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This version published online on October 2, 2003
Molecular Endocrinology, doi:10.1210/me.2003-0151
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Submitted on April 22, 2003
Accepted on September 29, 2003

The Peroxisome Proliferator Activated Receptor {beta}/{delta} agonist, GW501516, regulates the expression of genes involved in lipid catabolism and energy uncoupling in skeletal muscle cells

Uwe Dressel1, Tamara L. Allen1, Jyotsna B. Pippal1, Paul R. Rohde1, Patrick Lau1, and George E.O. Muscat1*

1 Institute for Molecular Bioscience, The University of Queensland, St. Lucia QLD 4072, AUSTRALIA

* To whom correspondence should be addressed. E-mail: G.Muscat{at}imb.uq.edu.au,.

Lipid homeostasis is controlled by the Peroxisome Proliferator Activated Receptors (PPAR{alpha}, -{beta}/{delta} and -{gamma}) that function as fatty acid dependent DNA-binding proteins that regulate lipid metabolism. In vitro and in vivo genetic and pharmacological studies have demonstrated PPAR{alpha} regulates lipid catabolism. In contrast PPAR{gamma} regulates the conflicting process of lipid storage. However, relatively little is known about PPAR{beta}/{delta} in the context of target tissues, target genes, lipid homeostasis and functional overlap with PPAR{alpha} and -{gamma}. PPAR{beta}/{delta}, a VLDL sensor, is abundantly expressed in skeletal muscle, a major mass peripheral tissue that accounts for ~40% of total body weight. Skeletal muscle is a metabolically active tissue, and a primary site of glucose metabolism, fatty acid oxidation, and cholesterol efflux. Consequently, it has a significant role in insulin sensitivity, the blood-lipid profile, and lipid homeostasis. Surprisingly, the role of PPAR{beta}/{delta} in skeletal muscle has not been investigated. We utilize selective PPAR{alpha}, -{beta}/{delta}, -{gamma}, and LXR agonists in skeletal muscle cells to understand the functional role of PPAR{beta}/{delta}, and the complementary and/or contrasting roles of PPARs in this major mass peripheral tissue. Activation of PPAR{beta}/{delta} by GW501516 in skeletal muscle cells induces the expression of genes involved in preferential lipid utilization, {beta}-oxidation, cholesterol efflux, and energy uncoupling. Furthermore we show that treatment of muscle cells with GW501516 increases apolipoprotein-A1 specific efflux of intracellular cholesterol thus identifying this tissue as an important target of PPAR{beta}/{delta} agonists. Interestingly, fenofibrate induces genes involved in fructose uptake, and glycogen formation. In contrast, rosiglitazone-mediated activation of PPAR{gamma} induces gene expression associated with glucose uptake, fatty acid synthesis and lipid storage. Furthermore, we show that the PPRE in the muscle carnitine palmitoyl-transferase-1 promoter is directly regulated by PPAR{beta}/{delta}, and not PPAR{alpha} in skeletal muscle cells in a PGC-1 dependent manner. This study demonstrates that PPARs have distinct roles in skeletal muscle cells with respect to the regulation of lipid, carbohydrate and energy homeostasis. Moreover, we surmise that PPAR{beta}/{delta} agonists would increase fatty acid catabolism, cholesterol efflux and energy expenditure in muscle, and speculate selective activators of PPAR{beta}/{delta} may have therapeutic utility in the treatment of hyperlipidemia, atherosclerosis and obesity.
Key words: PPARs • muscle-CPT1 • uncoupling proteins • obesity • GW501516 • PGC1

NURSA Molecule Pages Link:

Nuclear Receptors:   PPARα  |  PPARδ  |  PPARγ
Coregulators:   PGC-1  |  p300  |  GRIP1
Ligands:   Rosiglitazone



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