Reductions in energy expenditure and physical activity are central to the development of cardiometabolic diseases such as obesity, diabetes, and cardiovascular disease. The balance between food intake and energy expenditure determines the body fat mass, which is a major risk factor for disability and death. Obesity has surpassed even smoking as the major cause of morbidity and mortality in the US. Although human genetics has been a fruitful means of identifying associations of genetic changes with human disease, model systems are required to dissect the role of any given gene in energy homeostasis. In particular, the ability to elucidate determinants of energy expenditure using genetically modified mice is central to better understanding of the genetic architecture underlying the development of metabolic diseases and for the next generation of therapies for cardiometabolic diseases. This proposal requests the funds to support purchase of a TSE Systems Phenomaster, capable of measuring energy expenditure via indirect calorimetry, food consumption, overall activity level, exercise activity, and body mass. This system is state of the art in these capabilities, and further permits measurements to be conducted on 16 mice simultaneously in chambers with precise environmental control, a critical variable in studies of energy expenditure in rodents. A further improvement will be the ability to measure both standard activity and dedicated exercise activity on running wheels, both exceptionally important determinants of energy balance and body fat mass. It is critical that mice are disturbed minimally during acquisition of energy expenditure measurements as handling can significantly alter feeding and activity. The TSE Phenomaster has the major advantage of permitting measurements to be made for up to 10 days in a nearly fully automated way, allowing for highly reproducible and reliable assessment of energy expenditure. Many major projects at the MGH utilize genetic manipulation of mice to study metabolic endpoints, of which energy expenditure is key. The TSE Phenomaster will round out a detailed metabolic phenotyping setup at the MGH capable of studying body composition and insulin sensitivity using an EchoMRI100 Body Composition Analyzer and a setup for hyperinsulinemic-euglycemic clamp analysis, respectively. The MGH has committed significant funding to support the maintenance and operation of this critical instrument for metabolic research, including funds for operation and renovation of space within the MGH barrier animal facility for specific-pathogen free metabolic investigation. This equipment will fulfill a critical need at the MGH to enable targeted investigation of genetic models of disease which will directly inform human biology.
