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

Abstract

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 ␣ (ERR␣) was the first orphan nuclear receptor to be identified, and yet its physiologic function remains unknown. Here, we show that mice lacking ERR␣ 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 ERR␣ 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. ERR␣ 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 ERR␣ is a key regulator of mitochondrial biogenesis and oxidative metabolism, and essential for adaptive thermogenesis.mitochondrial biogenesis ͉ oxidative metabolism ͉ brown adipose tissue E lucidation of the physiologic roles of many nuclear receptor family members has not only revealed their importance in regulating aspects of metabolism but also suggested strategies by which synthetic ligands to such receptors [e.g., peroxisome proliferator-activated receptors (PPARs) or liver X receptor (LXRs)] can impact the treatment of metabolic disease (1). Estrogen-related receptor (ERR) ␣ is an orphan nuclear receptor and the founding member of the small subfamily of EstrogenRelated Receptors, which includes also ERR␤ and ERR␥ (2-4). Even though progress has been made in identifying cellular pathways regulated by ERR␣, the physiologic responses to which ERR␣ function contributes remain largely unknown (5-8).ERR␣ function has been linked to at least three pathways: estrogen signaling, bone formation and oxidative metabolism (reviewed in refs. 4, 9, and 10). Several lines of evidence support an ERR␣ role in oxidative metabolism. First, ERR␣ expression is high in tissues with high oxidative capacity (2, 11) and increased at physiologic states of increased energy demand, such as fasting, exposure to cold or exercise (12)(13)(14). Second, ERR␣ activity is regulated by the peroxisome proliferator-activated receptor ␥ coactivators (PGC)-1␣ and PGC-1␤ (13, 15, 16), which coordinate the expression of genes involved in mitochondrial biogenesis and oxidative metabolism (reviewed in refs. 17 and 18). Third, inhibition of ERR␣ in cultured cells diminishes the ability of PGC-1␣ to induce mitochondrial biogenesis and cellular respiration (6, 7). Conversely, constitutively active ERR␣ induces mitochondrial biogenesis and...

Orphan nuclear receptor estrogen-related receptor-β suppresses in vitro and in vivo growth of prostate cancer cells via p21WAF1/CIP1 induction and as a potential therapeutic target in prostate cancer

“…Cumulative evidences indicate that another ERR subtype, ERRa, plays significant roles in energy metabolism and mitochondrial biogenesis in certain target cells and tissues via direct regulation of genes involved in fatty acid oxidation, ERRb suppresses prostate cancer cell growth S Yu et al glucose metabolism, oxidative phosphorylation and mitochondrial fusion Huss et al, 2004;Schreiber et al, 2004;Wende et al, 2005;Soriano et al, 2006;Villena et al, 2007). Moreover, ectopic ERRa expression can promote lipid accumulation in primary cardiac myocytes (Huss et al, 2004), whereas its loss of function reduces body fat in ERRa-knockout mouse (Luo et al, 2003).…”

Nuclear receptors, mitochondria and lipid metabolism

“…(Puigserver et al 1998;Herzig et al 2001;Lin et al 2002;Puigserver et al 2003;Rhee et al 2003;Arany et al 2005;St-Pierre et al 2006;Handschin et al 2007). While named for its interaction with PPARγ, many of these PGC-1-dependent adaptations appear to be largely dependent on ERRs and other metabolic transcription factors that are independent of PPAR/RXR Rhee et al 2003;Schilling et al 2006;Alaynick et al 2007;Huss et al 2007;Villena et al 2007). …”

“…In the mouse intestine, ERRα controls the ApoA-IV promoter and loss results in reduced uptake of lipids (Luo et al 2003;Carrier et al 2004). At the cellular level, defects in oxidative metabolism have been seen in ERRα null intestine, skeletal muscle, heart, and BAT (Carrier et al 2004;Rodriguez-Calvo et al 2006;Huss et al 2007;Villena et al 2007). Several target genes have been identified by these studies including Ckmt2, Mcad, Sdha and Sdhb ).…”

Trichoplax, the simplest known animal, contains an estrogen-related receptor but no estrogen receptor: Implications for estrogen receptor evolution

“…In the last few years, there has been progress in beginning to elucidate ERR functions, which include regulating bone formation [2,3, 15,16] and mitochondrial biogenesis [16][17][18].…”