Limited Metabolic Effect of the CREBRFR457Q Obesity Variant in Mice.

Louise K Metcalfe,Nigel Turner,Peter R Shepherd,Greg C Smith

doi:10.3390/cells11030497

Louise K Metcalfe, Nigel Turner + Show 2 more

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https://doi.org/10.3390/cells11030497

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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.

Highlights

Obesity is one of the most significant contemporary health issues, due both to its sharply rising global prevalence and the substantial number of adverse health problems that are associated with the obese state
While there is an obvious link between the growing obesity epidemic and environmental factors, there has been great interest in searching for genetic factors that may contribute to this condition
To date the most prominent genetic variant linked with excess body weight is the recently identified R457Q variant in the CREBRF gene, a gene variant with a presence restricted to the Pacific Islands [1–3]

Summary

Introduction

Obesity is one of the most significant contemporary health issues, due both to its sharply rising global prevalence and the substantial number of adverse health problems that are associated with the obese state. The missense variant, which is located at a highly conserved position within the CREBRF gene, produced significant dose-dependent increases in obesity risk [1]. Occurrence of this Arg457Gln missense variant is tightly restricted by descent and geography. It is present in all surveyed Polynesian populations, with reported minor allele frequencies as high as 0.259 in the Samoan cohort, but comparatively scarce even among the geographically close Melanesian and Micronesian populations and virtually non-existent in individuals outside the Pacific Islands [1–6]

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