biostudies-literatureKanshana JSNational Institute of Diabetes and Digestive and Kidney DiseasesHoward Hughes Medical InstituteNIDDK NIH HHSNHLBI NIH HHSNational Heart, Lung, and Blood InstituteAmerican Diabetes AssociationPittsburgh Foundatione0251895https://www.ebi.ac.uk/biostudies/studies/S-EPMC8439463biostudies-literatureUnknown16(9)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. PloS oneA murine model of the human CREBRFR457Q obesity-risk variant does not influence energy or glucose homeostasis in response to nutritional stress.PMC8439463Medical Student Research FellowshipNIH T32 DK007052T32 DK007052R01 HL093093MR2018-98421Basic Science Award 1-17-IBS-128Mattila PEKershaw EEEwing MCGingras SKanshana JSKaufman BAWeeks DEWood ANHawley NLSchoiswohl GMinster RLMeyer ACRosenthal SLKowalski ALu RMcGarvey STfalseA 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 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. 2021-01-01T00:00:00Z20212026-05-08T22:03:01.445Z2022-02-11T11:07:55.778ZS-EPMC84394633452047210.1371/journal.pone.0251895