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 insulinstimulated 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.nuclear receptor 4A3 transgenic mice; nuclear receptor 4A3; type 2 diabetes; lipolysis; monoamine oxidase THE ORPHAN RECEPTOR NR4A SUBGROUP of the nuclear hormone receptor superfamily is comprised of three genes, NR4A1 (or Nur77), NR4A2 (or Nurr1), and NR4A3 (NOR-1 or MINOR). NR4A family members are early response genes in which expression is induced in a cell-type-specific manner by numerous stimuli, including fasting, exercise, inflammation, hypothalamic-pituitary-adrenal axis (HPA axis) hormones, tyrosinederived neurotransmitters, and cAMP analogs. NR4A receptors modulate expression of steroidogenic, gluconeogenic, glycolytic, and ␤-oxidative genes in both the HPA axis and target tissues (24, 28).Whereas NR4A family members are expressed in numerous tissues, NR4A3 expression is more limited, with high levels detected in metabolically active tissues such as muscle and adipose tissue. We have shown that NR4A3 is depleted in muscle and fat from several insulin-resistant rodent models (11); however, it is upregulated by insulin in human vastus lateralis muscle, and expression in muscle is increased in insulin-sensitive vs. insulin-resistant subjects (41). In addition, we have demonstrated that NR4A3 enhances insulin-stimulated glucose transport and insulin signaling when overexpressed in vitro in 3T3-L1 adipocytes (11) and C 2 C 12 muscle cells (42). These data indicated that NR4A3 might enhance insulin sensitivity, raising the possibility that NR4A3 agonism could constitute a viable pharmacological target for insulinsensitizing drugs, analogous to thiazolidinedione agonism of peroxisome proliferator-activated receptor (PPAR)-␥ nuclear re...

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