Researchers Identify Obesity-Resistant Factors in Lean Mice

A team of French and Slovenian researchers led by Matjaž Simončič of the University of Ljubljana (Domžale, Slovenia) has used gel filtration chromatography and fast protein liquid chromatography to analyze the genes and molecular mechanisms that allow mice to resist developing obesity.

Whereas previous studies on obesity development have focused primarily on obesity-susceptibility in “fat” mice, the team chose to examine both “lean” and “fat” mice as unique models for a polygenic form of resistance and susceptibility to obesity development. The team attempted to determine the molecular basis of obesity-resistance through analysis of various fat depots and organs, the liver transcriptome of selected metabolic pathways, plasma and lipid homeostasis, and expression of selected skeletal muscle genes.

The team separated plasma lipoproteins with gel filtration chromatography using a Superose 6 HR 10/30 column (GE Healthcare, Uppsala, Sweden). Cholesterol distribution was obtained from the lipoproteins using fast protein liquid chromatography to separate the major lipoprotein classes (VLDL, IDL+LDL, and HDL).

Mice characterized as “lean” exhibited a higher hepatic expression of cholesterol biosynthesis genes compared to mice characterized as “fat.” The “lean” mice showed elevated levels of HDL cholesterol, Cyp8b1 (a regulatory enzyme of bile acid synthesis), and Abcb11 (a bile acid transporter gene responsible for exporting acids to the bile). In addition, the “lean” mice also showed a higher content of blood circulating bile acids. The team proposed that this higher level of HDL cholesterol, when accompanied by upregulation of synthesis of bile acids, may explain how cholesterol is excreted from lean mice, allowing them to avoid becoming obese. The major differences between the two lines, according to the team, are increased liver cholesterol biosynthesis gene mRNA expression, bile acid metabolism, and the expression of selected muscle genes.

“We identified novel candidate molecular targets and metabolic changes which can, at least in part, explain resistance to obesity development in the ‘lean’ line,” the team wrote in the February 3, 2011, issue of BMC Genomics.