title: Loss of FXR protects against diet-induced obesity and accelerates liver carcinogenesis in ob/ob mice.
abstract: Farnesoid X receptor (FXR) is known to play important regulatory roles in bile acid, lipid, and carbohydrate metabolism. Aged (>12 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 (<11 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.
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio 44272, USA. yzhang@neomed.edu
authors.forename: Yanqiao
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xuemei
authors.initials: X
authors.lastname: Ge
authors.forename: Lydia A
authors.initials: LA
authors.lastname: Heemstra
authors.forename: Wei-Dong
authors.initials: WD
authors.lastname: Chen
authors.forename: Jiesi
authors.initials: J
authors.lastname: Xu
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Smith
authors.forename: Huiyan
authors.initials: H
authors.lastname: Ma
authors.forename: Neda
authors.initials: N
authors.lastname: Kasim
authors.forename: Peter A
authors.initials: PA
authors.lastname: Edwards
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Novak
mesh_terms: D002001:Adipose Tissue, Brown / Q000473:pathology; D050154:Adiposity / Q000235:genetics; D000818:Animals; D002277:Carcinoma / Q000209:etiology / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D059305:Diet, High-Fat / Q000009:adverse effects*; D004041:Dietary Fats / Q000378:metabolism; D004734:Energy Metabolism / Q000235:genetics; D005260:Female; D055786:Gene Knockout Techniques; D018149:Glucose Intolerance / Q000150:complications / Q000235:genetics; D007408:Intestinal Absorption; D020738:Leptin / Q000172:deficiency / Q000235:genetics; D008099:Liver / Q000473:pathology; D008113:Liver Neoplasms / Q000209:etiology / Q000235:genetics*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008820:Mice, Obese; D018482:Muscle, Skeletal / Q000378:metabolism; D009765:Obesity / Q000209:etiology* / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency* / Q000235:genetics; D012737:Sex Factors; D015430:Weight Gain / Q000235:genetics; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D004041:Dietary Fats; D020738:Leptin; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated