The focus of Project 1 on Bioenergetic and Metabolic Consequences of the Loss of Gonadal Function in Women in the Colorado SCORE (CO-SCORE) is based on the overarching hypothesis that the loss of gonadal function increases risk for chronic disease. The best-studied example of this is the accelerated decline in bone mineral density at menopause and the resulting risk for osteoporosis. However, the extent to which gonadal aging increases risk for chronic diseases other than osteoporosis is poorly understood. This is particularly relevant to women’s health, because gonadal failure is inevitable in women in mid-life but rare in men until much later in life. During the current SCORE award period, we advanced the clinical translation of the unequivocal evidence in animals that loss of estradiol (E2) is a trigger for excess abdominal fat accumulation and metabolic dysfunction. We demonstrated that suppression of ovarian function in premenopausal women (gonadotropin releasing hormone agonist;; GnRHAG) disrupts energy homeostasis, and results in a marked increase in abdominal subcutaneous and visceral fat that is prevented by E2 add-back. We also generated intriguing preliminary data to support the hypothesis that the conversion of cortisone to cortisol in abdominal adipose tissue by the enzyme 11β-hydroxysteroid dehydrogenase 1 (HSD1) is regulated by E2. Preclinical evidence strongly supports glucocorticoid metabolism as a regulator of abdominal adiposity. Accordingly, Aim 1 in the next award period is to determine whether adipose tissue and systemic glucocorticoid metabolism are regulated by E2 in women. Because a goal of the CO-SCORE is to advance paradigm- challenging research on sex differences, Aim 2 will investigate follicle stimulating hormone (FSH) as a mediator of energy homeostasis and cardiometabolic function. FSH was implicated recently as a mediator of metabolic actions traditionally attributed to the loss of E2. When compared with controls, mice treated with an FSH antibody had increased bone mass and decreased adiposity, including reductions in visceral and subcutaneous fat. Given the importance of understanding whether both E2 and FSH may be important therapeutic targets, rather than just E2, we will conduct the first proof-of-concept study of the effects of E2 vs FSH on outcomes that are responsive to the inhibition of FSH in mice. Projects 1, 2 (preclinical), and 3 (basic) will all address gaps in knowledge on whether the effects of E2-deficiency to increase abdominal adiposity are mediated by altered glucocorticoid metabolism and/or increased FSH. Adipose tissue samples from women in Project 1 and from animals in Projects 2 and 3 will be interrogated using similar approaches to accelerate the translational relevance of these areas of research. Finally, because blood and tissue samples from experiments in which we control E2 status are of great value across many disciplines, we will bank specimens fr...