Abstract 61: Histone Deacetylase 9 (HDAC9) Dysregulation Precipitates High-Fat-Diet--Induced Adipose Tissue Dysfunction and Systemic Metabolic Disorders

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.