An Arg457Gln variant in the CREBRF gene (encoding Cyclic AMP Response Element Binding Protein 3 Regulatory Factor) has previously been identified as driving excess body weight in Pacific/Oceanic populations. Intriguingly, despite the substantial increase in body mass, carriers of the Arg457Gln variant had a paradoxical reduction in type 2 diabetes risk, indicating a critical role in whole-body metabolism. To study its function in more detail, we have generated mice on an FVB background where this CREBRF Arg457Gln variant has been knocked in to replace the endogenous CREBRF. The whole-body metabolic phenotype was characterised for male and female mice on a regular chow diet or an 8-week high-fat challenge. The CREBRF variant significantly increased both lean mass and naso-anal length in male mice, with total body weight and fat mass unaltered. Although indirect calorimetry measures of whole-body energy expenditure were unaffected, the CREBRF variant exaggerated fasting-induced trends in nutrient homeostasis, including alterations to tissue glycogen and lipid contents as well as enhanced elevation of plasma NEFAs. Further in vitro examination of insulin and glucagon signalling pathways using a primary hepatocyte model revealed significant dampening of Akt/PKB signalling in cells isolated from male mice carrying the missense variant. Overall, this novel mouse model appears to show a whole-body growth phenotype effect of the CREBRF variant in males, with a speculative role in regulating energy homeostasis during periods of nutrient deprivation without benefit to insulin sensitivity or glucose tolerance. The mild effects of the mutation in mice may invite reconsideration of the link between CREBRF function and the risks of obesity and diabetes in variant allele carriers.