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Balanced Control of Thermogenesis by Nuclear Receptor Corepressors in Brown Adipose Tissue

ABSTRACT: Brown adipose tissue (BAT) is a key thermogenic organ, whose expression of Uncoupling Protein 1 (UCP1) and ability to maintain body temperature in response to acute cold exposure requires histone deacetylase 3 (HDAC3). HDAC3 exists in tight association with nuclear receptor corepressors NCoR1 and NCoR2(also known as Silencing Mediator of Retinoid and Thyroid Receptors, or SMRT), butthe functions of NCoR1/2 in BAT have not been established.Here we report that, as expected, genetic loss of NCoR1/2 in BAT (NCoR1/2 BAT-dKO) leads to loss of HDAC3 activity. In addition, HDAC3 is no longer bound at its physiological genomic sites in the absence of NCoR1/2, leading to a shared deregulation of BAT lipid metabolism between the NCoR1/2 BAT-dKO and HDAC3 BAT KO mice. Despite these commonalities, however, loss of NCoR1/2 in BAT does not phenocopy the cold sensitivity observed in the HDAC3 BAT-KO, nor does loss of either corepressor alone. Instead, BAT lacking NCoR1/2 is inflamed, particularly with respect to the IL-17 axis that increases thermogenic capacity by enhancing innervation. Integration of BAT RNA-seq and ChIP-seq data revealed that NCoR1/2 directly regulate Mmp9, which integrates extracellular matrix remodeling and inflammation. These findings reveal pleiotropic functions of the NCoR/HDAC3 corepressor complex in BAT, such that HDAC3-independent suppression of BAT inflammation counterbalances their stimulation of HDAC3 activity in the control of thermogenesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE199808 | GEO | 2022/07/27

REPOSITORIES: GEO

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