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); 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.
Highlights
IntroductionObesity is a global public health threat that is associated with additional metabolic abnormalities (i.e., insulin resistance, dyslipidemia) that increase the risk of common diseases such as diabetes and cardiovascular disease
Obesity is a global public health threat that is associated with additional metabolic abnormalities that increase the risk of common diseases such as diabetes and cardiovascular disease
These genome-wide association studies (GWAS) are historically enriched in populations with European ancestry and have not adequately assessed genetic contributions from underrepresented groups [5], many of which are disproportionately affected by obesity, diabetes, and cardiometabolic diseases
Summary
Obesity is a global public health threat that is associated with additional metabolic abnormalities (i.e., insulin resistance, dyslipidemia) that increase the risk of common diseases such as diabetes and cardiovascular disease. Over the past several decades, large genome-wide association studies (GWAS) have sought to identify the genetic contributions to this heritability These studies have been instrumental in linking numerous genes/loci to anthropometric and/or metabolic traits, including body mass index (BMI)/obesity [1, 2], regional adiposity/insulin biology [2, 3], and glycemia/diabetes [4]. These studies have revealed important insights into the underlying physiology/pathophysiology of these traits such as the critical role of central neuroendocrine regulation of energy homeostasis in obesity [1, 2], adipose tissue biology in insulin resistance [2, 3], and beta cell biology in diabetes [4]. Identifying novel genes/pathways underlying this “missing heritability” across diverse populations could improve prevention and/or treatment of obesity and its complications
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