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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL126949-01A1
Application #
9030314
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Olive, Michelle
Project Start
2016-03-01
Project End
2020-02-29
Budget Start
2016-03-01
Budget End
2017-02-28
Support Year
1
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Georgia Regents University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Augusta
State
GA
Country
United States
Zip Code
30912
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