FIGURE 2.

Role of corepressors in metabolic regulation. NcoR has three receptor interacting domains (RIDs) located in the COOH terminus. Unliganded TR interacts with RID 2 and 3 and recruits histone deacetylase 3 (HDAC3) to assemble a mediator complex, resulting in basal transcription repression. A: deletion of all three RID (NCoRi) or only RID2–3 (l-NCoRΔID) results in a corepressor that can no longer be recruited to unliganded-TR, although the repression mediator complex can still be assembled since the repression domains are intact. Without NCoR interaction, basal transcription is activated. This activation induces hepatocyte proliferation and T₃- and LXR-target genes activation in liver. B: global expression of the NCoRΔID enhances metabolic actions, such as energy expenditure, and can rescue the RTH phenotype produced by TRβ mutations and increase TH sensitivity. C: the conditional NCoR knockout in specific tissues demonstrates tissue-specific actions of NCoR. After NCoR knockout, basal transcription is activated. Muscle-specific NCoR inactivation enhanced metabolic actions of PPARδ and estrogen-related receptors (ERRs); MEF2, myocyte enhancer factor-2. Adipocyte-specific NCoR−/− enhanced PPARγ actions, inhibited NCoR phosphorylation, leading to constituitive activity, enhanced insulin sensitivity, reduced inflammation, and promoted obesity, consistent with the actions of a PPARγ agonist.