Abstract
Class I histone deacetylase inhibitors (HDACis) enhance whole body energy expenditure and attenuate high fat diet-induced insulin resistance. However, it is not clear whether this is exerted directly through activating brown fat thermogenesis. Here, we find that pan-HDACi TSA exerts paradoxical effects on brown fat gene expression, as it inhibits the expression of Ucp1, Pparγ and Prdm16 in brown adipocytes, while promoting the expression of other brown fat-specific genes such as Pgc1α, Pgc1β, Acox1 and Cidea. Further studies indicate that class I HDACi MS-275 significantly increases; whereas class II HDACi MC-1568 markedly reduces, the expression of Ucp1 and other brown fat-specific genes in treated brown adipocytes. ChIP assay reveals an enhanced H3 acetylation at the Pgc1α promoter in MS-275-treated brown adipocytes; whereas the effect of MC-1568 is associated with up-regulation of retinoblastoma protein (Rb) and an enhanced acetylation of H3K27 at the Rb promoter. Loss of function studies indicate that Pgc1α up-regulation largely mediates the stimulatory effect of class I HDACis on the thermogenic program, whereas up-regulation of Rb may be responsible for the inhibitory effect of class II HDACis. Thus, our data suggest that class I and II HDACis have differential effects on brown fat thermogenic gene expression.
Highlights
Most of the current studies investigating the mechanisms underlying the regulation of brown fat functions focus on cellular signaling pathways; less is known about the epigenetic mechanisms in this process
Further studies demonstrated that the beneficial effects of pan histone deacetylase inhibitors (HDACis) on energy metabolism and insulin sensitivity might be mediated through the inhibition of class I histone deacetylases (HDACs), since class I HDACi MS-275 mimics the beneficial effects of pan HDACis in diet-induced obese (DIO) mice[17]
We found that trichostatin A (TSA) (5, 50 and 500 nM) dose-dependently inhibited the expression of Ucp[1], Pparγ, PR domain-containing protein 16 (Prdm16) and Otop[1], while stimulating Pgc1α expression in BAT1 brown adipocyte cell line[18]
Summary
Most of the current studies investigating the mechanisms underlying the regulation of brown fat functions focus on cellular signaling pathways; less is known about the epigenetic mechanisms in this process. Further studies demonstrated that the beneficial effects of pan HDACis on energy metabolism and insulin sensitivity might be mediated through the inhibition of class I HDACs, since class I HDACi MS-275 mimics the beneficial effects of pan HDACis in DIO mice[17]. It is not clear whether class I HDACis enhance overall energy expenditure through activating brown fat thermogenesis, an integral part of total energy expenditure. Our previous data suggested a paradoxical effect of the pan-HDACis TSA and SAHA on brown adipocyte gene expression[18]. We assessed the histone acetylation status at the specific gene promoters and determined whether these genes mediated the effects of these HDACis via the loss of function approach with SiRNA knockdown
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