Mitochondrial PE in Brown Adipose Thermogenesis

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PROJECT SUMMARY Obesity is a comorbidity for diabetes, cardiovascular disease, stroke, and cancer. Obesity is caused by consuming calories in excess of energy expenditure for prolonged periods, which also often leads to insulin resistance and eventually type II diabetes. Exploiting brown adipose thermogenesis offers promising potential for the long-term treatment of obesity and hyperglycemia given its ability to increase caloric expenditure. Uncoupling protein 1 (UCP1), a protein located in the inner mitochondrial membrane (IMM), is responsible for thermogenesis in brown adipose tissue (BAT). Mitochondrial energetics are intimately tied to the IMM phospholipid composition. In addition to affecting cristae structure and function, these phospholipids regulate inner mitochondrial transmembrane protein activities due to phospholipid binding and interaction sites. My preliminary findings suggest that phosphatidylethanolamine (PE) plays an important adaptive role in BAT mitochondria. Mice housed in progressively colder environments displayed an increase in mitochondrial PE content concomitant with increased thermogenic capacity (as measured by UCP1-dependent respiration). Mice deficient in BAT mitochondrial PE are less cold tolerant with the isolated mitochondria from these mice exhibiting reduced respiratory rates. Based on these observations, I propose that mitochondrial PE is necessary for optimal UCP1 function and for cold- and diet-induced thermogenesis. To that end, I plan to interrogate this relationship by studying how increases or decreases in mitochondrial PE affect thermogenesis and if this phospholipid acts directly through UCP1. My extensive team of expert mentors will support my wholistic research training experience by reviewing my findings, identifying potential loopholes in my logic, and assisting with my future route of inquiry into BAT mitochondrial bioenergetics. Additionally, the collaborative and interactive learning environment at the University of Utah will facilitate my training in utilizing mouse models to generate quality data, conducting mitochondrial bioenergetic assays, interpreting data, and promoting diversity in biomedical research using my outreach skills. This proposal addresses a critical need in metabolic research and our hope is that these findings will provide an important steppingstone for future researchers to better understand and exploit BAT thermogenesis therapeutically.