Nutrient modulation of vagal afferent signalling

控制食物摄入的方式引起了人们的强烈兴趣。肥胖现在被广泛认为是对健康的主要威胁，要治疗肥胖，就需要了解这些系统。许多不同的因素被认为是导致肥胖流行的原因，包括遗传因素、生活方式和饮食的改变。虽然营养因子和基因之间的相互作用对健康的重要性得到了广泛的认识和经常讨论，但这些相互作用仍然知之甚少。目前的应用是基于最近的发现，这些发现表明了将肠道壁上营养物质的感知与与食物摄入控制相关的编码蛋白质的基因表达变化联系起来的新机制。最近的研究表明，在一顿饭之后，摄入的食物触发了几种不同的信号，这些信号汇聚到一条神经通路上，即所谓的迷走神经传入神经元，它将胃肠道与大脑连接起来。这些信号之间的相互作用比迄今为止认为的更为广泛，并且可能与控制食物摄入以及如何消化有关。最近的观察也表明在迷走神经传入神经元水平上有一种新的控制机制。特别是，24小时或更长时间内的食物摄入模式可能决定关键分子和受体的存在与否，受体识别调节我们吃多少的信号分子。这些变化被认为反映了编码大麻素受体（被称为CB1受体）的基因的不同活动，该受体已知参与控制食欲。拟议研究的总体目标是描述编码迷走神经信号通路关键成分的基因表达的变化，以一种可以为人类研究提供信息的方式。具体地说，拟议的研究将确定营养物质如何改变迷走神经传入神经元的基因表达，将建立对人类消化和喂养控制的意义，并将探索人与人之间的遗传差异在解释对营养物质的不同反应中的作用。

The way that food intake is controlled is attracting intense interest. An understanding of these systems is required for the treatment of obesity which is now widely recognised as a major threat to health. Many different factors are thought to contribute to the obesity epidemic including genetic factors and changes in life style and diet. While the importance to health of interactions between nutritional factors and genes is widely appreciated and often discussed, these interactions nevertheless remain poorly understood. The present application is based on recent findings that indicate new mechanisms linking the sensing of nutrients in the wall of the gut to changes in the expression of genes encoding proteins associated with control of food intake. Recent work suggests that following a meal, the ingested food triggers several different signals that converge to act on a nervous pathway, the so called vagal afferent neurones, that link the gastrointestinal tract to the brain. Interactions between these signals are more extensive than hitherto thought, and are likely to be relevant both to control of food intake, and to how it is digested. Recent observations also suggest a new type of control mechanism operating at the level of vagal afferent neurones. In particular, it appears that patterns of food intake over a period of 24 hr or more may determine the presence or absence of key molecules, receptors, that recognise signalling molecules regulating how much we eat. These changes are thought to reflect different activities of the genes that encode a receptor for cannabinoids (known as the CB1 receptor) that is known to be involved in control of appetite. The overall objective of the proposed studies is to characterise changes in expression of genes encoding key components of the vagal signalling pathway in a way that can inform human studies. Specifically, the proposed studies will define how nutrients change gene expression in vagal afferent neurons, will establish the significance for the control of digestion and feeding in humans, and will explore the role of genetic differences between people in accounting for different responses to nutrients.