The susceptibility to weight gain in male C57BL/6 mice fed high-fat diet is due to a small set of genes predominantly not expressed in the brain.

Obesity results from a gene by environment interaction. Understanding the impacts of environmental factors like diet on body weight/fatness has been greatly facilitated by rodent models. We previously identified the responses of males of five mouse strains fed 30 different diets. Two of these strains showed much greater weight gain and two were resistant. Sixty-six marker SNPs in 57 genes were identified, which have a genetic motif across the four strains reflecting their protection or susceptibility to high-fat diet (HFD). We used two of these strains: C57BL/6 and BALB/c, in a classic approach of cross-breeding the strains, to generate a F1 generation, and then cross-breeding their offspring to generate an F2 population. The F2 males were fed HFD and phenotyped for body weight, fat mass, and energy intake and genotyped for the 66 SNPs. Body mass gain on HFD was influenced by 17 SNPs in 11 genes explaining 87% of the individual variation in weight gain. We then measured gene expression of these 11 genes in 16 tissues of male and female C57BL/6 and Balb/c mice when fed high- or low-fat diets, and in 6 tissues of mice exposed to different levels of calorie restriction, to map their expression profiles. The genes were widely expressed in a diversity of tissues including several not normally suspected to be important for fat storage regulation (e.g., testis, lungs, and spleen) with only four expressed predominantly in the hypothalamus. Body fat regulation is probably more complex than current models focused on the brain-adipose axis suppose.