The combination of my prior research and clinical training uniquely situate me to investigate how Roux- en-Y gastric bypass (RYGB) causes weight loss and improves diabetes. Specifically, the surgical expertise that I obtained during my post-doctoral fellowship involving bariatric surgery in rodents complements the intensive basic science training in molecular mechanisms of diabetes that I received during my doctoral training. This surgical and intellectual expertise poises me to perform disease-oriented research investigating the physiologic and molecular effects of bariatric surgery on obesity and related metabolic disease, as proposed in this application. My immediate career goals include the further development of my research laboratory in terms of data, reagents, publications, and additional funding. My recent faculty appointment and substantial commitment of the Departmental of Medicine to my research efforts have greatly facilitated this process. My long-term career goals include continued publication of my data in peer-reviewed scientific journals, to further establish myself as an independent scientist, and to become recognized as a leader in the fields of obesity, diabetes, and gastrointestinal regulation of metabolism. Realizing these achievements will ensure my continued career advancement, particularly the transition from assistant to associate professor, and beyond. The research environment at UT Southwestern, particularly as coordinated within the Taskforce for Obesity Research at UT Southwestern (TORS), provides me with the ideal opportunity to attain these goals. Specifically, my daily exposure to the TORS faculty, and the UT Southwestern faculty at large, will provide the experience and mentoring I need to ensure my continued development as a clinical scientist. My career development will involve both informal interactions with my mentor, TORS faculty, and members of their laboratories as well as more structured opportunities that include weekly meetings with my mentor, regular participation and presentation at divisional and departmental WIP (works-in-progress) meetings, departmental seminars, and international/national scientific symposia. I will also have the opportunity to lecture trainees regarding my clinical and research expertise, and attend classes involving biostatistics, research design, scientific grant writing, research management, and the Responsible Conduct of Research. In addition, I will have access to the full complement of technical capabilities represented in the TORS laboratories as well as the TORS Mouse Metabolic Phenotyping Core Facility, the extensive use of which is detailed in this proposal. Thus, UT Southwestern is the ideal environment to help me in achieving my goals. My prior training ensures that I will maximize these opportunities, and any others that may arise. I have focused my research efforts on the problem of obesity because of the magnitude of its public health threat. While even modest weight loss improves patient outcomes, most current behavioral and medical therapies are ineffective. In contrast, bariatric surgery induces substantial weight loss and improvement of related comorbidities. Unfortunately, due to its inherent risk, it is only available to the severely obese. Safer options that may be more broadly applied are needed. We have developed a technique to perform RYGB, the most commonly performed bariatric procedure in the US, on obese mice to understand how it so effectively induces weight loss and improves diabetes. This weight loss occurs largely due to an increase in metabolic rate. Additionally, we have determined that RYGB fails to induce weight loss or improve diabetes in genetically-manipulated mice that lack the melanocortin-4 receptor (MC4R), an important regulator of body weight. This finding enables us to directly investigate the role of MC4R and putative target tissues in the beneficial effects of RYGB. It will further facilitate the development of safer, less-invasive therapies that may mimic the clinical efficacy of bariatric surgery. The MC4R is expressed in structures of the autonomic nervous system (ANS) that are involved in the regulation of body weight and glucose metabolism (which is dysregulated in diabetes), including the vagus nerve and motor neurons of the sympathetic nervous system (SNS). The vagus nerve relays information regarding nutrient intake to the brain and is involved in the responsive modulation of feeding behavior and glucose metabolism. Recent genetic experiments in mice have demonstrated that MC4R in the vagus nerve and motor neurons of the SNS are involved in the regulation of glucose metabolism and metabolic rate, respectively. These observations suggest that RYGB may mediate its effects on body weight, metabolic rate, and diabetes through MC4R in these autonomic components. In this application, we propose experiments to directly investigate this hypothesis. To address our aims, we will perform RYGB on mice that have been genetically-engineered to express MC4R exclusively in these components of the ANS. Complete phenotypic characterization of post-surgical animals will identify target tissues and MC4R-dependent physiologic mechanisms through which RYGB induces weight loss, increases metabolic rate, and improves diabetes. Medications that modulate MC4R function are already in clinical trials. These findings are critical in that they will identify target tissues to which pharmacologic therapy that modulates MC4R function may be directed, thereby facilitating the development of pharmacologic agents with increased specificity of action and clinical efficacy while limiting the risk of side effects.