Higher levels of physical activity and lower body weight or body fat are associated with a decreased risk of several types of cancer, in particular colorectal and postmenopausal breast cancer. Possible mechanistic pathways for this association involve inflammatory factors, steroid hormones, insulin like growth factors or insulin resistance, and lipid metabolism. Many of these mechanisms can be mediated by changes in energy balance such as weight change or changes in body composition. Adipose tissue plays a role in several of the proposed mechanisms, particularly via the production of proinflammatory cytokines and sex hormones. The proposed project will examine the intersection between energy balance specifically diet, physical activity and weight change and adipose tissue biology.There will be ancillary to a funded human clinical trial of exercise and caloric restriction in overweight or obese, previously sedentary, postmenopausal women. The project will collect subcutaneous abdominal adipose tissue sample sat base line and at 6 months in 60 women. Specific aims are (1) to investigate the effects of exercise (n=15), reduced calorie diet (n=15), exercise+diet (n=15) and usual lifestyle control (n=15) on adipose tissue mRNA and protein expression of specific proinflammatory cytokines (i.e.IL6andTNF1) and adipokines(i.e. leptin and adiponectin), as well as mRNA expression related to sex steroid hormone production (i.e. aromatase);(2) to investigate the impact of changes in body weight (kg) or body mass index (kg/m2) and physical activity (METhoursweek) on the above biomarkers;and (3) to explore changes in adipose tissue gene expression patterns using the Affymetrix U133 plus 2.0 Gene Chip microarray ,focusing on a subset of participants in the exercise + diet group (n=10) versus controls (n=10). The exercise + diet group is expected to have the largest change in percent body fat, thus providing the strongest contrast. To our knowledge, this study will be the first randomized controlled trial to test the effects of exercise, both alone and in combination with a calorie restricted diet, on mRNA and protein expression in subcutaneous adipose tissue in humans. Energy balance is becoming increasingly recognized as an important factor in cancer risk. The adipocyteis at the interface of the association between energy balance and the hypothesized mechanisms linking energy balance to carcinogenesis. Examination of adipose tissue is critical to further the understanding of this link. This trial will provide data on the effect of a lifestyle intervention on important aspects of adipose tissue biology. PROJECT NARRATIVE This project will investigate the effects of diet and exercise on fat tissue. Being physically inactive and overweight or obese has been linked to increased risk of some cancers. Thus, we want to understand how physical activity, a diet low in calories, and body composition changes alter biological factors in fat tissue that are thought to be associated with cancer risk. This information will allow us to develop better lifestyle recommendations on how to reduce cancer risk.