Transcriptome analysis revealed association of some P450 genes with obesity in a polygenic obese mouse model

Matjaž Simončič¹, Tadeja Režen², Peter Juvan², Catherine Fievet³, Bart Staels³, Damjana Rozman²
and Simon Horvat¹*

¹ University of Ljubljana, Biotechnical Faculty, Department of Animal Science, Groblje 3, 1230 Dom`ale, Slovenia
² University of Ljubljana, Institute of Biochemistry, Faculty of Medicine, Vrazov trg 2, 1000 Ljubljana, Slovenia
³ Institut Pasteur de Lille, Lille, F-59019 France; Inserm, U545, Lille, F-59019 France; Université de Lille 2 Droit et Santé, Faculté des Sciences Pharmaceutiques et Biologiques et Faculté de Médecine, Lille, F-59006 France
* Corresponding author: E-mail: simon.horvat@bfro.uni-lj.si;
Phone: +386-31-331-264

Abstract
Superfamily of cytochromes P450 (CYP) have been extensively investigated in xenobiotic metabolism studies but only a handful of these genes (e.g., Cyp19a1 and Cyp7a1) have been associated with obesity. Examining these associations in animal models is relevant since obesity and metabolic syndrome in humans have become a prevalent health problem. In previous studies we identified four loci affecting obesity in mouse lines selected for high (Fat line) or low (Lean line) body fat content. Here we developed a Congenic line carrying a chromosome 15 obesity segment from the Lean line and compared its liver transcriptome and obesity traits with the original Fat line. Congenic segment exhibited therapeutic effect on several obesity-related parameters such as lowering fat depot size by up to 29% and lowering fasting glucose levels. Using the Steroltalk microarray focused on cytochromes P450 and cholesterol metabolism, we identified 9 differentially expressed genes including two Cyp genes (Cyp26a1, Cyp2a4). Given the scarcity of literature reporting associations between obesity and Cyps, our results suggest that these genes might play a more pronounced role in regulating obesity than previously thought. Further functional studies are needed to explain the mechanism by which perturbations in these Cyps affect obesity in our polygenic model.

Keywords: Cyp26a1, Cyp2a4, obesity, cholesterol metabolism, quantitative trait locus, polygenic