Hepatocyte
retinoid X receptor (RXR)alpha-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 RXRalpha in
fatty acid and carbohydrate metabolism. Food intake was significantly reduced in hepatocyte RXRalpha-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-alpha target genes indicated that the
peroxisome proliferator-activated receptor-alpha-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 RXRalpha 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 RXRalpha-deficient mice.