PROJECT SUMMARY All women experience menopause, putting a female at risk for a number of chronic diseases, including an increased risk of obesity. Although post-menopausal replacement of estrogen (hormone replacement therapy - HRT) has been shown to be effective at protecting against the metabolic and inflammatory perturbations linked to estrogen-deficiency, HRT has been shown to pose unwanted health risks including an increased risk of stroke, heart attack, and a variety of cancers. As such, it has become a priority of the National Center for Complementary and Integrative Health to invest in the development of therapies that are both safe AND effective at combating menopause-induced side effects, including excess fat mass accrual and its related negative metabolic and inflammatory perturbations. One such potential alternative therapy is the potent phytoestrogen from the Humulus Lupus plant (hops), 8-prenylnaringenin (8-PN). The overall research objectives in this application are to determine 1) the dose of 8-PN that is both safe and effective at combating the metabolic and inflammatory perturbations linked to obesity in a setting of estrogen deficiency, 2) the tissue most responsive to 8-PN supplementation, and 3) elucidate the in vivo signaling mechanism of 8-PN action. The long-term goal is to develop a safe and effective natural therapy for the clinical treatment of menopause- associated metabolic impairments and inflammatory-driven health perturbations. The central hypothesis is that 8-PN can serve as a potent and safe natural therapeutic for estrogen-deficient-induced inflammatory and metabolic perturbations. The rationale for this project is that this pre-clinical work will lay the foundation for the utilization of 8-PN as a potent therapeutic for impaired metabolic and exacerbated inflammatory processes resulting from estrogen deficiency. The central hypothesis will be tested by pursuing two specific aims: 1) Determine the effective and safe dose of 8-PN to serve as a therapy for metabolic and inflammatory perturbations in an estrogen-deficient model, 2) will examine the hypothesis that skeletal muscle is the tissue most metabolically responsive to 8-PN therapy through estrogen-receptor alpha action. The research proposed in this application is innovative, in the applicant’s opinion, as, to date, no studies have systematically examined the protective capacity of 8-PN against metabolic and inflammatory perturbations or thoroughly assessed the potential toxicity of 8-PN’s long-term use in an estrogen-deficient model. The proposed research is significant as the results from this investigation will have an important positive impact for ALL women because they will lay the groundwork for future clinical trials using 8-PN as a therapy for the negative health side effects linked to estrogen deficiency.