Loss of FXR protects against diet-induced obesity and accelerates liver carcinogenesis in ob/ob mice.

Loss of FXR protects against diet-induced obesity and accelerates liver carcinogenesis in ob/ob mice.

Zhang Yanqiao; Ge Xuemei; Heemstra Lydia A; Chen Wei-Dong; Xu Jiesi; Smith Joseph L; Ma Huiyan; Kasim Neda; Edwards Peter A; Novak Colleen M

Molecular endocrinology (Baltimore, Md.)

2012

2012-02

Farnesoid X receptor (FXR) is known to play important regulatory roles in bile acid, lipid, and carbohydrate metabolism. Aged (\textgreater12 months old) Fxr(-/-) mice also develop spontaneous liver carcinomas. In this report, we used three mouse models to investigate the role of FXR deficiency in obesity. As compared with low-density lipoprotein receptor (Ldlr) knockout (Ldlr(-/-)) mice, the Ldlr(-/-)Fxr(-/-) double-knockout mice were highly resistant to diet-induced obesity, which was associated with increased expression of genes involved in energy metabolism in the skeletal muscle and brown adipose tissue. Such a striking effect of FXR deficiency on obesity on an Ldlr(-/-) background led us to investigate whether FXR deficiency alone is sufficient to affect obesity. As compared with wild-type mice, Fxr(-/-) mice showed resistance to diet-induced weight gain. Interestingly, only female Fxr(-/-) mice showed significant resistance to diet-induced obesity, which was accompanied by increased energy expenditure in these mice. Finally, we determined the effect of FXR deficiency on obesity in a genetically obese and diabetic mouse model. We generated ob(-/-)Fxr(-/-) mice that were deficient in both Leptin and Fxr. On a chow diet, ob(-/-)Fxr(-/-) mice gained less body weight and had reduced body fat mass as compared with ob/ob mice. In addition, we observed liver carcinomas in 43% of young (\textless11 months old) Ob(-/-)Fxr(-/-) mice. Together these data indicate that loss of FXR prevents diet-induced or genetic obesity and accelerates liver carcinogenesis under diabetic conditions.

Adipose Tissue; Adiposity/genetics; Animals; Brown/pathology; Carcinoma/etiology/*genetics; Cell Transformation; Cytoplasmic and Nuclear/*deficiency/genetics; Diet; Dietary Fats/metabolism; Energy Metabolism/genetics; Female; Gene Knockout Techniques; Glucose Intolerance/complications/genetics; High-Fat/*adverse effects; Intestinal Absorption; Knockout; Leptin/deficiency/genetics; Liver Neoplasms/etiology/*genetics; Liver/pathology; Male; Mice; Muscle; Neoplastic/genetics; Obese; Obesity/*etiology/genetics; Receptors; Sex Factors; Skeletal/metabolism; Weight Gain/genetics

Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).

272–280

2

26