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Retinoid X Receptor -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 (B.R.H., D.R.J., V.S., L.K.P., W.R.H., R.H.E.), Department of Medicine, and Center for Human Nutrition (R.H.E.), University of Colorado Health Sciences Center, Denver, Colorado 80262; and Institut de Genetique et de Biologie Moleculaire et Cellulaire (W.K., P.C.), Clinique de la Souris and College de France, 67404 Illkirch Cedex, Communaute Urbaine de Strasbourg, France

Address all correspondence and requests for reprints to: Bryan R. Haugen, M.D., B151, University of Colorado Health Sciences Center, 4200 East 9th Avenue, Denver, Colorado 80262. E-mail: bryan.haugen{at}uchsc.edu.

Retinoids, derivatives of vitamin A, induce hypertriglyceridemia through decreased clearance of very low-density lipoprotein 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 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 free fatty acids/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-wk 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 g; 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 rational design of RXR-selective agonists and antagonists that may be useful in common disorders such as dyslipidemia and obesity.

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