Class I and II Histone Deacetylase Inhibitors Differentially Regulate Thermogenic Gene Expression in Brown Adipocytes

Scientific Reports
Anubama RajanBingzhong Xue

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...Continue Reading

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Citations

Jun 17, 2020·Obesity Reviews : an Official Journal of the International Association for the Study of Obesity·Daniel Castellano-CastilloMaría Isabel Queipo-Ortuño
Jun 21, 2020·International Journal of Molecular Sciences·Melvin A AmbeleMichael S Pepper
Jul 7, 2020·Frontiers in Cell and Developmental Biology·Minjeong YeonDooil Jeoung
Jul 22, 2019·Molecular Aspects of Medicine·Li LiJohn R Speakman
Nov 17, 2020·Frontiers in Genetics·Shaza AsifKyoung-Han Kim
Apr 20, 2021·Life Sciences·M Janaki RamaiahRajasekhar Reddy Manyam
Oct 23, 2021·ELife·Sydney P Thomas, John M Denu

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Methods Mentioned

BETA
histone acetylation
acetylation
ChIP
PCR
gene knockdown
Immuno-Precipitation

Software Mentioned

GraphPad Prism

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