Title | AP2-NR4A3 transgenic mice display reduced serum epinephrine because of increased catecholamine catabolism in adipose tissue. |
Publication Type | Journal Article |
Year of Publication | 2016 |
Authors | R Walton G, Zhu X, Tian L, Heywood EB, Liu J, Hill HS, Liu J, Bruemmer D, Yang Q, Fu Y, W Garvey T |
Journal | Am J Physiol Endocrinol Metab |
Volume | 311 |
Issue | 1 |
Pagination | E69-81 |
Date Published | 2016 Jul 01 |
ISSN | 1522-1555 |
Keywords | Absorptiometry, Photon, Adipocytes, Adipose Tissue, Animals, Behavior, Animal, Blood Glucose, Blotting, Western, Body Composition, Body Temperature, Catecholamines, Cell Culture Techniques, Cholesterol, LDL, Chromatin Immunoprecipitation, DNA-Binding Proteins, Energy Metabolism, Epinephrine, Fatty Acid-Binding Proteins, Fatty Acids, Nonesterified, Glucose Intolerance, Glucose Tolerance Test, Immunohistochemistry, Insulin, Insulin Resistance, Lipolysis, Male, Metabolism, Mice, Mice, Transgenic, Monoamine Oxidase, Promoter Regions, Genetic, Real-Time Polymerase Chain Reaction, Receptors, Steroid, Receptors, Thyroid Hormone, Transcriptional Activation |
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. |
DOI | 10.1152/ajpendo.00330.2015 |
Alternate Journal | Am. J. Physiol. Endocrinol. Metab. |
PubMed ID | 27166283 |
PubMed Central ID | PMC4967153 |
Grant List | I01 CX000432 / CX / CSRD VA / United States P30 DK079626 / DK / NIDDK NIH HHS / United States |