Control Of Thermogenesis By Nuclear Receptor Corepressors And Rev-Erbs In Brown Adipose Tissue
Date of Award
Doctor of Philosophy (PhD)
Biochemistry & Molecular Biophysics
Mitchell A. Lazar
Kathryn E. Wellen
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), but the functions of NCoR1/2 in BAT have not been established. This corepressor complex of HDAC3 and NCoR1/2 can interact with a variety of nuclear receptors, including REV-ERBa/b which are related nuclear receptors (NRs) that couple the molecular clock with metabolism. 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. We also find that REV-ERBa/b do not tissue-autonomously control acute and circadian BAT thermogenesis. However, BAT REV-ERBa/b do regulate lipogenesis via Srebp1c in conditions of chronic cold. These findings reveal pleiotropic functions of the NCoR/HDAC3 corepressor complex in BAT, and one of their associated nuclear receptor partners, REV-ERBa/b. In sum, HDAC3-independent suppression of BAT inflammation counterbalances NCoR1/2 stimulation of HDAC3 activity in the control of thermogenesis, while REV-ERBa/b only control thermogenesis in BAT via fuel availability.
Richter, Hannah Joy, "Control Of Thermogenesis By Nuclear Receptor Corepressors And Rev-Erbs In Brown Adipose Tissue" (2022). Publicly Accessible Penn Dissertations. 4804.
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