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J. Biol. Chem., Vol. 280, Issue 13, 12573-12584, April 1, 2005

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Nur77 Regulates Lipolysis in Skeletal Muscle Cells

EVIDENCE FOR CROSS-TALK BETWEEN THE -ADRENERGIC AND AN ORPHAN NUCLEAR HORMONE RECEPTOR PATHWAY^*

Megan A. Maxwell, Mark E. Cleasby, Angus Harding¶, Annika Stark¶, Gregory J. Cooney, and George E. O. Muscat||

From the Institute for Molecular Bioscience Division of Molecular Genetics and Development and ^¶Division of Molecular Cell Biology, University of Queensland, St. Lucia Queensland 4072 and Diabetes and Obesity Research Program, Garvan Institute of Medical Research, 384 Victoria St., Darlinghurst, New South Wales 2010 Australia

Skeletal muscle is a major mass peripheral tissue that accounts for 40% of total body weight and 50% of energy expenditure and is a primary site of glucose disposal and fatty acid oxidation. Consequently, muscle has a significant role in insulin sensitivity, obesity, and the blood-lipid profile. Excessive caloric intake is sensed by the brain and induces -adrenergic receptor (-AR)-mediated adaptive thermogenesis. -AR null mice develop severe obesity on a high fat diet. However, the target gene(s), target tissues(s), and molecular mechanism involved remain obscure. We observed that 30–60 min of -AR agonist (isoprenaline) treatment of C2C12 skeletal muscle cells strikingly activated (>100-fold) the expression of the mRNA encoding the nuclear hormone receptor, Nur77. In contrast, the expression of other nuclear receptors that regulate lipid and carbohydrate metabolism was not induced. Stable transfection of Nur77-specific small interfering RNAs (siNur77) into skeletal muscle cells repressed endogenous Nur77 mRNA expression. Moreover, we observed attenuation of gene and protein expression associated with the regulation of energy expenditure and lipid homeostasis, for example AMP-activated protein kinase 3, UCP3, CD36, adiponectin receptor 2, GLUT4, and caveolin-3. Attenuation of Nur77 expression resulted in decreased lipolysis. Finally, in concordance with the cell culture model, injection and electrotransfer of siNur77 into mouse tibialis cranialis muscle resulted in the repression of UCP3 mRNA expression. This study demonstrates regulatory cross-talk between the nuclear hormone receptor and -AR signaling pathways. Moreover, it suggests Nur77 modulates the expression of genes that are key regulators of skeletal muscle lipid and energy homeostasis. In conclusion, we speculate that Nur77 agonists would stimulate lipolysis and increase energy expenditure in skeletal muscle and suggest selective activators of Nur77 may have therapeutic utility in the treatment of obesity.

Received for publication, August 20, 2004 , and in revised form, January 1, 2005.

^* This study was supported by a National Health and Medical Research Council of Australia project grant. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| A Principal Research Fellow of the National Health and Medical Research Council of Australia. To whom correspondence should be addressed. Tel.: 61-7-3346-2222; E-mail: g.muscat{at}imb.uq.edu.au.

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