SUMMARY Obesity is associated with the development of insulin resistance and resulting adverse cardiometabolic sequelae. Elevated fatty acid mobilization from subcutaneous adipose tissue has been identified as a key driver of obesity- induced insulin resistance; thus, determining mechanisms contributing to elevated fatty acid mobilization in obesity and examining potential countermeasures to decrease fatty acid mobilization in obese individuals are critical biomedical research priorities. Epidemiological data indicate that elevated circulating ferritin concentration (a marker of whole-body iron stores) is associated with the development of insulin resistance, and emerging evidence indicates that iron homeostasis is altered in obesity. However, the mechanisms linking iron and insulin resistance remain unclear. My overall working hypothesis is that, in obese humans, high whole-body and adipose iron levels contribute to elevated systemic fatty acid mobilization, thereby promoting insulin resistance. My novel preliminary data support the notion that elevated whole-body iron stores are associated with increased lipolytic activation in adipose tissue, elevated systemic fatty acid mobilization, and insulin resistance in obesity. In the project proposed in this application, I will expand on these exciting findings by determining the effects of reducing whole-body iron stores in obese subjects (via blood donation) on factors regulating iron homeostasis and lipolytic rate in adipose tissue, markers of oxidative stress in adipose tissue, and insulin resistance (Aim 1). Additionally, I will determine the effects of altering intracellular iron on basal and stimulated lipolytic rate in mature adipocytes ex vivo and in vitro, and examine the potential role of oxidative stress in mediating the relationship between iron and lipolysis (Aim 2). By combining these clinical/translational and ex vivo/in vitro studies, the overall findings from this project will determine the role of iron in the excessive fatty acid mobilization commonly found in obesity, and whether altered iron homeostasis may represent a key mechanism underlying impairments in metabolic health. This overall training plan will be overseen by my primary mentor, Dr. Jeffrey Horowitz, an expert in conducting integrative metabolic studies in humans. Together with the support of collaborating mentors Dr. Yatrik Shah, an expert in molecular physiology of iron homeostasis, and Dr. Charles Burant, an expert clinician and metabolism researcher, I am well-positioned to successfully carry out these studies and develop new skills and expertise that will enable me to pursue a career as an independent scientist investigating interactions between iron homeostasis and metabolic health.

NARRATIVE High rates of adipose tissue triglyceride “breakdown” (lipolysis) and a resultant elevation in the release of fatty acids into the systemic circulation have been identified as key mechanisms contributing to obesity-induced insulin resistance, which in turn underlies the development of several cardiometabolic diseases. Emerging evidence indicates that dysregulated iron homeostasis contributes to impaired metabolic health, but the mechanisms linking iron and insulin resistance remain unclear. In this project, I will examine the role of whole- body and adipose iron homeostasis on systemic fatty acid mobilization and insulin resistance, and investigate whether lowering systemic iron content (via blood donation) may improve metabolic health in obese humans.