Reduced Fat Mass in Mice Lacking Orphan Nuclear Receptor Estrogen-Related Receptor α

Abstract

The estrogen-related receptor ␣ (ERR␣) is an orphan member of the superfamily of nuclear hormone receptors expressed in tissues that preferentially metabolize fatty acids. Despite the molecular characterization of ERR␣ and identification of target genes, determination of its physiological function has been hampered by the lack of a natural ligand. To further understand the in vivo function of ERR␣, we generated and analyzed Estrra-null (ERR␣ ؊/؊ ) mutant mice. Here we show that ERR␣ ؊/؊ mice are viable, fertile and display no gross anatomical alterations, with the exception of reduced body weight and peripheral fat deposits. No significant changes in food consumption and energy expenditure or serum biochemistry parameters were observed in the mutant animals. However, the mutant animals are resistant to a high-fat diet-induced obesity. Importantly, DNA microarray analysis of gene expression in adipose tissue demonstrates altered regulation of several enzymes involved in lipid, eicosanoid, and steroid synthesis, suggesting that the loss of ERR␣ might interfere with other nuclear receptor signaling pathways. In addition, the microarray study shows alteration in the expression of genes regulating adipogenesis as well as energy metabolism. In agreement with these findings, metabolic studies showed reduced lipogenesis in adipose tissues. This study suggests that ERR␣ functions as a metabolic regulator and that the ERR␣ ؊/؊ mice provide a novel model for the investigation of metabolic regulation by nuclear receptors.Nuclear receptors are ligand-regulated transcription factors that control key pathways required for normal development and maintenance of homeostasis throughout life (37). Nuclear receptors now comprise a family of 48 genes in mice and humans that encode structurally and functionally related proteins. However, the existence of fewer than 10 receptors had been predicted by classic physiological and biochemical studies (10). Since the discovery of many nuclear receptors had not been anticipated and thus is not linked to recognized natural ligands, these new gene products were referred to as orphan nuclear receptors. During the last decade, extensive study of this gene family revealed that orphan nuclear receptors control essential developmental and metabolic functions in response to natural ligands as diverse as steroid hormones, retinoic acids, leukotrienes, bile acids, cholesterol metabolites, and long-chain fatty acids (reviewed in references 5, 26, and 48). In addition, orphan nuclear receptors have been shown to react to the presence of exogenous ligands such as pesticides (15, 70), phenobarbital (53, 61), and a wide variety of xenobiotic agents and drugs (2,24,39,55,66,68,69). Gene deletion analyses in mice have been particularly useful to uncover biological functions of orphan nuclear receptors. Nuclear orphan receptors have been shown to participate in the development and/or maintenance of the placenta, somitogenesis, brain, heart, hypothalamus-pituitary axis, immune system, and pathways controlling s...

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). In a recent expression profiling study of all 49 NRs in mouse tissues, ERRb is shown to be widely and rhythmically expressed in many organ systems, suggesting that ERRb together with other NRs are important in maintaining global basal metabolism under circadian control Yang et al, 2006).…”

Genetic analysis of the estrogen-related receptor α and studies of association with obesity and type 2 diabetes

“…9,10 The phenotype of the esrra KO mouse also indicates that ERRa is involved in energy metabolism. 9 Similarly, the obese phenotype observed in the esra KO mouse argues that ERRa by crossreaction with EREs might play an important role in energy metabolism.…”

“…9,10 The phenotype of the esrra KO mouse also indicates that ERRa is involved in energy metabolism. 9 Similarly, the obese phenotype observed in the esra KO mouse argues that ERRa by crossreaction with EREs might play an important role in energy metabolism. 18 A recent study by Laflamme et al 17 provided evidence that the long repeats of ESSRA23 are associated with a higher lumbar spine bone mineral density, indicating cross-regulation by ERRa and ERa of phenotypes in addition to those of energy metabolism.…”

“…1,8 The esrra knockout (KO) mouse has reduced body weight, diminished lipogenesis in adipose cells and exhibits resistance to dietinduced obesity, indicating that ERRa may be a potent regulator of energy metabolism in vivo. 9 Specifically, through interaction with the peroxisome proliferator-activated receptor-g coactivator-1a (PGC-1a) and the peroxisome proliferator-activated receptor a (PPARa), ERRa has been reported to regulate the medium-chain acyl-CoA dehydrogenase (MCAD), an enzyme involved in the oxidation of fatty acids. [9][10][11] The chromosomal location, the interaction with PGC-1a in the regulation of b-oxidation and the phenotype of the esrraKO mouse make ESRRA a plausible candidate gene for metabolic diseases such as obesity and type 2 diabetes.…”

Nuclear receptors, mitochondria and lipid metabolism

“…The activity of ERRs appears to be constitutive, with the ligand binding pocket stably arranged in an active conformation without ligand (Xie et al 1999;Greschik et al 2002;Greschik et al 2004). Because ERRα is widely expressed in adult tissues, especially in tissues that utilize or can utilize fatty acid β-oxidation, many studies have addressed its role in cellular energetics (Luo et al 2003). Loss of ERRβ results in placental defects and mid-gestational death of embryos, despite relatively limited expression in adult (Luo et al 1997).…”