Project No.2260

Primary Supervisor

Dr Jenny Tullet – University of Kent

Co-Supervisor(s)

Dr Tim Fenton – University of Southampton

Summary

Obesity and age are major risk factors for a range of serious health complications.

By understanding the intricate connections between our environment, genetics, nervous system, and body at different life stages, we can find ways to improve our health, and where necessary treat disease. Many genes linked to obesity are implicated in the neuronal signalling pathways that control eating behaviours. Appetite drives food consumption and satiety is the feeling of fulness after eating, to stop further food intake. Information on food is obtained via the sensory nervous system and integrates with internal cues from the body relating to hunger or satiety.

These signals control food intake, maintain homeostasis and prevent disease. Our lab has identified a new genetic component of this system in C. elegans, and hypothesise that it acts in a neuronal-physiological-behavioural axis to influence eating behaviour and metabolism across species. This gene (SKN-1/Nrf) acts in neurons to receive signals from the environment, integrate them and harness hormonal and neuromodulator signalling connections to alter the animals behaviour and muscle/mitochondrial physiology (Tataridas-Pallas et al., 2021 PLoS Genetics). Our eating habits also change dramatically with age, as does our metabolism and body composition. SKN-1/Nrf is also a well-characterised longevity gene (Tullet et al, 2008 Cell, Tullet et al., 2017 Aging Cell), and as food intake has massive implications for age-related diseases (e.g. diabetes, cancer, cardiovascular disease) which are also impacted by over eating, by studying SKN-1’s neurological role we will be able to link eating behaviours, longevity, and age-related health so that they can be harnessed to improve the health and fitness of our population. The mammalian equivalent of SKN-1, Nrf, is also expressed in the brain important for regulating eating behaviour (hypothalamus), suggesting a new, as yet uncovered role for this gene in humans. This creative, curiosity-driven project will provide a step change in the way we view Nrf function. We are offering a multi-disciplinary project will use the pioneering whole organism system C. elegans to study SKN-1 neurobiology (Tullet lab), and mammalian cell culture to study Nrf (Fenton lab). Using genetics, molecular and cellular biology, and a variety of physiological, metabolic and behavioural assays you will map the neurotransmitters and neuropeptide circuits involved in eating behaviour, discover the transcriptional role of SKN-1/Nrf, and fully explore the physiological effects of disrupted eating behaviours on the mitochondria and whole body physiology across the life course.