Metabolic and behavioural phenotyping system

The prevalence of obesity and metabolic disease in UK society and the clear impact of modern life and diet on our health and wellbeing, has driven increased interest and research into energy metabolism and feeding behaviour. There is also an increasing recognition that nutrition, energy supply and metabolism play an essential role in diverse aspects of our biology, including how we age, functioning of our immune system, and response to injury and disease. Despite this increased focus and recent advances, there remain fundamental gaps in understanding about how energy metabolism is regulated across the cells and tissue of the body, how internal systems such as the body clock orchestrate metabolic responses to deal with recurrent cycling between fasted and fed states, and how regulatory processes in the brain and body adapt to changes in environment, age, infection and disease. Our research strives to address these questions.

Underpinning this work is the ability to study and characterise fundamental aspects of animal behaviour and physiology. In this proposal we are requesting funds for the purchase of a state-of-the-art platform to study mice and other small laboratory animals at a level not previously possible. This system allows fully automated and perfectly synchronized assessment of numerous important parameters with high precision in a home-cage environment (thus greatly reducing stress to the animals). The ability to collect all of these measures simultaneously, from individual animals will allow us to understand the interaction of different behaviours, diet manipulations and metabolic processes. The system also provides very tight control over external conditions such as light, temperature, and food availability, which will allow us to conduct studies in a range of environmental settings (including mimicking more natural conditions).

This system will provide significant advance to a wide range of ongoing research programmes. These include understanding i) how the brain dictates what, when, and how much we eat; ii) how the body clock organises hugely diverse processes across our body, and how it being undermined by our 24hr modern society; iii) how fine genetic processes operating in the cells of our body can drive huge shifts in metabolism and body composition, iv) how are metabolic state has such a major influence on how well our immune system works during disease or infection, and v) how bacteria in our gut (the microbiome) can have a major influence on both metabolism and the immune system.

We request funds to purchase of the TSE PhenoMaster System, a unique phenotyping system that provides simultaneous tracking of physiological, behavioural and metabolic parameters in individual animals. Briefly, the PhenoMaster system provides continuous indirect gas calorimetry measures of O2 consumption and CO2 production, allowing derivation of key metabolic parameters (energy expenditure, VO2, respiratory exchange rate (RER), fatty acid vs carbohydrate oxidation). Cages include inbuilt body-weight monitoring, access controlled and programmable food and drink dispensers, voluntary running wheel (also programmable access), and infrared beam-break monitors. Importantly, the system includes a counterbalance arm and access port for drug infusion, electrophysiological recording/stimulation, optical stimulation and fibre photometry. These sophisticated approaches are routine in our work, and are critical advance for the interrogation of neurological pathways and processes involved in animal physiology and behaviour. The system is housed within a specialised environmental control cabinet with programmable control of light, temperature (4-35C) and humidity. This is essential in metabolic studies as it allows full experimentation under thermoneutrality and temperature challenges. Control of the cabinet is integrated into the PhenoMaster software, and so can be coordinated directly into experimental design (e.g. matching diurnal rhythms in light and temperature to mimic naturalistic conditions). The cabinet meets all AAALAC, FELASA and UK animal welfare guidelines, all within a 'home-cage' environment (greatly reducing any impact to the animals). This system will provide significant advance to innovative and exciting research programmes. These include i) neural control of energy balance; ii) circadian clock control of physiology; iii) genetic/epigenetic regulation of cell metabolism, iv) coupling of metabolic and immune response, and v) microbiome, metabolism and immunity.