ABSTRACT Pre-menopausal women display a significantly lower incidence of cardiovascular disease than age-matched men. However, the incidence of female cardiovascular disease increases markedly after the onset of menopause, resulting in a relative loss of protection from heart disease. Decreased levels of estrogen are closely linked to the loss of cardioprotection after menopause, but the biological mechanisms underlying this connection are incompletely understood. While we know that estrogen signaling mediates the response to various pathophysiological stimuli, we do not fully understand how estrogen regulates key metabolic pathways in the failing heart. In the current proposal, we seek to understand whether relative reductions in cardiac fatty acid oxidation underpin the loss of cardioprotection in post-menopausal female hearts. In Specific Aim 1, we will determine how estrogen controls the abundance of GCN5L1, an enzyme that regulates cardiac fatty acid oxidation. In Specific Aim 2, we will determine how GCN5L1 regulates cardiac fatty acid oxidation in mouse models of female menopause. In Specific Aim 3, we will determine the requirement for fatty acid oxidation in female cardioprotection.