How does the brain stop us overeating? Neuro-genetic control of eating, and how it changes with age.

肥胖和年龄是一系列严重健康并发症的主要危险因素。通过了解我们不同生命阶段的环境、基因、神经系统和身体之间的复杂联系，我们可以找到改善健康的方法，并在必要时治疗疾病。许多与肥胖有关的基因都与控制饮食行为的神经信号通路有关。食欲驱动食物消耗，饱腹感是吃完后的饱腹感，以阻止进一步的食物摄入。有关食物的信息是通过感觉神经系统获得的，并与来自身体的有关饥饿或饱腹感的内部信号相结合。这些信号控制食物摄入，维持体内平衡和预防疾病。我们的实验室已经在秀丽隐杆线虫中发现了这个系统的一个新的遗传成分，并假设它在神经元-生理-行为轴上起作用，影响物种间的饮食行为和新陈代谢。该基因（SKN-1/Nrf）在神经元中起作用，接收来自环境的信号，整合这些信号，并利用激素和神经调节剂信号连接来改变动物的行为和肌肉/线粒体生理（Tataridas-Pallas等人，2021 PLoS Genetics）。我们的饮食习惯也会随着年龄的增长而发生巨大的变化，就像我们的新陈代谢和身体组成一样。SKN-1/Nrf也是一个特征良好的长寿基因（Tullet et al., 2008 Cell, Tullet et al., 2017 Aging Cell），由于食物摄入对与年龄相关的疾病（例如糖尿病，癌症，心血管疾病）也会受到过度饮食的影响，因此通过研究SKN-1的神经系统作用，我们将能够将饮食行为，寿命和与年龄相关的健康联系起来，从而可以利用它们来改善我们人群的健康和健康。哺乳动物中与SKN-1类似的Nrf基因也在大脑中表达，对调节饮食行为很重要（下丘脑），这表明该基因在人类中有一个新的、尚未发现的作用。这个创造性的、好奇心驱动的项目将为我们看待Nrf功能的方式提供一个台阶。我们正在提供一个多学科项目，将使用开创性的整个生物系统秀丽隐杆线虫研究SKN-1神经生物学（Tullet实验室），以及哺乳动物细胞培养研究Nrf （Fenton实验室）。使用遗传学，分子和细胞生物学，以及各种生理，代谢和行为分析，您将绘制与饮食行为有关的神经递质和神经肽回路，发现SKN-1/Nrf的转录作用，并充分探索在整个生命过程中饮食行为中断对线粒体和全身生理的生理影响。

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.