Nutrient modulation of vagal afferent signalling

控制食物摄入量的方式引起了人们的强烈兴趣。对于肥胖症的治疗需要了解这些系统，肥胖症现在被广泛认为是对健康的主要威胁。许多不同的因素被认为是导致肥胖症流行的原因，包括遗传因素和生活方式和饮食的变化。虽然营养因素和基因之间的相互作用对健康的重要性被广泛认识并经常被讨论，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觉与编码与控制食物摄入量相关的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，摄入的食物会触发几个不同的信号，这些信号会聚在一起作用于一条神经路径，即所谓的迷走神经传入神经元，该神经通路连接胃肠道和大脑。这些信号之间的相互作用比迄今认为的要广泛得多，很可能与食物摄入量的控制和食物的消化方式有关。最近的观察还表明，一种新型的控制机制在迷走神经传入神经元水平上运行。特别是，似乎在24小时或更长时间内的食物摄入模式可能决定着关键分子-受体的存在或缺失，这些分子识别控制我们进食量的信号分子。这些变化被认为反映了编码大麻素受体(即已知的CB-1受体)的基因的不同活动，该受体参与控制食欲。这项拟议研究的总体目标是以一种可以为人类研究提供信息的方式，描述迷走神经信号通路关键成分编码基因表达的变化。具体地说，拟议的研究将定义营养物质如何改变迷走神经传入神经元的基因表达，将确立控制人类消化和摄食的意义，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所起的作用。

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 CB-1 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.