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

Abstract

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.

Mechanisms of Resistance of Hepatocyte Retinoid X Receptor α-Null Mice to WY-14,643-induced Hepatocyte Proliferation and Cholestasis

“…Age-matched WT (of mixed genetic background of C57/Bl/6, 129/SvEvTac, and DBA-2) (18,19) and H-RXR␣-null mice (10 -12 weeks old) were used in all the experiments. The mice were housed in steel microisolator cages at 22°C with a 12:12-h, light/dark cycle.…”

Retinoid X Receptor α Regulates Glutathione Homeostasis and Xenobiotic Detoxification Processes in Mouse Liver

“…RNA was transferred to a nylon membrane by capillary blotting in 10ϫ standard saline citrate and cross-linked by UV irradiation. Probe labeling and hybridization were performed as described previously (Wan et al, 2003). The fold differentialexpression was determined by densitometry analysis.…”

Retinoid X receptors: common heterodimerization partners with distinct functions

“…From a developmental point of view, RXRα seems to be the main player since mice expressing only RXRα from one allele are viable, indicating a strong functional redundancy 23 . Tissue-specific inactivation of Rxra in hepatocytes [24][25][26][27][28] or epithelia 29,30 induces strong phenotypes, indicating a major role of RXRα in these tissues, whereas…”