title: AP2-NR4A3 transgenic mice display reduced serum epinephrine because of increased catecholamine catabolism in adipose tissue.
abstract: The NR4A orphan nuclear receptors function as early response genes to numerous stimuli. Our laboratory has previously demonstrated that overexpression of NR4A3 (NOR-1, MINOR) in 3T3-L1 adipocytes enhances insulin-stimulated glucose uptake. To assess the in vivo effect of NR4A3 on adipocytes, we generated transgenic mice with NR4A3 overexpression driven by the adipocyte fatty acid-binding protein (AP2) promoter (AP2-NR4A3 mice). We hypothesized that AP2-NR4A3 mice would display enhanced glucose tolerance and insulin sensitivity. However, AP2-NR4A3 mice exhibit metabolic impairment, including increased fasting glucose and insulin, impaired glucose tolerance, insulin resistance, decreased serum free fatty acids, and increased low-density lipoprotein-cholesterol. AP2-NR4A3 mice also display a significant reduction in serum epinephrine due to increased expression of catecholamine-catabolizing enzymes in adipose tissue, including monoamine oxidase-A. Furthermore, enhanced expression of monoamine oxidase-A is due to direct transcriptional activation by NR4A3. Finally, AP2-NR4A3 mice display cardiac and behavioral alterations consistent with chronically low circulating epinephrine levels. In conclusion, overexpression of NR4A3 in adipocytes produces a complex phenotype characterized by impaired glucose metabolism and low serum catecholamines due to enhanced degradation by adipose tissue.
authors.affiliation: Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, Alabama; r.grace.walton@uky.edu.
authors.forename: R Grace
authors.initials: RG
authors.lastname: Walton
authors.affiliation: Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, Alabama;
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, Alabama;
authors.forename: Ling
authors.initials: L
authors.lastname: Tian
authors.affiliation: Saha Cardiovascular Research Center and Graduate Center for Nutritional Sciences, University of Kentucky, Lexington, Kentucky;
authors.forename: Elizabeth B
authors.initials: EB
authors.lastname: Heywood
authors.affiliation: Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, Alabama;
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, Alabama;
authors.forename: Helliner S
authors.initials: HS
authors.lastname: Hill
authors.affiliation: Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama; and.
authors.forename: Jiarong
authors.initials: J
authors.lastname: Liu
authors.affiliation: Saha Cardiovascular Research Center and Graduate Center for Nutritional Sciences, University of Kentucky, Lexington, Kentucky;
authors.forename: Dennis
authors.initials: D
authors.lastname: Bruemmer
authors.affiliation: Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, Alabama;
authors.forename: Qinglin
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, Alabama;
authors.forename: Yuchang
authors.initials: Y
authors.lastname: Fu
authors.affiliation: Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, Alabama; Birmingham Veterans Affairs Medical Center, Birmingham, Alabama.
authors.forename: W Timothy
authors.initials: WT
authors.lastname: Garvey
mesh_terms: D015502:Absorptiometry, Photon; D017667:Adipocytes / Q000378:metabolism*; D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D001522:Behavior, Animal; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D001823:Body Composition / Q000235:genetics; D001831:Body Temperature; D002395:Catecholamines / Q000378:metabolism*; D018929:Cell Culture Techniques; D008078:Cholesterol, LDL / Q000097:blood; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000235:genetics*; D004734:Energy Metabolism; D004837:Epinephrine / Q000097:blood*; D050556:Fatty Acid-Binding Proteins / Q000235:genetics; D005230:Fatty Acids, Nonesterified / Q000097:blood; D018149:Glucose Intolerance / Q000235:genetics; D005951:Glucose Tolerance Test; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics; D008066:Lipolysis; D008297:Male; D008660:Metabolism; D051379:Mice; D008822:Mice, Transgenic; D008995:Monoamine Oxidase / Q000378:metabolism; D011401:Promoter Regions, Genetic; D060888:Real-Time Polymerase Chain Reaction; D011987:Receptors, Steroid / Q000235:genetics*; D011988:Receptors, Thyroid Hormone / Q000235:genetics*; D015533:Transcriptional Activation / Q000235:genetics
chemical_list: D001786:Blood Glucose; D002395:Catecholamines; D008078:Cholesterol, LDL; D004268:DNA-Binding Proteins; C493411:Fabp4 protein, mouse; D050556:Fatty Acid-Binding Proteins; D005230:Fatty Acids, Nonesterified; D007328:Insulin; C490412:NR4A3 protein, human; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone; D008995:Monoamine Oxidase; D004837:Epinephrine
keywords: lipolysis; monoamine oxidase; nuclear receptor 4A3; nuclear receptor 4A3 transgenic mice; type 2 diabetes