Understanding the Role of the CREBRF R457Q Variant in Increased BMI and Decreased Type‐2 Diabetes Risk in Māori and Pacific Island People

Abstract

A coding variant in the CREBRF gene (p. Arg457Gln), unique to the Polynesian population, is associated with a reduced risk of T2D despite also being associated with a large increase in BMI. The most characterised function of the CREBRF protein is that it binds to and inhibits CREB3, an ER stress-activated transcription factor involved in unfolded protein response (UPR). CREBRF and CREB3 have also been shown to regulate the transcriptional activity of the glucocorticoid receptor (GR). ER and Golgi stress and long-term elevated glucocorticoid (GC) are pathophysiologically linked to T2D progression. It is, therefore, important to investigate how the variant alters CREBRF regulation of CREB3 and GR activity. Hence, we evaluated the basal gene expression in mouse embryonic fibroblasts (MEFs) derived from both wild-type (WT) and knock-in (KI) mice carrying the orthologous R458Q Crebrf variant.

MEFs were treated with Brefeldin A (BFA), an ER-Golgi stress inducer, Dexamethasone (DEX), a synthetic GC and tested under serum starvation conditions. The long-term effects of Dex on physiology and gene expression were investigated in mice, including a Dex-induced 8- day muscle wasting protocol. The Crebrf variant did not impact DST, fasting glucose or ACTH serum levels, but we did see an increased serum GC in KI female FVB/NJ mice. Male and female KI FVB/NJ had lower and higher hair GC levels, respectively. These studies found that Dex treatment upregulated Crebrf but downregulated Creb3 expression significantly in both KI MEFs and mice.

Another important finding was that the myostatin (Mstn) gene expression level was decreased in mice with the R458Q Crebrf variant. As this is a negative regulator of muscle mass, this has important implications for body composition. Together, these studies provide evidence that the R458Q Crebrf variant does have differential effects on signalling in the CREB3 and GC systems. Understanding how these responses affect the metabolism might reveal the mechanisms by which the CREBRF variant alters body composition in a way that can be beneficial to glucose metabolism and thereby protective of T2D.