The incidence of obesity is increasing at an alarming rate world-wide and represents a major risk factor for both diabetes and cardiovascular disease. In diet-induced obesity (DIO), the most common form of human obesity, adipose tissue expands predominately by hypertrophy of pre-existing adipocytes. Although conversion of preadipocytes to adipocytes occurs in DIO, it is insufficient to match caloric consumption. Over time, adipocytes enlarge beyond their physiological limit and become mechanically stressed, inflamed, and insulin resistant, thus contributing to cardiometabolic disease. The causes and consequences of this block in efficient adipogenic differentiation during DIO are unclear. We present novel evidence that expression of histone deacetylase 9 (HDAC9), an endogenous repressor of adipogenic differentiation, is markedly upregulated in adipose tissues during DIO, in conjunction with impaired adipogenic differentiation. Genetic ablation of HDAC9 alleviates the block in adipogenic differentiation and improves glucose tolerance and insulin sensitivity. Moreover, ablation of HDAC9 stimulates thermogenic beige adipocytes, thus improving energy balance and preventing ectopic lipid deposition. HDAC9 gene deletion also favorably impacts perivascular adipose tissue (PVAT) and diminishes atherosclerosis in LDLr knockout mice. We hypothesize that HDAC9 acts as a molecular brake on adipogenic differentiation during DIO, thus contributing to insulin resistance and accelerated atherosclerosis. To test this hypothesis, we propose three specific aims:
Aim 1 will identify the epigenetic mechanisms leading to aberrant HDAC9 expression during DIO, focusing on the histone methyltransferase EZH2. Our preliminary data suggest that EZH2 fails to silence the HDAC9 promoter during DIO, thus contributing to impaired adipogenic differentiation.
In Aim 2, we will determine whether adipocyte-specific HDAC9 gene deletion improves adipogenic differentiation, glucose tolerance and insulin sensitivity during DIO using a novel floxed mouse created for this application.
In Aim 3, we will determine whether adipocyte-specific HDAC9 gene deletion is sufficient to attenuate atherosclerosis in LDLr knockout mice in the setting of DIO. Using a novel PVAT transplantation model developed in our lab, we will also determine whether deletion of HDAC9 in PVAT locally modulates the development of atherosclerosis. The proposed studies will provide novel insight into the role of HDAC9 in adipose tissue biology and atherosclerosis and may also form the basis for development of selective HDAC9 blocking agents to counter DIO.

Public Health Relevance

Consumption of a high fat diet can lead to development of obesity-related disease, a leading cause of heart attacks. We have identified a particular protein, histone deacetylase 9, expression of which is increased in fat tissue during high fat diet and contributes to obesity-related disease. We will examine how the expression of this protein is elevated by high fat diet, where it works in the body to cause obesity-related disease, and how it contributes to atherosclerosis, the underlying cause of heart attacks.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Vascular Cell and Molecular Biology Study Section (VCMB)
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Olive, Michelle
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Georgia Regents University
Internal Medicine/Medicine
Schools of Medicine
United States
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Benson, Tyler W; Weintraub, Neal L; Kim, Ha Won et al. (2018) A single high-fat meal provokes pathological erythrocyte remodeling and increases myeloperoxidase levels: implications for acute coronary syndrome. Lab Invest 98:1300-1310
Bayoumi, Ahmed S; Park, Kyoung-Mi; Wang, Yongchao et al. (2018) A carvedilol-responsive microRNA, miR-125b-5p protects the heart from acute myocardial infarction by repressing pro-apoptotic bak1 and klf13 in cardiomyocytes. J Mol Cell Cardiol 114:72-82
Zhang, Hanfang; Hudson, Farlyn Z; Xu, Zhimin et al. (2018) Neurofibromin Deficiency Induces Endothelial Cell Proliferation and Retinal Neovascularization. Invest Ophthalmol Vis Sci 59:2520-2528
Cuomo, Jason R; Javaheri, Sean P; Sharma, Gyanendra K et al. (2018) How to prevent and manage radiation-induced coronary artery disease. Heart 104:1647-1653
Yang, Qiuhua; Xu, Jiean; Ma, Qian et al. (2018) PRKAA1/AMPK?1-driven glycolysis in endothelial cells exposed to disturbed flow protects against atherosclerosis. Nat Commun 9:4667
Teoh, Jian-Peng; Bayoumi, Ahmed S; Aonuma, Tatsuya et al. (2018) ?-arrestin-biased agonism of ?-adrenergic receptor regulates Dicer-mediated microRNA maturation to promote cardioprotective signaling. J Mol Cell Cardiol 118:225-236
Ruan, Xiao-Fen; Li, Yong-Jun; Ju, Cheng-Wei et al. (2018) Exosomes from Suxiao Jiuxin pill-treated cardiac mesenchymal stem cells decrease H3K27 demethylase UTX expression in mouse cardiomyocytes in vitro. Acta Pharmacol Sin 39:579-586
Benson, Tyler W; Weintraub, Daniel S; Crowe, Matthew et al. (2018) Deletion of the Duffy antigen receptor for chemokines (DARC) promotes insulin resistance and adipose tissue inflammation during high fat feeding. Mol Cell Endocrinol 473:79-88
Ren, Xiaoping; Roessler, Anne E; Lynch 4th, Thomas L et al. (2018) Cardioprotection via the skin; Nociceptor-Induced Conditioning Against Cardiac MI, in the NIC of time. Am J Physiol Heart Circ Physiol :
Zhang, Min; Zeng, Xianqiu; Yang, Qiuhua et al. (2018) Ablation of Myeloid ADK (Adenosine Kinase) Epigenetically Suppresses Atherosclerosis in ApoE-/- (Apolipoprotein E Deficient) Mice. Arterioscler Thromb Vasc Biol 38:2780-2792

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