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Hepatocyte Retinoid X Receptor--Deficient Mice Have Reduced Food Intake, Increased Body Weight, and Improved Glucose Tolerance

Department of Pathology, Harbor-University of California, Los Angeles Medical Center, Torrance, California 90509

Address all correspondence and requests for reprints to: Yu-Jui Yvonne Wan, Ph.D., Department of Pathology, Harbor-University of California, Los Angeles Medical Center, 1000 West Carson Street, Torrance, California 90509. E-mail: agarose{at}ucla.edu.

Hepatocyte retinoid X receptor (RXR)-deficient mice and wild-type mice were fed either a regular or a high-saturated-fat diet for 12 wk to study the functional role of hepatocyte RXR in fatty acid and carbohydrate metabolism. Food intake was significantly reduced in hepatocyte RXR-deficient mice when either diet was used. The amount of food intake was negatively associated with serum leptin level. Although mutant mice ate less, body weight and fat content were significantly higher in mutant than wild-type mice. Examination of the expression of peroxisome proliferator-activated receptor- target genes indicated that the peroxisome proliferator-activated receptor--mediated pathway was compromised in the mutant mice, which, in turn, might affect fatty-acid metabolism and result in increased body weight and fat content. Although mutant mice were obese, they demonstrated the same degree of insulin sensitivity and the same level of serum insulin as the wild-type mice. However, these mutant mice have improved glucose tolerance. To explore a mechanism that may be responsible for the improved glucose tolerance, serum IGF-I level was examined. Serum IGF-1 level was significantly increased in mutant mice compared with wild-type mice. Taken together, hepatocyte RXR deficiency increases leptin level and reduces food intake. Those mice also develop obesity, with an unexpected improvement of glucose tolerance. The result also suggests that an increase in serum IGF-I level might be one of the mechanisms leading to improved glucose tolerance in hepatocyte RXR-deficient mice.

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