transgenic mice display reduced serum epinephrine due to 1 increased catecholamine catabolism in adipose tissue 2

37 The NR4A orphan nuclear receptors function as early response genes to numerous 38 stimuli. Our laboratory has previously demonstrated that over-expression of NR4A3 39 (NOR-1, MINOR) in 3T3-L1 adipocytes enhances insulin-stimulated glucose uptake. 40 To assess the in vivo effect of NR4A3 on adipocytes, we generated transgenic mice 41 with NR4A3 over-expression driven by the adipocyte AP2 promoter (AP2-NR4A3 42 mice). We hypothesized that AP2-NR4A3 mice would display enhanced glucose 43 tolerance and insulin sensitivity. However, AP2-NR4A3 mice exhibit metabolic 44 impairment, including increased fasting glucose and insulin, impaired glucose 45 tolerance, insulin resistance, decreased serum free fatty acids, and increased LDL46 cholesterol. Furthermore, AP2-NR4A3 mice display a significant reduction in serum 47 epinephrine due to increased expression of catecholamine catabolizing enzymes in 48 adipose tissue, including monoamine oxidase-A. Furthermore, enhanced 49 expression of monoamine oxidase-A is due to direct transcriptional activation by 50 NR4A3. Finally, AP2-NR4A3 mice display cardiac and behavioral alterations 51 consistent with chronically low circulating epinephrine levels. In conclusion, 52 overexpression of NR4A3 in adipocytes produces a complex phenotype 53 characterized by impaired glucose metabolism and low serum catecholamines, due 54 to enhanced degradation by adipose tissue. 55