A murine model of the human CREBRF R457Q obesity-risk variant does not influence energy or glucose homeostasis in response to nutritional stress
Loading...
Date
2021-09-14
Journal Title
Journal ISSN
Volume Title
Publisher
PLoS ONE
Abstract
Obesity and diabetes have strong heritable components, yet the genetic contributions to these diseases remain largely
unexplained. In humans, a missense variant in Creb3 regulatory factor (CREBRF) [rs373863828 (p.Arg457Gln); CREBRF ] is
strongly associated with increased odds of obesity but decreased odds of diabetes. Although virtually nothing is known about
CREBRF’s mechanism of action, emerging evidence implicates it in the adaptive transcriptional response to nutritional stress
downstream of TORC1. The objectives of this study were to generate a murine model with knockin of the orthologous variant in
mice (CREBRF ) and to test the hypothesis that this CREBRF variant promotes obesity and protects against diabetes by
regulating energy and glucose homeostasis downstream of TORC1. To test this hypothesis, we performed extensive phenotypic
analysis of CREBRF knockin mice at baseline and in response to acute (fasting/refeeding), chronic (low- and high-fat diet
feeding), and extreme (prolonged fasting) nutritional stress as well as with pharmacological TORC1 inhibition, and aging to 52
weeks. The results demonstrate that the murine CREBRF model of the human CREBRF variant does not influence
energy/glucose homeostasis in response to these interventions, with the exception of possible greater loss of fat relative to lean
mass with age. Alternative preclinical models and/or studies in humans will be required to decipher the mechanisms linking this
variant to human health and disease.
Description
Keywords
Ashlee N. Wood, Gabriele Schoiswohl, Anna C. Meyer, Aneta Kowalski, obesity-risk, diabetes, ACE: Genetic Medicine, WAGMC, University of Ghana, Ghana
Citation
Kanshana JS, Mattila PE, Ewing MC, Wood AN, Schoiswohl G, Meyer AC, et al. (2021) A murine model of the human CREBRF obesity-risk variant does not influence energy or glucose homeostasis in response to nutritional stress. PLoS ONE 16(9): e0251895. https://doi.org/10.1371/journal.pone.0251895