Hdac3 shapes adipocyte size, death susceptibility, macrophage turnover, and vascular remodeling in a mouse model of obesity

The crosstalk between adipocytes and macrophages is crucial in adipose tissue biology. The aim of this study was to investigate the role of adipocyte-expressed histone deacetylase 3 (Hdac3) on adipose tissue plasticity and immune cell composition in response to high-fat feeding. Here we show that adipocyte-speci c deletion of Hdac3 gene in mice affects the response to high-fat overload, by reducing fat mass and adipocyte size in visceral fat of knockout mice. In the absence of adipocyte Hdac3, visceral fat shows vascular remodeling and increased macrophage content. Colocalization of F4/80 with Ki-67 indicates proliferation of resident macrophages. This is coupled with increased crown-like structures and adipocyte death in visceral fat of knockout mice, exacerbated by high-fat feeding. Hdac3 silencing in cultured adipocytes and inactivation in mice promotes a pro-apoptotic microenvironment, as assessed by positivity to Annexin V and cleaved Caspase 3. In conclusion, we propose that Hdac3 acts as a rheostat in visceral fat, differentially affecting lipid accumulation and adipocyte size during the progress of HFD feeding, and limiting cell death, vascularization, and macrophage proliferation, in a mouse model of obesity.