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

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. Overall design: RNA-Seq: There are 4 samples for each group: NCoR2 Control, NCoR2 BAT-sKO, NCoR1/2 Control, NCoR1/2 BAT-dKO, NCoR1 Control. 3 samples for NCoR1 BAT-KO We analyzed an n of 4 for each group: NCoR2 Control, NCoR2 BAT-sKO, NCoR1/2 Control, NCoR1/2 BAT-dKO. Isolated RNA from these groups was sequenced at Novogene using an Illumina Platform, PE150, with approximately 30 million reads per sample. For NCoR1 Control (n=4) and NCoR1 BAT-sKO (n=3), libraries were prepared using the TruSeq Stranded Total RNA kit (Illumina) and sequenced at the Next-Generation Sequencing Core at the University of Pennsylvania on the NextSeq 500 platform (Illumina) at 75SR for a total of 20-40 million reads per sample. ChIP-Seq: There are 2 samples of HDAC3 in HDAC3-KO, used as background, and 3 samples each of HDAC3 in Control and NCoR1/2-dKO An n=3 was sequenced for NCoR1/2 Control and NCoR1/2 BAT-dKO groups, n=2 for HDAC3 BAT-KO, and n=1 each for input and IgG. The sequencing was done at the Next-Generation Sequencing Core at the University of Pennsylvania on a NextSeq platform (Illumina) at 100SR for a total of 30 million reads per sample.