PROJECT SUMMARY/ABSTRACT This proposal seeks to investigate the predictive ability of psychological and epigenetic markers for success of lifestyle interventions in patients with obesity. Obesity is a growing public health crisis, and in the coming decades it is expected that 50% of Americans will have obesity. Current treatment practice typically begins with lifestyle interventions, followed by the addition of pharmacologic or surgical treatment if lifestyle interventions fail. However, many individuals fail lifestyle interventions, their obesity continues to progress, and they develop additional obesity-related comorbidities such as Type II Diabetes. While patients may be placed on anti-obesity medications following the failure of lifestyle interventions, studies have demonstrated that increased duration of obesity increases the risks of obesity-related morbidity. Both behavioral and biological factors contribute to the development, maintenance, and progression of obesity and obesity-related diseases. Stress has been found to increase the risk of obesity, and psychological resilience factors such as self-control affect feeding behavior as well as biological markers such as insulin resistance. Research has also suggested epigenetic modifications as a potential biological mechanism through which environmental factors may affect obesity and may contribute to comorbidities such as Type II Diabetes. Methylation of specific CpG sites has been associated with obesity and there are indications specific methylation patterns may be predictive of worsening obesity and/or the development of insulin resistance. The objective of this proposal is to utilize psychological and epigenetic data to predict obesity, insulin resistance, and HgbA1C in response to lifestyle interventions. Findings from this study may be directly applicable to clinical practice. By identifying patients with psychological (Aim #1) or epigenetic (Aim #2) factors at baseline that predict likely failure of lifestyle interventions, these patients could be directed toward pharmacologic or other treatment more likely to help. Specific epigenetic changes following lifestyle interventions (Aim #3) could also predict long-term success or failure and may guide whether escalation of treatment is needed. Ultimately, we hope this study will lead to development of a multi-modal predictor of treatment outcomes (Exploratory Aim) which can provide individualized, prospective guidance of treatment decisions. This proposal will integrate state-of-the-art facilities at Yale with a highly interdisciplinary team and an established, well-funded ongoing study. The applicant has assembled a team of expert mentors in clinical trials treating obesity, the neurobiology of obesity, stress and resilience, epigenetics, and advanced computational methods. Formal didactics, scientific workshops, and national meetings will support the applicant’s training and help leverage his robust clinical foundation with fellowship ...