Role of histone deacetylase 9 in the development of adipose tissue senescence

Abstract

Background Senescence is a state associated with aging and obesity in which cells stop replicating. It has recently been shown that elimination of senescent cells by senolytic therapy can extend health and lifespan in mice. Our previous studies showed that global histone deacetylase 9 (HDAC9) gene deletion protected mice against obesity-associated metabolic disorder. Here, we hypothesized that HDAC9 expression during aging plays an important role in the development of adipose tissue senescence. Methods and Results Adipose tissue from 20-month old wild type mice showed increased expression of HDAC9 (2 fold) and senescence markers, p16 (5 fold) and p21 (2 fold) compared to 3-month old mice, as examined by qRT-PCR. Furthermore, HDAC9 expression in human subcutaneous adipose tissue positively correlated with age (r2=0.088, p=0.034). Intriguingly, adipose tissues from HDAC9 knockout (KO) mice exhibited reduced levels of senescence-associated beta-galactosidase (SABG) staining and lower expression of p16 and p21 (0.4 fold and 0.2 fold, respectively). Preadipocytes reside in adipose tissue and replenish aged or dying adipocytes, thus playing an important role in regulating adipose tissue health and senescence. Interestingly, reduced SABG staining was also observed in early passage primary preadipocyte culture derived from HDAC9 KO adipose tissue as compared to WT (17% vs 30% SABG+). Furthermore, we found that HDAC9 KO primary preadipocytes were resistant to senescence-inducing stimuli such as H2O2 treatment or UV light exposure as evaluated by senescent marker expression. Next, we measured adipose tissue mitochondrial function which is mechanistically linked to cellular senescence. Interestingly, HDAC9 gene deletion significantly increased adipose tissue mitochondrial oxygen consumption rate (e.g. increased basal and maximal respiration, greater proton leak and ATP production) in adipose tissue, as measured by the Seahorse Analyzer. Conclusion HDAC9 plays a crucial role in the development of adipose tissue senescence, possibly through regulating mitochondrial function, and thus, HDAC9 may be a promising target to combat the development of a senescent phenotype and to maintain healthy adipose tissue.