A putative white adipose tissue specific nuclear orphan receptor that interacts with the cAMP-response element of the human Î²3-adrenergic receptor gene

Kutoh, Eiji; Ongenae, Nicolas; Verheyen, Willy; Cheyns, Paul; Neefs, Jean-Marc; Kaijen, Paul

doi:10.1016/s0303-7207(00)00262-8

Cited by 3 publications

(3 citation statements)

References 41 publications

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“…Finally, the observed upregulation of the gene encoding the ␤3 adrenergic receptor suggests that lipolysis in white adipocytes could also be affected (7), although more specific studies will be required to validate this hypothesis. It is, however, interesting that the Adrb3 promoter has been shown to encode a putative binding site for ERR␣ (28). Although the physiological significance of the alteration in expression of each specific gene remains to be fully investigated, this ensemble is in agreement with the observed reduced fat mass in the ERR␣ Ϫ/Ϫ mice.…”

supporting

confidence: 58%

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

Luo

Sladek

Carrier

et al. 2003

Molecular and Cellular Biology

344

324

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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...

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supporting

confidence: 58%

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

Luo

Sladek

Carrier

et al. 2003

Molecular and Cellular Biology

344

324

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“…A fragment of frozen retroperitoneal fat was subjected to subcellular fractionation (n ¼ 6 per group) using the technique of Kutoh et al 25 NFkB activity was measured in both nuclear and cytosolic extracts using the high-throughput TransAMÔ enzyme-linked immunosorbent assay (Active Motif, Carlsbad, CA, USA). The TransAM kit contains a 96well plate coated with immobilized oligonucleotide that contains the NFkB consensus site (5 0 -GGGACTTTCC-3 0 ).…”

Section: Tissue Nfkb Activitymentioning

confidence: 99%

Regular Tart Cherry Intake Alters Abdominal Adiposity, Adipose Gene Transcription, and Inflammation in Obesity-Prone Rats Fed a High Fat Diet

Seymour

Lewis

Urcuyo-Llanes

et al. 2009

Journal of Medicinal Food

127

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Obesity, systemic inflammation, and hyperlipidemia are among the components of metabolic syndrome, a spectrum of phenotypes that can precede the development of type 2 diabetes and cardiovascular disease. Animal studies show that intake of anthocyanin-rich extracts can affect these phenotypes. Anthocyanins can alter the activity of tissue peroxisome proliferator-activated receptors (PPARs), which affect energy substrate metabolism and inflammation. However, it is unknown if physiologically relevant, anthocyanin-containing whole foods confer similar effects to concentrated, anthocyanin extracts. The effect of anthocyanin-rich tart cherries was tested in the Zucker fatty rat model of obesity and metabolic syndrome. For 90 days, rats were pair-fed a higher fat diet supplemented with either 1% (wt/wt) freeze-dried, whole tart cherry powder or with a calorie- and macronutrient-matched control diet. Tart cherry intake was associated with reduced hyperlipidemia, percentage fat mass, abdominal fat (retroperitoneal) weight, retroperitoneal interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) expression, and plasma IL-6 and TNF-alpha. Tart cherry diet also increased retroperitoneal fat PPAR-alpha and PPAR-gamma mRNA (P = .12), decreased IL-6 and TNF-alpha mRNA, and decreased nuclear factor kappaB activity. In conclusion, in at-risk obese rats fed a high fat diet, physiologically relevant tart cherry consumption reduced several phenotypes of metabolic syndrome and reduced both systemic and local inflammation. Tart cherries may reduce the degree or trajectory of metabolic syndrome, thereby reducing risk for the development of type 2 diabetes and heart disease.

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“…Response elements for these receptors generally consist of paired hexamer sites that bind receptor homo-or heterodimers, with specificity determined, at least in part, by the relative orientation and spacing of hexamers (Forman & Evans 1995, Khorasanizadeh & Rastinejad 2001. However, some members of these receptors are known to bind to the single hexamer sites as monomers (Kutoh et al 2000, Lee & Moore 2002.…”

Section: Introductionmentioning

confidence: 99%

Functional interference between estrogen-related receptor alpha and peroxisome proliferator-activated receptor alpha/9-cis-retinoic acid receptor alpha heterodimer complex in the nuclear receptor response element-1 of the medium chain acyl-coenzyme A dehydrogenase gene

Maehara¹,

Hida²,

Abe³

et al. 2003

Journal of Molecular Endocrinology

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We undertook a study of molecular interference of nuclear orphan receptors. Nuclear receptor response element-1 (NRRE-1) from the human medium-chain acyl coenzyme A dehydrogenase (MCAD) gene promoter was shown to contain three hexamer elements (site 1 through 3) that are known to interact with a number of nuclear receptors including chicken ovalbumin upstream promoter transcription factor (COUP-TF) and estrogen-related receptor alpha (ERRα). We demonstrated that the peroxisome proliferator-activated receptor alpha/9-cis-retinoic acid receptor alpha (PPARα/RXRα) heterodimer complex can also bind to the two hexamer repeat sequences (between site 1 and site 3) arranged as an everted imperfect repeat separated by 14 bp (ER14). Mutations of the putative core elements have shown that these three sites are differentially involved in ERRα and PPARα/RXRα binding. Homodimer of ERRα was shown to interact between site 1 and site 3 (ER14). To date, no nuclear receptor is known to bind to response elements over such long intervals. Interestingly, site 1 was shown to be essential for ERRα binding while site 3 supports its binding only in the presence of site 1. Furthermore, it was shown that the binding profile of ERRα and PPARα/RXRα are competitive rather than making a high order complex within NRRE-1. At the cellular level, transcriptional activation driven by the PPARα/RXRα complex was counteracted by the expression of ERRα in HeLa cells. These results suggest that ERRα and PPARα/RXRα could interfere with each other's function through binding to similar DNA elements, thereby finetuning the transcriptional outcome of the target gene. Our findings suggest a mechanism whereby multiple nuclear receptors can activate or repress DNA binding or transcription via a single pleiotropic regulatory element.

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A putative white adipose tissue specific nuclear orphan receptor that interacts with the cAMP-response element of the human Î²3-adrenergic receptor gene

Cited by 3 publications

References 41 publications

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

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

Regular Tart Cherry Intake Alters Abdominal Adiposity, Adipose Gene Transcription, and Inflammation in Obesity-Prone Rats Fed a High Fat Diet

Functional interference between estrogen-related receptor alpha and peroxisome proliferator-activated receptor alpha/9-cis-retinoic acid receptor alpha heterodimer complex in the nuclear receptor response element-1 of the medium chain acyl-coenzyme A dehydrogenase gene

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