tong, Alex B Lentsch, Neal L WeintraubAbstract:During chronic caloric excess, adipose tissue expands primarily by enlargement of individual adipocytes, which become stressed with lipid overloading, thereby contributing to obesity-related disease. Although adipose tissue contains numerous preadipocytes, differentiation into functionally competent adipocytes is insufficient to accommodate the chronic caloric excess and prevent adipocyte overloading. We report for the first time that a chronic high-fat diet (HFD) impairs adipogenic differentiation, leading to accumulation of inefficiently differentiated adipocytes with blunted expression of adipogenic differentiation-specific genes. Preadipocytes from these mice likewise exhibit impaired adipogenic differentiation, and this phenotype persists during in vitro cell culture. HFD-induced impaired adipogenic differentiation is associated with elevated expression of Histone Deacetylase 9 (HDAC9), an endogenous negative regulator of adipogenic differentiation. Genetic ablation of HDAC9 improves adipogenic differentiation and systemic metabolic state during an HFD, resulting in diminished weight gain, improved glucose tolerance and insulin sensitivity, and reduced hepatosteatosis. Moreover, compared with wild-type mice, HDAC9 knockout mice exhibit upregulated expression of beige adipocyte marker genes, particularly during an HFD, in association with increased energy expenditure and adaptive thermogenesis. These results suggest that targeting HDAC9 may be an effective strategy for combating obesity-related metabolic disease.
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abstract 61 Histone Deacetylase 9 hdac9 dysregulation precipitates high fat diet induced adipose tissue dysfunction and systemic metabolic disorders
Arteriosclerosis Thrombosis and Vascular Biology, 2012Co-Authors: Tapan K. Chatterjee, Andra L. Blomkalns, Joshua E Basford, David Y Hui, Ellen Knoll, Wilson Tong, Neal L WeintraubAbstract:During chronic overfeeding, adipose tissue expansion contributes to adipose inflammation, insulin resistance and obesity-related diabetes. Consequently, identifying mechanisms that promote “healthy” growth of adipose tissues could potentially improve obesity-related disease. We previously demonstrated that endogenous HDAC9 negatively regulates adipogenic differentiation in isolated preadipocytes. Here, we investigated the role of HDAC9 in regulating adipose tissue function and glucose intolerance in high fat fed mice. High fat feeding upregulated HDAC9 expression in adipose tissues, isolated preadipocytes and adipocytes, in conjunction with reduced expression of adipocyte differentiation-specific genes C/EBPα, PPARγ, FABP4, and adiponectin. HDAC9 gene knockout completely prevented these effects of high fat feeding on adipocyte differentiation-specific gene expression and adipogenic differentiation in vitro. HDAC9 knockout mice also gained less weight and exhibited less visceral adiposity, despite similar food intake, as compared to wild type mice during high fat feeding. In addition, HDAC9 gene deletion blunted elevations of plasma pro-inflammatory adipokines leptin and resistin, and resulted in improved systemic glucose tolerance, in the setting of high fat diet. Adipocytes were smaller in HDAC9 knockout mice, while ectopic lipid accumulation, as revealed by hepatosteatosis, following high fat feeding was completely prevented by HDAC9 gene knockout. Interestingly, adipose tissues of high fat fed HDAC9 knockout mice accumulated more anti-inflammatory M2 polarized macrophages and Treg cells, consistent with reduced adipose tissue inflammation. These findings suggest that HDAC9 disrupts adipose tissue function in high fat feeding, leading thereby to adipose tissue inflammation and glucose intolerance. Thus, HDAC9 could be a novel therapeutic target in the treatment of disorders associated with diet-induced obesity.
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Histone Deacetylase 9 Is a Negative Regulator of Adipogenic Differentiation
The Journal of biological chemistry, 2011Co-Authors: Tapan K. Chatterjee, Gila Idelman, Víctor M. Blanco, Andra L. Blomkalns, Mark Piegore, Daniel S. Weintraub, Santosh Kumar, Srinivas Rajsheker, David Manka, Steven M. RudichAbstract:Differentiation of preadipocytes into mature adipocytes capable of efficiently storing lipids is an important regulatory mechanism in obesity. Here, we examined the involvement of Histone Deacetylases (HDACs) and Histone acetyltransferases (HATs) in the regulation of adipogenesis. We find that among the various members of the HDAC and HAT families, only HDAC9 exhibited dramatic down-regulation preceding adipogenic differentiation. Preadipocytes from HDAC9 gene knock-out mice exhibited accelerated adipogenic differentiation, whereas HDAC9 overexpression in 3T3-L1 preadipocytes suppressed adipogenic differentiation, demonstrating its direct role as a negative regulator of adipogenesis. HDAC9 expression was higher in visceral as compared with subcutaneous preadipocytes, negatively correlating with their potential to undergo adipogenic differentiation in vitro. HDAC9 localized in the nucleus, and its negative regulation of adipogenesis segregates with the N-terminal nuclear targeting domain, whereas the C-terminal Deacetylase domain is dispensable for this function. HDAC9 co-precipitates with USF1 and is recruited with USF1 at the E-box region of the C/EBPα gene promoter in preadipocytes. Upon induction of adipogenic differentiation, HDAC9 is down-regulated, leading to its dissociation from the USF1 complex, whereas p300 HAT is up-regulated to allow its association with USF1 and accumulation at the E-box site of the C/EBPα promoter in differentiated adipocytes. This reciprocal regulation of HDAC9 and p300 HAT in the USF1 complex is associated with increased C/EBPα expression, a master regulator of adipogenic differentiation. These findings provide new insights into mechanisms of adipogenic differentiation and document a critical regulatory role for HDAC9 in adipogenic differentiation through a Deacetylase-independent mechanism.
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abstract 15527 Histone Deacetylase 9 hdac9 is an endogenous inhibitor of adipocyte differentiation role in diet induced obesity
Circulation, 2010Co-Authors: Tapan K. Chatterjee, Gila Idelman, Víctor M. Blanco, Andra L. Blomkalns, Mark Piegore, Daniel S. Weintraub, Santosh Kumar, Srinivas Rajsheker, David Manka, Yao Liang TangAbstract:Failure of adipocytes to efficiently differentiate and store energy in obesity is associated with adipose tissue inflammation, ectopic lipid deposition, insulin resistance, and increased cardiovasc...