A murine model of the human CREBRFR457Q obesity-risk variant does not influence energy or glucose homeostasis in response to nutritional stress.
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); CREBRFR457Q] is strongly associated with increased odds of obesity but decr...
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Public Library of Science (PLoS)
2021
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oai:doaj.org-article:89877e3193b84a7a9605cc11de25289c2021-12-02T20:08:17ZA murine model of the human CREBRFR457Q obesity-risk variant does not influence energy or glucose homeostasis in response to nutritional stress.1932-620310.1371/journal.pone.0251895https://doaj.org/article/89877e3193b84a7a9605cc11de25289c2021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0251895https://doaj.org/toc/1932-6203Obesity 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); CREBRFR457Q] 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 (CREBRFR458Q) 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 CREBRFR458Q 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 CREBRFR458Q model of the human CREBRFR457Q 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.Jitendra S KanshanaPolly E MattilaMichael C EwingAshlee N WoodGabriele SchoiswohlAnna C MeyerAneta KowalskiSamantha L RosenthalSebastien GingrasBrett A KaufmanRay LuDaniel E WeeksStephen T McGarveyRyan L MinsterNicola L HawleyErin E KershawPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 9, p e0251895 (2021) |
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Medicine R Science Q |
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Medicine R Science Q Jitendra S Kanshana Polly E Mattila Michael C Ewing Ashlee N Wood Gabriele Schoiswohl Anna C Meyer Aneta Kowalski Samantha L Rosenthal Sebastien Gingras Brett A Kaufman Ray Lu Daniel E Weeks Stephen T McGarvey Ryan L Minster Nicola L Hawley Erin E Kershaw A murine model of the human CREBRFR457Q obesity-risk variant does not influence energy or glucose homeostasis in response to nutritional stress. |
| description |
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); CREBRFR457Q] 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 (CREBRFR458Q) 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 CREBRFR458Q 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 CREBRFR458Q model of the human CREBRFR457Q 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. |
| format |
article |
| author |
Jitendra S Kanshana Polly E Mattila Michael C Ewing Ashlee N Wood Gabriele Schoiswohl Anna C Meyer Aneta Kowalski Samantha L Rosenthal Sebastien Gingras Brett A Kaufman Ray Lu Daniel E Weeks Stephen T McGarvey Ryan L Minster Nicola L Hawley Erin E Kershaw |
| author_facet |
Jitendra S Kanshana Polly E Mattila Michael C Ewing Ashlee N Wood Gabriele Schoiswohl Anna C Meyer Aneta Kowalski Samantha L Rosenthal Sebastien Gingras Brett A Kaufman Ray Lu Daniel E Weeks Stephen T McGarvey Ryan L Minster Nicola L Hawley Erin E Kershaw |
| author_sort |
Jitendra S Kanshana |
| title |
A murine model of the human CREBRFR457Q obesity-risk variant does not influence energy or glucose homeostasis in response to nutritional stress. |
| title_short |
A murine model of the human CREBRFR457Q obesity-risk variant does not influence energy or glucose homeostasis in response to nutritional stress. |
| title_full |
A murine model of the human CREBRFR457Q obesity-risk variant does not influence energy or glucose homeostasis in response to nutritional stress. |
| title_fullStr |
A murine model of the human CREBRFR457Q obesity-risk variant does not influence energy or glucose homeostasis in response to nutritional stress. |
| title_full_unstemmed |
A murine model of the human CREBRFR457Q obesity-risk variant does not influence energy or glucose homeostasis in response to nutritional stress. |
| title_sort |
murine model of the human crebrfr457q obesity-risk variant does not influence energy or glucose homeostasis in response to nutritional stress. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2021 |
| url |
https://doaj.org/article/89877e3193b84a7a9605cc11de25289c |
| work_keys_str_mv |
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