Naturally occurring and genetically modified mouse models are powerful preclinical tools to study the pathogenesis of human disease. Specifically, they are commonly used to study obesity, the metabolic syndrome and the mechanistic connections among obesity, diabetes, the gut microbiome, cardiovascular disease and many forms of cancer. In order to understand the physiology of such models and the alterations in metabolism that underlie their phenotypes, equipment capable of specialized and precise measurements must be employed to examine energy balance and metabolic variables. The equipment requested is a Promethion Core for simultaneous metabolic and behavioral measurements of 16 mice. It includes two Sable-modified Darwin temperature-controlled cabinets that each hold 8 mouse cages. Sable Systems, Inc. HD High Definition Technology is built into each Promethion Core system to capture high-resolution respirometry (indirect calorimetry) data including oxygen consumption and carbon dioxide production. These data are used to calculate energy expenditure and respiratory quotient. The entire system is controlled by Ethoscan software for additional, automated behavioral analyses relevant to studies of energy balance. Each cage will include the following modular monitoring devices: an access control module for ad libitum, paired or yoked food access from a food intake module, a water intake module, a body weight module, a running wheel activity module, a position/movement module and a rearing activity module. The calorimetry system will also include a monitor that detects the concentration of the naturally occurring stable isotopes of carbon, [13C] and [12C]. The ratio of these two nonradioactive isotopes in the exhaled carbon dioxide of mice housed within the calorimetry chambers is the most sensitive measurement of the relative oxidation of dietary lipids and carbohydrates. These ?breath tests? are also used for the analysis of gut absorption, gastric emptying time and other metabolic parameters whose detection can be amplified by the prior administration of artificially enriched [13C]-labeled precursor molecules. With the addition of 8 modified cages designed to contain germ-free mice in a sterile condition and specialized gas monitoring devices for hydrogen and volatile organic chemicals, the system will also be used to study the interactions of the gut microbiome, genotype and diet on the regulation of body weight and glucose homeostasis. The Michigan Mouse Metabolic Phenotyping Center (MMPC) currently has one 16-cage and one 8-cage Comprehensive Laboratory Animal Monitoring Systems for indirect calorimetry (CLAMS) that are in constant use. One of these systems is 11 years old and frequently in need of costly repairs. It will be replaced by the state-of-the-art Promethion Core to continue meeting current and future demand in a timely fashion and provide an array of unique experimental measurements not possible with our existing CLAMS instruments.
Obesity is a major contributor to the worldwide burden of diabetes and its chronic complications, cardiovascular disease and many forms of cancer. Mice are useful preclinical models to study the pathogenesis of obesity and the mechanisms linking it to chronic diseases. The Promethion Core equipment requested in this proposal will be used to study energy balance in mice and the interaction between the gut microbiome and diet on the regulation of body weight and blood sugar.