The overarching scientific objective of the CO-SCORE is to advance our understanding of how gonadal aging affects bioenergetics, abdominal adiposity, metabolism, and disease risk, by conducting mechanistically-driven research across the basic-to-clinical translational spectrum. CO-SCORE Project 2 will leverage preclinical models and interventions to provide a bi-directional, basic-to-clinical translational bridge between the clinically relevant studies of Project 1 and the basic discovery studies in Project 3. The long-term objective of Project 2 is to work collaboratively with CO-SCORE investigators to develop better strategies for treating and preventing the pathological consequences of gonadal aging, which disproportionately afflict women. Menopause is associated reduced levels of physical activity, weight gain, and abdominal adiposity, and predisposes women to a number of age-related disorders that include insulin resistance, diabetes, cancer, osteoporosis, and cardiovascular disease. Studies from Projects 1 and 2 in the current cycle of the award demonstrated that estrogen (E2) is an important mediator of the bioenergetic and metabolic consequences of the loss of ovarian function. In our preclinical model of the loss of ovarian function (surgical ovariectomy, OVX), we have also observed that the decline in physical activity occurs rapidly, precedes changes in body weight and fat mass, and predicts the subsequent gain in weight and fat mass. Studies from Project 3 provide evidence that these OVX-induced changes in adipose tissues are the result of the infiltration and accumulation of bone marrow-derived adipocytes (BMDA), which impart a proinflammatory harmful phenotype. Recent evidence has suggested that elevated levels of follicle stimulating hormone (FSH) may contribute to all of these detrimental effects that occur with the loss of ovarian function. In AIM 1 of Project 2, we manipulate these hormones in a preclinical model to dissect the independent and combined roles of ¯E2 and FSH on the OVX- induced decline in spontaneous physical activity (SPA), energy balance, the accumulation of abdominal fat, and the functional, cellular, and molecular characteristics of adipose tissue. In AIM 2 of Project 2, we examine the mechanisms by which regular exercise counters OVX-induced changes in the functional, cellular and molecular characteristics of adipose tissue, including the enrichment of BMDA. These studies will provide novel evidence regarding the roles of ↑FSH, ↓SPA, and adipose tissue enrichment of BMDA in the metabolic consequences of the loss of ovarian function. Elucidating the specific contributions of these factors to the detrimental consequences of the loss of ovarian function will lead to innovative strategies for the prevention and treatment of age-related diseases that accompany ovarian failure.