Nuclear Receptor CoRepressors, NCOR1 and SMRT, are required for maintaining systemic metabolic homeostasis

Objective: The nuclear receptor corepressor 1 (NCOR1) and the silencing mediator of retinoic acid and thyroid hormone (SMRT, also known as NCOR2) play critical and specific roles in nuclear receptor action. NCOR1, both in vitro and in vivo specifically regulates thyroid hormone (TH) action in the context of individual organs such as the liver, and systemically in the context of the hypothalamic-pituitary-thyroid (HPT) axis. In contrast, selective deletion of SMRT in the liver or globally has shown that it plays very little role in TH signaling. However, both NCOR1 and SMRT have some overlapping roles in hepatic metabolism and lipogenesis. Here, we determine the roles of NCOR1 and SMRT in global physiologic function and find if SMRT could play a compensatory role in the regulation of TH action, globally. Methods: We used a postnatal deletion strategy to disrupt both NCOR1 and SMRT together in all tissues at 8e9 weeks of age in male and female mice. This was performed using a tamoxifen-inducible Cre recombinase (UBC-Cre-ERT2) to KO (knockout) NCOR1, SMRT, or NCOR1 and SMRT together. We used the same strategy to KO HDAC3 in male and female mice of the same age. Metabolic parameters, gene expression, and thyroid function tests were analyzed. Results: Surprisingly, adult mice that acquired NCOR1 and SMRT deletion rapidly became hypoglycemic and hypothermic and perished within ten days of deletion of both corepressors. Postnatal deletion of either NCOR1 or SMRT had no impact on mortality. NCOR1/SMRT KO mice rapidly developed hepatosteatosis and mild elevations in liver function tests. Additionally, alterations in lipogenesis, beta oxidation, along with hepatic triglyceride and glycogen levels suggested defects in hepatic metabolism. The intestinal function was intact in the NCOR1/SMRT knockout (KO) mice. The KO of HDAC3 resulted in a distinct phenotype from the NCOR1/SMRT KO mice, whereas none of the HDAC3 KO mice succumbed after tamoxifen injection. Conclusions: The KO of NCOR1 and SMRT rapidly leads to significant metabolic abnormalities that do not survive e including hypoglycemia, hypothermia, and weight loss. Hepatosteatosis rapidly developed along with alterations in hepatic metabolism suggesting a contribution to the dramatic phenotype from liver injury. Glucose production and absorption were intact in NCOR1/SMRT KO mice, demonstrating a multifactorial process leading to their demise. HDAC3 KO mice have a distinct phenotype from the NCOR1/SMRT KO micedwhich implies that NCOR1/SMRT together regulate a critical pathway that is required for survival in adulthood and is separate from HDAC3. O 2021 The Author(s). Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Automated summary

NCOR1 and SMRT play critical and specific roles in nuclear receptor action, with some overlapping functions. While SMRT plays little role in thyroid hormone signaling in the liver, it is involved in hepatic metabolism and lipogenesis.