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Identification and validation of the pathways and functions regulated by the orphan nuclear receptor, ROR alpha1, in skeletal muscle

Citation

Raichur, S and Fitzsimmons, RL and Myers, SA and Pearen, MA and Lau, P and Eriksson, N and Wang, SM and Muscat, GEO, Identification and validation of the pathways and functions regulated by the orphan nuclear receptor, ROR alpha1, in skeletal muscle, Nucleic Acids Research, 38, (13) pp. 4296-4312. ISSN 0305-1048 (2010) [Refereed Article]


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Copyright 2010 The Authors Licenced under the terms of the Creative Commons Attribution Non-Commercial License http://creativecommons.org/licenses/by-nc/2.5

DOI: doi:10.1093/nar/gkq180

Abstract

The retinoic acid receptor-related orphan receptor (ROR) alpha has been demonstrated to regulate lipid metabolism. We were interested in the ROR alpha 1 dependent physiological functions in skeletal muscle. This major mass organ accounts for approximately 40% of the total body mass and significant levels of lipid catabolism, glucose disposal and energy expenditure. We utilized the strategy of targeted muscle-specific expression of a truncated (dominant negative) ROR alpha 1 Delta DE in transgenic mice to investigate ROR alpha 1 signaling in this tissue. Expression profiling and pathway analysis indicated that ROR alpha influenced genes involved in: (i) lipid and carbohydrate metabolism, cardiovascular and metabolic disease; (ii) LXR nuclear receptor signaling and (iii) Akt and AMPK signaling. This analysis was validated by quantitative PCR analysis using TaqMan low-density arrays, coupled to statistical analysis (with Empirical Bayes and Benjamini-Hochberg). Moreover, westerns and metabolic profiling were utilized to validate the genes, proteins and pathways (lipogenic, Akt, AMPK and fatty acid oxidation) involved in the regulation of metabolism by ROR alpha 1. The identified genes and pathways were in concordance with the demonstration of hyperglycemia, glucose intolerance, attenuated insulin-stimulated phosphorylation of Akt and impaired glucose uptake in the transgenic heterozygous Tg-ROR alpha 1 Delta DE animals. In conclusion, we propose that ROR alpha 1 is involved in regulating the Akt2-AMPK signaling pathways in the context of lipid homeostasis in skeletal muscle.

Item Details

Item Type:Refereed Article
Keywords:Nuclear receptors, Diabetes
Research Division:Biological Sciences
Research Group:Biochemistry and Cell Biology
Research Field:Cell Metabolism
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Diabetes
Author:Myers, SA (Dr Stephen Myers)
ID Code:101152
Year Published:2010
Web of Science® Times Cited:28
Deposited By:Health Sciences B
Deposited On:2015-06-11
Last Modified:2015-09-15
Downloads:232 View Download Statistics

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