Abstract 13138: Adipocyte Histone Deacetylase 9 is a Temperature Sensitive Gene That Regulates the Balance Between Energy Storage and Consumption in Obesity

IntroductionCold temperatures elicit adaptive thermogenesis in subcutaneous white adipose tissues (sWAT), and identifying the mechanisms may uncover new therapeutic targets in obesity. We reported that adipose histone deacetylase 9 (HDAC9) is upregulated in mice with diet-induced obesity (DIO), and global HDAC9 gene deletion protected mice against DIO. Here, we tested the impact of adipose-specific HDAC9 gene deletion on DIO, and the impact of temperature on sWAT HDAC9 expression.MethodsMice were housed in either thermoneutral (30-32°C) or ambient (20-22°C) environments and fed high fat diet (HFD, 60%) or chow diet (CD). sWAT with or without skin was incubated ex vivo with 10 mL/g DMEM at 12°C or 37°C for 1-8 hours. sWAT was separated from the skin, flash frozen for qRT-PCR analysis, and conditioned medium was collected. sWAT from 14 patients undergoing abdominal surgeries were collected and flash frozen for analysis.ResultsAdipose-specific HDAC9 knockout mice (created by breeding HDAC9 floxed mice with adipo-Cre mice) exhibited selective downregulation of HDAC9 expression in mature adipocytes. When fed a HFD, these mice exhibited 30% less weight gain compared to controls, despite 1.4 fold increased food intake, in association with increased energy expenditure and O2 consumption, leading to improved insulin sensitivity and glucose tolerance, and recapitulating the phenotype of global HDAC9 knockout mice. CL57BI/6 mice housed at ambient temperature gained 34% less weight compared to mice housed at thermoneutral temperature, in association with a 10 fold decrease in adipose HDAC9 expression. Ex vivo incubation of sWAT at 13°C for 8 hours selectively reduced HDAC9 expression by 60% (no effect on HDAC4, 5, or 7) compared to 37°C, which did not require the presence of skin. Furthermore, the conditioned medium from 13°C-exposed sWAT significantly downregulated HDAC9 expression by 30% in sWAT incubated at 37°C, indicating that cold temperature-induced HDAC9 downregulation in sWAT is mediated by a transferrable factor. Mechanistically, expression of miR-203, which is predicted to bind to the 3’UTR of HDAC9, is upregulated in 13°C-exposed sWAT. In humans, HDAC9 levels in sWAT were positively linearly correlated with BMI (r=.40, p