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Submitted on October 17, 2003
Accepted on April 8, 2004
Deficient Mice Have Increased Skeletal Muscle Lipoprotein Lipase Activity and Less Weight Gain when Fed a High Fat Diet
Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado; Center for Human Nutrition, University of Colorado Health Sciences Center, Denver, Colorado; Institut de Genetique et de Biologie Moleculaire et Cellulaire, Clinique de la Souris and College de France, B.P. 10142, 67404 Illkirch Cedex, Communaute Urbaine de Strasbourg, France
* To whom correspondence should be addressed. E-mail: bryan.haugen{at}uchsc.edu.
Retinoids, derivatives of vitamin A, induce hypertriglyceridemia through decreased clearance of VLDL by a lipoprotein lipase (LPL)-dependent pathway. The retinoid X receptor RXR
isotype, which is highly expressed in skeletal muscle, may be important in mediating the effects of retinoids on skeletal muscle metabolism and triglyceride (TG) clearance. RXR deficient (-/-) mice had lower fasting plasma TG levels compared with wild-type (WT) littermates (33.1 ± 2.0 vs. 51.7 ± 6.3 mg/dl respectively, P < 0.05). Skeletal muscle LPL activity was higher in RXR mice (18.7 ± 2.2 vs. 13.3 ± 1.3 nmol FFA/min/g, P = 0.03), but LPL activity was not different in adipose and cardiac tissue, suggesting a specific effect of RXR in skeletal muscle. In addition, when exposed to a 14-week high-fat diet, RXR -/- mice had less weight gain which was entirely due to lower fat mass (11.9 ± 1.8 vs. 14.4 ± 1.1 grams, P = 0.01), and leptin levels were also lower in the RXR -/- mice (17.6 ± 5.0 vs. 30.9 ± 6.4 ng/ml, P = 0.03). These data suggest that RXR -/- mice are resistant to gain in fat mass in response to high fat feeding. This occurs, at least in part, through up-regulation of LPL activity in skeletal muscle. An understanding of the mechanisms governing the role of RXR in TG disposal and metabolism may lead to the rationale design of RXR-selective agonists and antagonists that may be useful in common disorders such as dyslipidemia and obesity.
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