Our greatest public health challenge is obesity and the co-morbidities of metabolic syndrome (MetS). Age is an established risk factor for MetS and specific to women, data indicates that the prevalence of MetS increases substantially with the menopausal transition with postmenopausal women having a 60% increased risk of MetS. Menopause also contributes to reductions in strength, physical function and often psychological well-being (e.g. fatigue). Obese individuals also have: a) impaired immune function and chronic inflammatory responses associated with changes in the white blood cell population in blood and fat tissues; and, b) increased secretion of and signaling by proteins in their fat cells. Weight loss, which requires an energy deficit through increased physical activity and/or caloric restriction (EX+CR), reduces risk for MetS in older sedentary obese women by reducing insulin resistance and chronic systemic inflammation. Science and clinical practice will be advanced by examining the molecular mechanisms by which EX+CR affects risk for MetS in older women. The primary aim is to determine if CD4+ T cells will report the differential epigenetic reprogramming of relevant gene expression associated with metabolic indices resulting from EX+CR induced weight loss in older women known to be at risk for MetS. This pilot data will be used to generate an NIH proposal of the same topic. A secondary aim is to assess the impact of weight loss on physical function and psychological well-being which will provide pilot data for an additional grant proposal regarding weight management in postmenopausal women.