Obesity directly contributes to comorbid diseases which account for the leading causes of morbidity and mortality in much of the world. Although functional brown adipose tissue (BAT) was only recently shown to be present in adult humans, studies in animal models and humans over the past fifteen years have shown that BAT can convey remarkable protection against obesity, type 2 diabetes, and associated disorders. However, we still have a very limited understanding of how BAT function in humans is regulated, and its genetic underpinnings have yet to be studied. At present there is no reliable biomarker or widely accessible diagnostic test to measure BAT function, necessitating creative approaches to study its genetic regulation. This proposal employs innovative strategies to leverage data from unique human cohorts to discover genetic variants explaining BAT function and linking BAT to metabolic traits and susceptibility to disease. We will utilize two complementary approaches: (1) Identify functional genetic variants in individuals with exceptionally high BAT activity and then cross-reference candidates with data from large human cohorts to ascertain whether these variants are associated with cardiometabolic phenotypes, and (2) Identify predicted functional variants in genes important for BAT function and perform phenome wide association study (PheWAS) and quantitative trait analyses focused on cardiometabolic traits. High confidence candidate variants identified through these approaches will then be investigated functionally in human brown adipocytes. This bedside-bench approach has the potential to provide a fundamentally new understanding of human BAT biology, a valuable new resource for the field, and to identify new mechanism-based targets for obesity, type 2 diabetes, and other metabolic diseases.
