Obesity is one of the most pressing health problems facing humanity, affecting over 650 million adults worldwide. Excess body weight is a major risk factor for the leading causes of morbidity and mortality in much of the world including type 2 diabetes, hypertension, cardiovascular disease, cancer, and COVID-19. Obesity is defined by excess white fat, which contributes to associated diseases, but mammals also possess thermogenic brown and beige fat, which can convert chemical energy into heat. We have contributed to the understanding of molecular and tissue-level regulation of thermogenic fat, but this tissue was long thought to have a limited role in human health and disease. We have recently used a large patient cohort study to show that brown fat is in fact associated with significant metabolic and cardiovascular health benefits. My lab investigates the biology and genetics of thermogenic fat to understand how it mediates these pleiotropic effects. Centered on human biology and employing unique patient cohorts and novel imaging and biochemical methods, we use a systems-based approach to address four interrelated themes: (1) Cellular and developmental biology of thermogenic adipocytes; (2) Understanding how thermogenic fat contributes to cardiovascular protection; (3) Comprehensive analysis of humoral factors secreted by thermogenic fat and their role in maintaining metabolic health; and (3) Mechanistic studies of thermogenic fat informed by human genetics. Our integrated approaches seek to leverage brown and beige fat biology to provide new therapeutic opportunities to address a crucial and unmet need threatening human health.