The prevalence of obesity in the United States population is over 30%, predisposing a large portion of the population to metabolic diseases. Cortisol, a steroid hormone, is of critical importance in obesity, as it is responsible for stimulating gluconeogenesis in the liver and promoting adipocyte differentiation and maturation. Cortisol is activated from cortisone by the intracellular enzyme 11?-hydroxysteroid dehydrogenase type 1 (11?- HSD1). The overall aim of this proposal is to examine whole-body 11?-HSD1 enzyme distribution levels during normal physiology and in response to weight gain, insulin resistance and obesity using the novel 18F-FMOZAT PET radioligand in rodent and human populations. Whole-body PET imaging can provide a direct measure of the distribution of 11?-HSD1 allowing comparison to conventional methods using urinary or plasma cortisol metabolites in both lean and non-diabetic obese human individuals. We propose an obese Zucker fatty (ZF) rat model that will allow direct in vivo PET imaging of 11?-HSD1 levels in various tissues during progression to obesity (Aim 1). We also propose to examine 11?-HSD1 levels in lean and non-diabetic obese individuals with 18F-FMOZAT PET to assess tissue-specific variability in whole-body 11?-HSD1 enzyme levels, and compare these novel direct measures with current methods using urinary metabolites of cortisol (Aim 2). The program of research and training described in this K01 Mentored Career Development Award application will provide the candidate with the requisite skills and experience to become an independent investigator in the field of endocrinology (obesity). Under the mentorship of field-leading experts in endocrinology and obesity, and PET imaging, the proposed aims will afford training in the design, conduct and analysis of novel translational PET imaging techniques to be uniquely applied to metabolic syndromes in endocrinology, such as obesity. In pursuit of this goal, the candidate proposes to undertake further training in three primary areas 1) build expertise in clinical endocrinology (obesity) research 2) receive education in the pathophysiology of obesity and 3) continue to enhance my knowledge of cutting-edge whole-body PET imaging. The opportunities afforded by this award would enable the candidate to embark on a comprehensive, structured 5-year program of training and research designed to develop an expertise in innovative endocrinology research methods toward a career as an independent investigator.
Obesity negatively impacts an individual's health and quality of life, and affects a substantial burden on communities and society. The proposed research program will investigate the changes in cortisol metabolism during normal physiology, and during the progression to obesity in an attempt to understand the role of cortisol metabolism in obesity. A better understanding of cortisol metabolism, and particularly the relationship between an enzyme that activates cortisol and obesity, may inform more effective treatment strategies, improving quality of life and reducing societal burden.