Poster only 3rd Metabolic Diseases; Breakthrough Discoveries in Diabetes & Obesity 2022

Using mice to understand how the CREBRF variant drives larger size and lower diabetes risk. (#127)

Kate L Lee 1 , Sanaz Vakili 1 , Prasanna Kallingappa 1 , Peter R Shepherd 1
  1. University of Auckland, Grafton, AUCKLAND, New Zealand

A coding SNP (p.Arg457Gln) in the CREBRF gene, found in ~25% of Māori and peoples of the Pacific islands, is associated with a large increase in BMI, yet paradoxically, it is also associated with an approximately 50% reduction in the incidence of type-2 diabetes [1,2].  The mechanism by which this variant drives these associated phenotypes is unknown and CREBRF itself has been subject to minimal study.  Despite this, we know CREBRF is involved in regulation of bZip transcription factors that are ubiquitously expressed and have roles in several key cellular processes.  Body size and glucose metabolism are regulated by the synchronous activities of many organs; requiring us to use a whole-body model system. Due to strong conservation in the CREBRF gene, we are able to use mice carrying the orthologous SNP to study this variant.  We focused phenotyping on older mice as well as looking at global and targeted gene expression in tissues and mouse embryonic fibroblasts.  Our in vitro work has confirmed the variant changes levels of CREBRF-regulated mRNA; basally and in response to stimuli. This data indicates glucocorticoid receptor activity is affected by the variant which may have clinical implications considering this is a target of commonly-prescribed anti-inflammatory drugs.   We have characterised 20-month-old mice and show there are differences in body composition that manifest at this age and in males this is accompanied by increased grip strength and rotarod performance as well as lower serum myostatin levels [3].  Body composition changes are accompanied by improvements in glucose metabolism; improved insulin responsiveness accompanied by lower serum insulin in response to stimuli.  The SNP does not lead to phenotypic outcomes that are seen in CREBRF genetic ablation models.  Our mouse models will be useful for further exploring the molecular mechanisms by which the CREBRF variant can confer metabolic protection. 

  1. 1. Minster, R. L., Hawley, N. L., Su, C.-T., Sun, G., Kershaw, E. E., Cheng, H., Buhule, O. D., Lin, J., Reupena, M. S., Viali, S., Tuitele, J., Naseri, T., Urban, Z., Deka, R., Weeks, D. E., &; McGarvey, S. T. (2016). A thrifty variant in CREBRF strongly influences body mass index in Samoans. Nat Genet,48(9), 1049–1054.
  2. 2. Krishnan, M., Major, T. J., Topless, R. K., Dewes, O., Yu, L., Thompson, J. M. D., McCowan, L., de Zoysa, J., Stamp, L. K., Dalbeth, N., Harré Hindmarsh, J., Rapana, N., Deka, R., Eng, W. W. H., Weeks, D. E., Minster, R. L., McGarvey, S. T., Viali, S., Naseri, T., … Merriman, T. R. (2018). Discordant association of the CREBRF rs373863828 A allele with increased BMI and protection from type 2 diabetes in Māori and Pacific (Polynesian) people living in Aotearoa/New Zealand. Diabetologia, 61(7), 1603–1613.
  3. 3. Lee, K., Vakili, S., Burden, H. J., Adams, S., Smith, G. C., Kulatea, B., Wright-McNaughton, M., Sword, D., Watene-O’Sullivan, C., Atiola, R. D., Paul, R. G., Plank, L. D., Wilcox, P., Kallingappa, P., Merriman, T. R., Krebs, J. D., Hall, R. M., Murphy, R., Merry, T. L., &; Shepherd, P. R. (2022). The minor allele of the CREBRF rs373863828 p.R457Q coding variant is associated with reduced levels of myostatin in males: Implications for body composition. Molecular Metabolism, 59.