Balanced control of thermogenesis by nuclear receptor corepressors in brown adipose tissue.
Proc Natl Acad Sci U S A
; 119(33): e2205276119, 2022 08 16.
Article
en En
| MEDLINE
| ID: mdl-35939699
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 require histone deacetylase 3 (HDAC3). HDAC3 exists in tight association with nuclear receptor corepressors (NCoRs) NCoR1 and NCoR2 (also known as silencing mediator of retinoid and thyroid receptors [SMRT]), but the 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 NCoR1/2 BAT-dKO and HDAC3 BAT-KO mice. Despite these commonalities, loss of NCoR1/2 in BAT does not phenocopy the cold sensitivity observed in HDAC3 BAT-KO, nor does loss of either corepressor alone. Instead, BAT lacking NCoR1/2 is inflamed, particularly with respect to the interleukin-17 axis that increases thermogenic capacity by enhancing innervation. Integration of BAT RNA sequencing and chromatin immunoprecipitation sequencing 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 stimulation of HDAC3 activity in the control of thermogenesis.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Tejido Adiposo Pardo
/
Termogénesis
/
Co-Represor 1 de Receptor Nuclear
/
Co-Represor 2 de Receptor Nuclear
Límite:
Animals
Idioma:
En
Revista:
Proc Natl Acad Sci U S A
Año:
2022
Tipo del documento:
Article