Estrogen-related receptor ␣ (ERR␣) is one of the first orphan nuclear receptors to be identified, yet its physiological functions are still unclear. We show here that ERR␣ is an effector of the transcriptional coactivator PGC-1␣ [peroxisome proliferator-activated receptor ␥ (PPAR␥) coactivator 1␣], and that it regulates the expression of genes involved in oxidative phosphorylation and mitochondrial biogenesis. Inhibition of ERR␣ compromises the ability of PGC-1␣ to induce the expression of genes encoding mitochondrial proteins and to increase mitochondrial DNA content. A constitutively active form of ERR␣ is sufficient to elicit both responses. ERR␣ binding sites are present in the transcriptional control regions of ERR␣͞PGC-1␣-induced genes and contribute to the transcriptional response to PGC-1␣. The ERR␣-regulated genes described here have been reported to be expressed at reduced levels in humans that are insulin-resistant. Thus, changes in ERR␣ activity could be linked to pathological changes in metabolic disease, such as diabetes. E strogen-related receptor ␣ (ERR␣, NR3B1) was identified on the basis of its sequence similarity to classical, hormoneregulated steroid receptors (1). Based on its ability to recognize similar DNA sequences as the estrogen receptors, ERR␣ has been proposed to modulate estrogen signaling (2-5). ERR␣ may also regulate bone formation, given that it is highly expressed at ossification sites, promotes osteoblast differentiation in vitro, and activates the promoter of the bone matrix protein osteopontin (6, 7). Finally, ERR␣ may regulate fatty acid oxidation. Consistent with this function, ERR␣ is prominently expressed in tissues with high capacity for ␤-oxidation of fatty acids, such as brown fat, heart, muscle, and kidney, and induces the expression of the medium-chain acyl-CoA dehydrogenase gene (8,9).A better understanding of the transcriptional programs and cellular pathways that depend on ERR␣ has been hampered by the lack of tools to regulate the activity of this receptor. Despite the high similarity between ERR␣ and other ligand-dependent nuclear receptors, it is not clear whether ERR␣ activity is regulated by small lipophilic ligands. Compounds that inhibit ERR␣-dependent transcription, such as toxaphene, chlordane, and diethylstilbestrol, have been described (10, 11). However, these compounds are not specific enough for ERR␣ to facilitate studies of its cellular function. Recently, we demonstrated that the transcriptional coactivator peroxisome proliferator-activated receptor ␥ (PPAR␥) coactivator 1␣ (PGC-1␣) regulates ERR␣ function (12). PGC-1␣ induces the expression of ERR␣ and interacts physically with ERR␣, enabling it to activate transcription (12, 13). These findings suggest that PGC-1␣ can be used as a protein ''ligand'' to regulate ERR␣-dependent transcription and study ERR␣ function.PGC-1␣ has been identified as a tissue-specific coactivator of nuclear receptors (14-16). The expression of PGC-1␣ is most prominent in tissues with high energy demands, similar to the ex...

The peroxisome proliferator-activated receptor (PPAR)-␥ coactivator-1 (PGC-1) can induce mitochondria biogenesis and has been implicated in the development of oxidative type I muscle fibers. The PPAR isoforms ␣, ␤/␦, and ␥ control the transcription of genes involved in fatty acid and glucose metabolism. As endurance training increases skeletal muscle mitochondria and type I fiber content and fatty acid oxidative capacity, our aim was to determine whether these increases could be mediated by possible effects on PGC-1 or PPAR-␣, -␤/␦, and -␥. Seven healthy men performed 6 weeks of endurance training and the expression levels of PGC-1 and PPAR-␣, -␤/␦, and -␥ mRNA as well as the fiber type distribution of the PGC-1 and PPAR-␣ proteins were measured in biopsies from their vastus lateralis muscle. PGC-1 and PPAR-␣ mRNA expression increased by 2.7-and 2.2-fold (P < 0.01), respectively, after endurance training. PGC-1 expression was 2.2-and 6-fold greater in the type IIa than in the type I and IIx fibers, respectively. It increased by 2.8-fold in the type IIa fibers and by 1.5-fold in both the type I and IIx fibers after endurance training (P < 0.015). PPAR-␣ was 1.9-fold greater in type I than in the II fibers and increased by 3.0-fold and 1.5-fold in these respective fibers after endurance training (P < 0.001). The increases in PGC-1 and PPAR-␣ levels reported in this study may play an important role in the changes in muscle mitochondria content, oxidative phenotype, and sensitivity to insulin known to be induced by endurance training. Diabetes 52:2874 -2881, 2003

The estrogen-related receptor ␣ (ERR␣) is one of the first orphan nuclear receptors identified. Still, we know little about the mechanisms that regulate its expression and its activity. In this study, we show that the transcriptional coactivator PGC-1, which is implicated in the control of energy metabolism, regulates ERR␣ at two levels. First, PGC-1 induces the expression of ERR␣. Consistent with this induction, levels of ERR␣ mRNA in vivo are highest in PGC-1 expressing tissues, such as heart, kidney, and muscle, and up-regulated in response to signals that induce PGC-1, such as exposure to cold. Second, PGC-1 interacts physically with ERR␣ and enables it to activate transcription. Strikingly, we find that PGC-1 converts ERR␣ from a factor with little or no transcriptional activity to a potent regulator of gene expression, suggesting that ERR␣ is not a constitutively active nuclear receptor but rather one that is regulated by protein ligands, such as PGC-1. Our findings suggest that the two proteins act in a common pathway to regulate processes relating to energy metabolism. In support of this hypothesis, adenovirus-mediated delivery of small interfering RNA for ERR␣, or of PGC-1 mutants that interact selectively with different types of nuclear receptors, shows that PGC-1 can induce the fatty acid oxidation enzyme MCAD (medium-chain acyl-coenzyme A dehydrogenase) in an ERR␣-dependent manner.The nuclear receptor ERR␣ 1 was identified in 1988 as a protein that shares significant sequence similarity to known steroid receptors, such as the estrogen receptor (1). ERR␣ and its relatives ERR␤ and ERR␥ form a small family of orphan nuclear receptors that are evolutionarily related to the estrogen receptors ER␣ and ER␤, and whose in vivo function is still unclear (Refs. 1 and 2 and reviewed in Ref.3). The three ERRs recognize and bind similar DNA sequences, which include estrogen response elements (EREs) recognized by ERs, as well as extended ERE half-sites that have been termed ERR response elements (4 -7). Despite their high similarity to ligand-dependent receptors, ERRs seem to regulate transcription in the absence of known natural lipophilic agonist ligands. Searches for ligands have so far identified only synthetic antagonists. 4-Hydroxytamoxifen, which binds ERR␤ and ERR␥ but not ERR␣, and diethylstilbestrol, which binds all three ERRs, inhibit the ability of ERRs to activate transcription (8, 9). In support of the pharmacological data, elucidation of the crystal structure of the ERR␥ LBD suggests that the ERRs assume the conformation of ligand-activated nuclear receptors in the absence of ligand (10) and that agonist ligands may not be required. These findings raise the question of how the activity of these nuclear receptors is regulated.One way to control orphan receptor activity is to express the receptors in a temporally and spatially restricted manner. ERR␣ is expressed widely; however, particularly high ERR␣ mRNA levels have been noted at sites of ossification during development, and in heart, kidney, brown...