β-adrenergic regulation of the nuclear hormone receptor 4A subgroup in skeletal muscle: insights into the control of metabolism

Michael Pearen (2009). β-adrenergic regulation of the nuclear hormone receptor 4A subgroup in skeletal muscle: insights into the control of metabolism PhD Thesis, Institute for Molecular Bioscience, The University of Queensland.

       
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Author Michael Pearen
Thesis Title β-adrenergic regulation of the nuclear hormone receptor 4A subgroup in skeletal muscle: insights into the control of metabolism
School, Centre or Institute Institute for Molecular Bioscience
Institution The University of Queensland
Publication date 2009-11
Thesis type PhD Thesis
Supervisor Professor George Muscat
Total pages 219
Total colour pages 37
Total black and white pages 182
Subjects 11 Medical and Health Sciences
Abstract/Summary Metabolic diseases such as obesity, type II diabetes and atherosclerosis are major causes of morbidity and mortality throughout industrialised nations across the world. Skeletal muscle, the largest and most metabolically active organ, is a key tissue involved in the pathophysiology of such metabolic diseases. At the molecular level, a number of nuclear receptors, which are a large family of ligand-modulated and constitutively active transcription factors have been shown to regulate metabolic function in skeletal muscle and therefore the pathophysiology of such metabolic diseases. At the start of this project, the three mammalian members of the NR4A subgroup (Nur77, Nurr1 and Nor-1) of orphan nuclear receptors had not been directly implicated in the control of energy, lipid or carbohydrate metabolism in skeletal muscle or any other tissue. Previous sporadic publications had suggested that one member of the NR4A subgroup, Nur77 is induced by β-adrenoceptor agonists. As β-adrenoceptors and many nuclear receptors mediate energy, lipid and carbohydrate metabolism in skeletal muscle, the induction of Nur77 implied that the NR4A subgroup may mediate metabolic control in skeletal muscle. We hypothesised that regulatory crosstalk occurred between β-adrenergic and NR4A signalling in skeletal muscle. Therefore, the overall goal of this project was to examine if crosstalk occurs between the NR4A subgroup and β-adrenoceptors in skeletal muscle and to determine the contribution one member of the NR4A subgroup, Nor-1 has on skeletal muscle lipid, carbohydrate and energy homeostasis. This thesis presents extensive evidence (both in vivo and in vitro) that the expression of the three mammalian members of the NR4A subgroup (Nur77, Nurr1 and Nor-1) are highly and transiently induced by β-adrenergic signalling in skeletal muscle. Furthermore, the work in this thesis implicated cAMP, PKA, MAP kinase and CREB as mediators of the NR4A induction by β-adrenoceptors in vitro. To examine the metabolic function of Nor-1 in skeletal muscle, Nor-1 expression was suppressed in vitro using siRNA. This suppression resulted in decreased fatty acid oxidation coupled with increased glycolytic (and anaerobic) activity and the concordant regulation of genes involved in lipid, carbohydrate and energy metabolism. Furthermore, this thesis also characterised global gene expression associated with β-adrenergic stimulation in skeletal muscle in vivo. This revealed that acute β-adrenergic stimulation of skeletal muscle resulted in significant expression changes in genes associated with skeletal muscle hypertrophy, myoblast differentiation, metabolism, circadian rhythm, transcription, histones, and oxidative stress. This work also included the previously unreported regulation of key genes associated with metabolism and skeletal muscle hypertrophy. Taken together, the work within this thesis potentially connects together β-adrenergic signalling, transcriptional regulation of genes by β-adrenergic signalling and the NR4A receptors as transcriptional mediators of some aspects of β-adrenergic signalling. To investigate the in vivo role of Nor-1 in skeletal muscle, we created a transgenic mouse line with the specific activation of Nor-1 in skeletal muscle. This resulted in mice exhibiting decreased adiposity, improved glucose tolerance and widespread changes to the expression of genes associated with energy, lipid or carbohydrate in skeletal muscle. The phenotype and skeletal muscle transcriptional changes present in the transgenic mice are suggestive of increased energy utilisation by these animals. While further study needs to be performed on Nor-1 in vivo, the phenotype of the activated Nor-1 transgenic mouse line suggests that Nor-1 may represent a useful pharmacological target. An agonist of Nor-1 could therefore potentially prevent or treat several metabolic diseases such as obesity and type II diabetes and atherosclerosis.
Keyword Nor-1
Nor1
NR4A
Nur77
Nurr1
nuclear receptors
adrenoceptors
skeletal muscle
metabolism
diabetes
Additional Notes Colour pages: 3, 4, 5, 6, 7, 8, 10, 11, 13, 17, 19, 27, 32, 56, 61, 47, 48, 77, 84, 93, 101, 115, 118, 123, 124, 126, 136, 142, 145, 149, 153, 155, 157, 167, 169, 206, 215

 
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Created: Fri, 25 Jun 2010, 12:09:57 EST by Mr Michael Pearen on behalf of Library - Information Access Service