Lay summary
The CREBRF variant (R457Q) specific to Māori and Pacific populations has the largest effect size of any single genetic variant on body mass index (BMI) and yet despite higher BMI it is associated with a 50% reduction in diabetes. Our research to date has characterised two mouse models carrying this variant and shown that the mice are protected from large increases in body fat which has metabolic benefit over a lifetime. We have also shown there are several potential mechanisms driving these phenotypes; some of which are important pathways for metabolic health and disease and also have implications for activity of commonly used pharmaceuticals. Our research proposal seeks to refine our understanding of this variant at a cellular and molecular level with a focus on fat and muscle cells. This knowledge will inform future clinical studies that aim to improve healthcare for metabolic disease in Māori and Pacific people.