Role of the nuclear receptor Farnesoid X Receptor (FXR) in energy homeostasis – FXRen

Obesity, defined as an “excess accumulation of fat” by the WHO, reaches “epidemic” proportions worldwide and is a public health problem. Almost 50% of adult people are overweight or obese in France. To develop new therapeutic strategies for obesity and its metabolic and cardiovascular complications is a challenge of the next decades. An impairment of bile acid profile is one of the metabolic perturbations associated with obesity and diabetes. For a long time thought to be solely dietary lipid detergents, bile acids now appear as signalling molecules regulating glucose, lipid and energy homeostasis which are unbalanced in obesity. Among the mechanism via which bile acids control metabolism is through binding to the nuclear receptor Farnesoid X Receptor (FXR). A number of studies identified a crucial role for FXR in liver in the control of systemic metabolism (Lefebvre P, 2009). Recent papers, however, also identified a role for FXR in peripheral tissues (Cariou B, 2006 ; van Dijk TH, 2009 ; Popescu I, 2010 ; Abdelkarim M, 2010). Moreover, our preliminary data suggest a role for FXR in peripheral tissues and the brain in the control of systemic energy homeostasis. The aim of this project is to investigate the role of FXR in the control of energy homeostasis via its functions in peripheral tissues (adipose tissue and intestine) and the inter-relations with the central nervous system. To reach this goal we will study the functions of FXR in adipose tissue, the intestine and brain via the following approaches. 1/ To unravel the role of FXR in adipose tissue, we will generate and characterize adipose tissue-specific FXR-deficient mice on chow and high fat diets. A screening to identify FXR target genes during adipocyte differentiation will be performed to understand the molecular regulation of adipocyte differentiation and functions by FXR. Finally, the use of FRET and mass spectrophotometry technologies will allow us to identify novel FXR ligands in adipocytes. 2/ To unravel the functions of FXR in the intestine, we plan to study the expression profiles of incretins and gut hormones in lean and obese wild-type and FXR-deficient mice fed different diets. The impact of FXR activation on these pathways will be studied after FXR activation in vivo, in mice, and ex vivo, in intestinal biopsies from humans and minipigs. Finally, molecular mechanisms of FXR-mediated effects and of potential cross-talks with pathways known to regulate incretin production by L type enteroendocrine cells will be studied in vitro. 3/ To unravel the functions of FXR in brain, we will first determine by quantitative PCR the brain regions expressing FXR. The impact of FXR deficiency on neuropeptide and feeding-related marker gene expression in brain regions will be studied in vivo, in wild-type and FXR-deficient mice fed different diets. Finally, FXR silencing by lentiviral approach in specific brain regions will allow us to study the role of FXR in brain in the control of energy homeostasis. The obtained data will result in a better understanding of how bile acids via FXR control energy homeostasis and may yield new therapeutic approaches to treat obesity and its associated metabolic diseases.