Reduced fat mass in mice lacking orphan nuclear receptor estrogen-related receptor alpha.
The estrogen-related receptor alpha (ERRalpha) is an orphan member of the superfamily of nuclear hormone receptors expressed in tissues that preferentially metabolize fatty acids. Despite the molecular characterization of ERRalpha 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 ERRalpha, we generated and analyzed Estrra-null (ERRalpha-/-) mutant mice. Here we show that ERRalpha-/- 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 ERRalpha 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 ERRalpha functions as a metabolic regulator and that the ERRalpha-/- mice provide a novel model for the investigation of metabolic regulation by nuclear receptors.
Molecular Oncology Group, Department of Medicine, McGill University Health Centre, 687 Pine Avenue West, Montréal, Québec, Canada H3A 1A1.
Jiangming
J
Luo
Robert
R
Sladek
Julie
J
Carrier
Jo-Ann
JA
Bader
Denis
D
Richard
Vincent
V
Giguère
D000273:Adipose Tissue / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D001835:Body Weight; D004041:Dietary Fats / Q000008:administration & dosage; D004734:Energy Metabolism; D005260:Female; D020869:Gene Expression Profiling; D008055:Lipids / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000209:etiology; D020411:Oligonucleotide Array Sequence Analysis; D009929:Organ Size; D010641:Phenotype; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000172:deficiency* / Q000235:genetics; D015398:Signal Transduction; D000097983:ERRalpha Estrogen-Related Receptor
D004041:Dietary Fats; D008055:Lipids; D018160:Receptors, Cytoplasmic and Nuclear; D011960:Receptors, Estrogen; D000097983:ERRalpha Estrogen-Related Receptor