Orphan nuclear receptor estrogen-related receptor α is essential for adaptive thermogenesis

Survival of organisms requires the ability to adapt to changes in the environment. Adaptation of oxidative metabolism is essential for meeting increased energy demands in response to stressors, such as exposure to cold temperatures or increased physical activity. Adaptive changes in metabolism are often achieved at the level of gene expression, and nuclear receptors have prevalent roles in mediating such responses. Estrogen-related receptor α (ERRα) was the first orphan nuclear receptor to be identified, and yet its physiologic function remains unknown. Here, we show that mice lacking ERRα are unable to maintain body temperature when exposed to cold. Surprisingly, the inability to adapt to cold is not due to defects in the acute transcriptional induction of genes important for thermogenesis. Rather, we show that ERRα is needed for the high levels of mitochondrial biogenesis and oxidative capacity characteristic of brown adipose tissue (BAT), and thus for providing the energy necessary for thermogenesis. ERRα fulfills this role by acting directly at genes important for mitochondrial function, parallel to other factors controlling mitochondrial gene expression, such as NRF1 and NRF2/GABPA. Our findings demonstrate that ERRα is a key regulator of mitochondrial biogenesis and oxidative metabolism, and essential for adaptive thermogenesis

4-Hydroxytamoxifen binds to and deactivates the estrogen-related receptor γ

The estrogen-related receptors (ERRα, ERRβ, and ERRγ) form a family of orphan nuclear receptors that share significant amino acid identity with the estrogen receptors, but for which physiologic roles remain largely unknown. By using a peptide sensor assay, we have identified the stilbenes diethylstilbestrol (DES), tamoxifen (TAM), and 4-hydroxytamoxifen (4-OHT) as high-affinity ligands for ERRγ. In direct binding assays, 4-OHT had a K(d) value of 35 nM, and both DES and TAM displaced radiolabeled 4-OHT with K(i) values of 870 nM. In cell-based assays, 4-OHT binding caused a dissociation of the complex between ERRγ and the steroid receptor coactivator-1, and led to an inhibition of the constitutive transcriptional activity of ERRγ. ERRα did not bind 4-OHT, but replacing a single amino acid predicted to be in the ERRα ligand-binding pocket with the corresponding ERRγ residue allowed high-affinity 4-OHT binding. These results demonstrate the existence of high-affinity ligands for the ERR family of orphan receptors, and identify 4-OHT as a molecule that can regulate the transcriptional activity of ERRγ