Limited Metabolic Effect of the CREBRFR457Q Obesity Variant in Mice

Abstract

The Arg457Gln missense variant in the CREBRF gene has previously been identified as driving excess body weight in Pacific/Oceanic populations. Intriguingly, Arg457Gln variant carriers also demonstrate paradoxical reductions in diabetes risk, indicating that the gene has a critical role in whole-body metabolism. To study the function of this variant in more detail, we generated mice on an FVB/N background with the Crebrf Arg458Gln variant knocked in to replace the endogenous Crebrf. The whole-body metabolic phenotype was characterized for male and female mice on a regular chow diet or an 8-week high-fat challenge. Regular assessment of body composition found that the Crebrf variant had no influence on total body weight or fat mass at any time point. Glucose tolerance tests demonstrated no obvious genotype effect on glucose homeostasis, with indirect calorimetry measures of whole-body energy expenditure likewise unaffected. Male chow-fed variant carriers displayed a trend towards increased lean mass and significantly reduced sensitivity to insulin administration. Overall, this novel mouse model showed only limited phenotypic effects associated with the Crebrf missense variant. The inability to recapitulate results of human association studies may invite reconsideration of the precise mechanistic link between CREBRF function and the risks of obesity and diabetes in variant allele carriers.