Walton R Grace, Zhu Xiaolin, Tian Ling, Heywood Elizabeth B, Liu Jian, Hill Helliner S, Liu Jiarong, Bruemmer Dennis, Yang Qinglin, Fu Yuchang, Garvey W Timothy
Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, Alabama;
Saha Cardiovascular Research Center and Graduate Center for Nutritional Sciences, University of Kentucky, Lexington, Kentucky;
Am J Physiol Endocrinol Metab. 2016 Jul 1;311(1):E69-81. doi: 10.1152/ajpendo.00330.2015. Epub 2016 May 10.
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.
NR4A孤儿核受体作为对多种刺激的早期反应基因发挥作用。我们实验室先前已证明，在3T3-L1脂肪细胞中过表达NR4A3（NOR-1，MINOR）可增强胰岛素刺激的葡萄糖摄取。为了评估NR4A3在体内对脂肪细胞的影响，我们构建了由脂肪细胞脂肪酸结合蛋白（AP2）启动子驱动NR4A3过表达的转基因小鼠（AP2-NR4A3小鼠）。我们假设AP2-NR4A3小鼠会表现出增强的葡萄糖耐量和胰岛素敏感性。然而，AP2-NR4A3小鼠表现出代谢受损，包括空腹血糖和胰岛素升高、葡萄糖耐量受损、胰岛素抵抗、血清游离脂肪酸降低以及低密度脂蛋白胆固醇升高。由于脂肪组织中儿茶酚胺分解酶（包括单胺氧化酶-A）的表达增加，AP2-NR4A3小鼠的血清肾上腺素也显著降低。此外，单胺氧化酶-A的表达增强是由于NR4A3的直接转录激活。最后，AP2-NR4A3小鼠表现出与慢性低循环肾上腺素水平一致的心脏和行为改变。总之，脂肪细胞中NR4A3的过表达产生了一种复杂的表型，其特征是葡萄糖代谢受损和血清儿茶酚胺水平低，这是由于脂肪组织降解增强所致。
