Oral Presentation The Annual Scientific Meeting of the Endocrine Society of Australia and the Society for Reproductive Biology 2013

The nuclear hormone receptor, Nor-1/NR4A3, regulates adiposity, substrate utilization and endurance. (#158)

Michael A Pearen 1 , Joel M Goode 1 , Rebecca L Fitzsimmons 1 , Natalie A Eriksson 1 , Gethin P Thomas 1 , Gary J Cowin 1 , S -C Mary Wang 1 , Zewen K Tuong 1 , George Muscat 1
  1. University of Queensland, Brisbane, QLD, Australia

The mRNA encoding the nuclear hormone receptor (NR), Nor-1/NR4A3, is markedly induced by adrenergic signaling in type I/slow twitch and II/fast twitch skeletal muscle. In skeletal muscle cells, Nor-1 expression is necessary for oxidative metabolism. Transgenic skeletal muscle specific expression of Nor-1 resulted in the acquisition of an endurance phenotype, and type IIA/X oxidative muscle fibers, and increased numbers of mitochondria. We employed DXA and MRI analysis to establish decreased adiposity in the transgenic Nor-1 mice, relative to wild type littermates. Furthermore, the transgenic Nor-1 mice were resistant to weight gain, and maintained normal fasting glucose on a high fat diet, in contrast to wild type littermates. Array and RT-qPCR analysis identified significant increases in genes involved in glycolysis, the TCA cycle, oxidative phosphorylation, fatty acid oxidation, and glycogen synthesis, in concordance with the lean phenotype. Moreover, expression profiling identified several Z-disc and sarcomeric binding proteins that modulate fiber type and fatigue resistance in humans. In addition, we demonstrated changes in the NAD+/NADH ratio associated with metabolic pathway changes that increase aerobic ATP production. In conclusion muscle specific Nor-1 expression controls genes and pathways that regulate fat deposition, skeletal muscle reprogramming, oxidative metabolism and endurance.