Brainstem GABA neurons orchestrate feeding and body weight

如今生活在英国的普通人超重或肥胖。这一点之所以重要，是因为不良的饮食和过多的体脂通常会对健康产生有害影响。肥胖会增加罹患多种疾病和死于新冠肺炎的风险。肥胖还会缩短近十年的寿命，每年花费英国58亿英镑的医疗费用。超重的主要原因是摄入了比身体所需更多的食物，卡路里随后储存在脂肪中。这项应用的重点是澄清食物选择(为什么我们更喜欢蛋糕而不是卷心菜？)、膳食规模和增加体脂背后的生物学。这项研究的另一个重点是理解为什么通过节食很难长期减肥。饥饿通常是人们难以坚持节食或减肥的原因。在这里，我们研究了一种抑制或减少饥饿的新方法，以帮助促进长期减肥。我们把重点放在大脑上，因为它是饥饿的主协调者，利用离散的交织电路不断评估和回应从食物中摄取的能量的变化。这个网络中的一个主要交叉点是大脑的一部分，称为孤束核(NTS)。血液中从食物中消化的营养物质、来自我们器官的激素和其他信号汇聚在NTS内，向大脑通报我们的能量状况。NTS整合了这些信息，并将决定转发给大脑中控制饥饿和饱腹感的其他部分，然后促使我们的行为(例如，感觉饿并找到食物，或感觉饱并停止进食)。然而，由于缺乏准确的工具来了解饥饿、食欲和体重是如何控制的，这一方向的发现受到了阻碍。最近的技术进步现在提供了一种克服这一障碍的方法，提供了一种方法来发现大脑是如何工作的，以监测能量水平(低或高)，然后指示行为(吃或不吃)，这会影响体重。我们现在可以发现大脑产生的化学物质的位置，这些化学物质影响我们决定吃什么食物，吃多少食物，以及这些卡路里是被使用还是储存在体内脂肪中。我们认为，一种名为GABA的化学物质--我们的大脑通常会制造这种化学物质来关闭其他细胞--起到了消除饥饿的作用。具体地说，我们认为，在NTS中制造的GABA在我们吃食物时从身体接收信息，然后传递这些信息来消除饥饿感，因此我们停止进食。我们在NTS中关于GABA的初步工作支持这一想法。在拟议的研究计划中，我们将结合最先进的技术，测试这种特定来源的GABA在饥饿和体脂中的作用。这项工作很重要，因为我们相信我们已经找到了大脑控制饥饿、食物选择和体重的基本方法。我们预计这些研究将提供对食欲、食物选择、体重和体脂的生物学基础的基本见解，以及与预防和治疗肥胖症相关的发现。

The average person living in the UK today is overweight or obese. The reason this is important is because poor diet and excess body fat commonly have a detrimental impact on health. Obesity increases the risk of developing multiple diseases and dying from COVID-19. Obesity also shortens lifespan by nearly a decade, and costs the UK £5.8 billion every year in medical fees. The primary cause of excess body weight is the consumption of more food than the body requires, calories that are then stored in fat. The focus of this application is clarifying the biology behind food choice (why do we prefer cake to cabbage?), meal size and increasing body fat. Another focus of this research is understanding why it can be difficult to lose weight over the long term through dieting. Hunger is commonly the reason it can be difficult to stick to a diet or to keep the weight off. Here we examine a new way to suppress or diminish hunger to help promote long term weight loss. Our focus is on the brain because it is the master coordinator of hunger, employing discrete interwoven circuits to continually appraise and respond to changes in energy availability taken in from food. A principal intersection within this network is the part of the brain called the nucleus of the solitary tract (NTS). Digested nutrients from food in the bloodstream, hormones from our organs and other signals converge within the NTS to inform the brain about our energy status. The NTS integrates this information and forwards a decision to other parts of the brain that control hunger and fullness that then prompt our behaviour (e.g. feel hungry and find food or feel full and stop eating). However, discoveries in this direction have been hindered by a lack of precise tools to understand how hunger, appetite and body weight are controlled. Recent technological advances now provide a means to overcome this obstacle, affording a way to discover how the brain works to monitor energy levels (low or high) to then instruct behaviour (to eat or not to eat), which influences body weight. We can now uncover the location of the chemicals made by the brain that influence our decisions about which foods we choose to eat, how much food we eat and whether these calories are then used or stored in body fat. We think that a chemical called GABA, which our brain makes to typically turn other cells off, works to turn off hunger. Specifically, we believe that GABA made in the NTS receives information from the body when we are eating food and then transmits this information to remove the feeling of hunger so we stop eating. Our initial work on GABA in the NTS supports this idea. Using a combination of state of the art techniques, we will test the function of this specific source of GABA in hunger and body fat in the proposed research programme. This work is important because we believe we have found an essential way that the brain controls hunger, food choice and body weight. We anticipate that these studies will provide fundamental insight into the biological underpinnings of appetite, food choice, body weight and body fat, findings relevant to the prevention and treatment of obesity.