Abstract 15527: Histone Deacetylase 9 (HDAC9) is an Endogenous Inhibitor of Adipocyte Differentiation: Role in Diet-Induced Obesity
Failure of adipocytes to efficiently differentiate and store energy in obesity is associated with adipose tissue inflammation, ectopic lipid deposition, insulin resistance, and increased cardiovascular risk. However, the mechanisms that regulate adipocyte differentiation and function in obesity remain to be elucidated. Here, we provide novel evidence that HDAC9 is an endogenous inhibitor of adipocyte differentiation, and that upregulated HDAC9 expression in adipose tissues during high fat feeding may contribute to adipose tissue dysfunction in obesity. We found that amongst the 11 members of the HDAC gene family, only HDAC9 displayed a dramatic down-regulation (mRNA and protein) during differentiation of human, mouse, and 3T3-L1 preadipocytes. Down-regulation of HDAC9 preceded induction of the adipogenic gene program and accumulation of lipid droplets during in vitro differentiation of preadipocytes, while HDAC9 overexpression by transient transfection blunted adipogenic differentiation of 3T3-L1 cells. Moreover, preadipocytes isolated from HDAC9 knockout mice exhibited accelerated lipid droplet accumulation during in vitro differentiation as compared to their wild type counterparts. During high fat feeding, HDAC9 expression in murine adipose tissues was markedly upregulated, in conjunction with adipose tissue inflammation and reduced expression of adipocyte-specific genes. Moreover, as compared with chow fed mice, preadipocytes isolated from high fat fed mice displayed impaired in vitro adipogenic differentiation and lipid droplet accumulation. Co-immunoprecipitation and chromatin immunoprecipitation assays with preadipocytes demonstrated that HDAC9 physically interacts with the transcription factor USF1 at the proximal promoter region of the C/EBPα gene, a master regulator of adipogenesis. During induction of adipogenesis, HDAC9 is dissociated from the transcription factor complex, thereby activating the adipogenic gene program. Together, these data establish HDAC9 as an endogenous inhibitor of adipocyte differentiation and suggest that dysregulated expression of HDAC9 in adipose tissues may contribute to impaired adipocyte differentiation and adipose tissue dysfunction in obesity.
- © 2010 by American Heart Association, Inc.