MASSACHUSETTS GENERAL HOSPITAL, THE

The burden of disease attributable to obesity is enormous. Obesity is highly prevalent and associated with more than 60 metabolic, inflammatory, degenerative, cognitive, and neoplastic disorders. Broadly effective preventive and therapeutic strategies have been elusive, and rates of obesity continue to increase in all parts of the world. Among the current therapies for obesity, various forms of gastrointestinal weight loss surgery (GIWLS; bariatric surgery) have proven to be far and away the most effective and durable. Recent studies have demonstrated that these operations work primarily by affecting the physiological regulation of body weight. They affect multiple aspects of metabolic function, in some cases through mechanisms independent of weight loss or diminished food intake. These characteristics make use of GIWLS an attractive approach to examining physiological regulation of metabolic function. Using surgery to probe physiological mechanism is complementary to other means of studying these regulatory pathways, such as pharmacological or genetic manipulation. Combining the power of surgical, genetic, nutritional and pharmacological approaches will facilitate greater understanding of the cellular and molecular mechanisms underlying metabolic physiology in normal and disease states. The recent development of rat and mouse models of nearly all of the currently available GIWLS procedures will strongly facilitate this effort, but the technical difficulty and high cost of developing and maintaining these models is a formidable barrier to their use. The overall goal of this proposal is to establish a Small Animal Metabolic Surgery (SAMS) Core Resource whose services would reduce these barriers and facilitate use of these powerful models more broadly within the scientific community. More than 25 distinct rat and mouse surgical models of GIWLS procedures and related operations are available within the SAMS Core laboratory. The SAMS Core Resource will facilitate their effective use by (1) preparing and distributing surgical models and specimens from these models, (2) training investigators in their preparation and use, (3) performing metabolic and behavioral assessment of surgically manipulated animals, (4) assessing their physiology by in vivo functional imaging, and (5) establishing and maintaining a database of the effects of GIWLS in various rodent strains, genetically manipulated animals and disease models. The greater use of rodent models of GIWLS facilitated by the proposed SAMS Core will increase our understanding of the cellular and molecular regulation of metabolic function. It will also help to identify the mechanisms underlying the therapeutic benefits of these operations. Greater understanding of these mechanisms will contribute to the identification of new, more effective therapies for the several dozen diseases caused or promoted by obesity and will facilitate the development of more effective means of preventing and treating obesity itself. PUBLIC HEALTH RELEVANCE: The profound physiological effects of gastrointestinal weight loss surgery on body weight and metabolic function make these interventions valuable tools for probing the regulation of these physiological functions. The recent development of stable, reliable and reproducible models of these surgical procedures and related implantable devices in rats and mice strongly enhances their value to the scientific community, but the technical and economic barriers to their use are formidable. This proposal aims to establish a Small Animal Metabolic Surgery (SAMS) Core Resource Facility to facilitate the effective use of these rodent models by investigators working in the many disciplines affected by obesity and metabolic disorders. In response to the needs of Core users, the SAMS Core will prepare animal models for study by Core users, train investigators to prepare their models within their own laboratories, and use metabolic and behavioral assessment and several

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