Loss of FXR Protects against Diet-Induced Obesity and Accelerates Liver Carcinogenesis in ob/ob Mice
- 1 February 2012
- journal article
- other
- Published by The Endocrine Society in Molecular Endocrinology
- Vol. 26 (2), 272-280
- https://doi.org/10.1210/me.2011-1157
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.Keywords
This publication has 35 references indexed in Scilit:
- Epigenetic histone H3 lysine 9 methylation in metabolic memory and inflammatory phenotype of vascular smooth muscle cells in diabetesProceedings of the National Academy of Sciences of the United States of America, 2008
- Carbohydrate response element binding protein, ChREBP, a transcription factor coupling hepatic glucose utilization and lipid synthesisCell Metabolism, 2006
- Anatomical Profiling of Nuclear Receptor Expression Reveals a Hierarchical Transcriptional NetworkCell, 2006
- Bile acids induce energy expenditure by promoting intracellular thyroid hormone activationNature, 2006
- A Farnesoid X Receptor-Small Heterodimer Partner Regulatory Cascade Modulates Tissue Metalloproteinase Inhibitor-1 and Matrix Metalloprotease Expression in Hepatic Stellate Cells and Promotes Resolution of Liver FibrosisThe Journal of pharmacology and experimental therapeutics, 2005
- Peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) regulates triglyceride metabolism by activation of the nuclear receptor FXRGenes & Development, 2004
- Enterohepatic Circulation of Bile Salts in Farnesoid X Receptor-deficient MicePublished by Elsevier BV ,2003
- Natural Structural Variants of the Nuclear Receptor Farnesoid X Receptor Affect Transcriptional ActivationJournal of Biological Chemistry, 2003
- Targeted Disruption of the Nuclear Receptor FXR/BAR Impairs Bile Acid and Lipid HomeostasisCell, 2000
- A RAPID METHOD OF TOTAL LIPID EXTRACTION AND PURIFICATIONCanadian Journal of Biochemistry and Physiology, 1959