The study of obesity and metabolism in mammals requires an understanding of processes affecting rates of energy intake and energy expenditure?including information about the energy available for cellular use. This application requests funds to bring next-generation technology capable of measuring all these metabolic factors simultaneously in vivo in unrestrained, conscious, freely moving mice. The Sable Systems? Promethion is an indirect calorimeter yielding frequent quantitative measurements of oxygen consumption (VO2), carbon dioxide production (VCO2), body weight, and body temperature. From these measurements, we can calculate the respiratory exchange ratio - an indicator of fat or carbohydrate utilization. The indirect calorimeter also provides measures of locomotor activity, caloric food intake and water volume consumed. When integrated, indirect calorimetry provides comprehensive information about the energy balance?energy taken in minus energy consumed. Energy balance is critical as it predicts weight gain or weight loss. The DSI HD-XG system measures continuous glucose telemetry that will for the first time allow second-by-second measurement of the amount of energy (glucose) available for cellular metabolism in mice. These glucose data are collected from animals while simultaneously recording metabolic data within the Promethion indirect calorimeter. The ability to combine information about glucose levels with feeding data and metabolic rate will be transformative in our understanding of metabolic regulation in vivo. This instrumentation will replace a highly utilized first-generation CLAMS indirect calorimeter, with a cage design incompatible with the proposed DSI glucose telemetry system. The proposed system will permit monitoring of up to 24 mice per experiment with greater sensitivity, precision, and frequency. This new system will allow for studies of thermogenesis by tight control of cage temperature, and monitoring of core body temperature and glucose simultaneously, key factors affecting metabolic rate. The proposed instrumentation will support user groups investigating the control of neural circuits controlling food intake, effects of the microbiome on host metabolism, and factors capable of elevating metabolic rate. Many of these projects aim to capture rapidly-changing processes using optogenetics, chemogenetics, or acute environmental changes to trigger physiological responses that are missed by the slow rate of data collection and lack of sensitivity of our current apparatus. Because indirect calorimetry is an absolutely essential technology for the understanding of mouse metabolism, the proposed instrumentation will fulfill a critical need and increase research productivity. This instrumentation will support modern techniques of genetic and pharmacologic interrogation of factors controlling glucose and energy balance. The proposed apparatus will markedly accelerate research and discovery, particularly in common metabolic disorders that include obesity, type 1 and type 2 diabetes.
Mechanisms that control food intake and metabolic rate hold great promise as targets for the treatment of obesity and diabetes, major health burdens to society. This application requests funds to purchase an indirect calorimeter to measure energy balance while coupled to new continuous glucose monitoring technology to measure energy available in circulation. Together, these systems will provide unparalleled instrumentation for users studying pathways modified in mice by both genetic and pharmacological interventions targeting metabolism.
