Sex-Dependent Role of Adipose Tissue HDAC9 in Diet-Induced Obesity and Metabolic Dysfunction

Abstract

Obesity is a major risk factor for both metabolic and cardiovascular disease. We reported that, in obese male mice, histone deacetylase 9 (HDAC9) is upregulated in adipose tissues, and global deletion of HDAC9 protected against high fat diet (HFD)-induced obesity and metabolic disease. Here, we investigated the impact of adipocyte-specific HDAC9 gene deletion on diet-induced obesity in male and female mice. The HDAC9 gene expression was increased in adipose tissues of obese male and female mice and HDAC9 expression correlated positively with body mass index in humans. Interestingly, female, but not male, adipocyte-specific HDAC9 KO mice on HFD exhibited reduced body weight and visceral adipose tissue mass, adipocyte hypertrophy, and improved insulin sensitivity, glucose tolerance and adipogenic differentiation gene expression. Furthermore, adipocyte-specific HDAC9 gene deletion in female mice improved metabolic health as assessed by whole body energy expenditure, oxygen consumption, and adaptive thermogenesis. Mechanistically, compared to female mice, HFD-fed male mice exhibited preferential HDAC9 expression in the stromovascular fraction, which may have offset the impact of adipocyte-specific HDAC9 gene deletion in male mice. These results suggest that HDAC9 expressed in adipocytes is detrimental to obesity in female mice and provides novel evidence of sex-related differences in HDAC9 cellular expression and contribution to obesity-related metabolic disease.

Sex- and Age-Dependent Changes in the Adiponectin/Leptin Ratio in Experimental Diet-Induced Obesity in Mice

“…Despite the well-known differences in metabolic physiological systems, diseases and treatment outcomes among sex, the models used in the study of obesity are limited by the underrepresentation of females [ 23 , 24 , 25 ], as the presence of both sexes in animal as well as in cell-based studies has been recently considered [ 26 ]. In this context, it is necessary to examine the sex-specific characteristics of glucose metabolism as they are clearly involved in regulatory mechanisms in clinical pathologies including metabolic syndrome, obesity and T2D [ 27 , 28 ]. Obesity superimposed on aging drastically alters the inflammatory status, promoting the development of metabolic diseases, such as T2D, metabolic syndrome and cardiovascular disease [ 29 ].…”

Impact of housing temperature on adipose tissue HDAC9 expression and adipogenic differentiation in high fat‐fed mice

“…Nevertheless, adipogenic differentiation of preadipocytes derived from human subcutaneous adipose tissue has been negatively correlated with body mass index [36]. Accordingly, we recently showed that body mass index positively correlates with subcutaneous adipose tissue HDAC9 expression in humans, who typically live in climate‐controlled environments [37], suggesting that our findings are potentially translationally relevant.…”

Identification of novel prognostic targets in coronary artery disease and related complications using bioinformatics and next generation sequencing data analysis

“…Studies have found that CEACAM1 [237], STAT1 [238], ARG1 [239], TLR4 [240], LRRK2 [241], ABCA1 [242], PTGS2 [243], CYP2D6 [244], JAK2 [245], TLR2 [246], DUSP6 [247], CYP1B1 [248], CCR1 [249], HDAC9 [250], LATS2 [251], IL1RN [252], GCH1 [253], PELI1 [254], EGR1 [255], HIPK3 [256], CCR2 [257], GCLC (glutamate-cysteine ligase catalytic subunit) [258], KLF3 [259], VEGFA (vascular endothelial growth factor A) [260], ITGB1 [261], RASA1 [262], PTPN12 [263], SNRK (SNF related kinase) [264], PRKAR1A [265], LDLR (low density lipoprotein receptor) [266], SIRT1 [267], NOD2 [268], VCAN (versican) [269], TET2 [270], PFKFB2 [271], ZBTB20 [272], MYBL2 [273], PF4 [274], VEGFB (vascular endothelial growth factor B) [275], CCR7 [276], PRDX2 [277], HSPB1 [278], ZNF791 [279], IGFBP4 [280], ESF1 [281], SNHG8 [282], LGALS3 [283] and LGMN (legumain) [284] are altered expression in myocardial infarction. Altered expression of CEACAM1 [176], ACSL1 [285], STAT1 [286], TLR4 [287], ABCA1 [288], TLR5 [183], F2RL1 [289], CYP2D6 [290], PDK4 [291], RNF213 [186], JAK2 [292], TLR8 [189], NOTCH2 [293], CENPJ (centromere protein J) [294], FNIP1 [295], TLR2 [296], KIDINS220 [297], DUSP6 [298], CYP1B1 [299], S1PR3 [300], NCOA2 [301], HDAC9 [302], PELI1 [303], EGR1 [304], HIF1A [305], CCR2 [306], IR...…”