Defining mechanisms through which neuropeptide Y drives hunger and body weight

近几十年来，肥胖在世界各地变得越来越普遍，这给全球卫生系统和社会带来了日益严重的问题。就身体健康而言，肥胖会增加患心脏病、糖尿病、癌症及相关并发症的风险。肥胖的主要原因是吃的食物比我们身体需要的多，多余的卡路里被储存为身体脂肪。因此，为了能够解决肥胖及其并发症，有必要了解大脑是如何感知饥饿和饱腹感的。半个多世纪以前，研究人员发现了大脑中对控制饥饿感至关重要的一部分，这个区域被称为外侧下丘脑。尽管人们早就知道这一点，但人们仍然不知道大脑的这个区域是如何从根本上控制食欲和体重的。到目前为止，大部分注意力都集中在这个区域产生的大脑化学物质上，称为食欲素-下丘脑分泌素和黑色素浓缩激素（MCH）。然而，尚未研究的是饥饿的主要调节因子神经肽Y （NPY）。这种小蛋白质在我们大脑的几个区域产生，使饥饿感大大增加，比食欲素-下丘脑分泌素或MCH要大得多。从历史上看，研究的重点是NPY的一个子集，针刺相关蛋白和GABA共同表达的细胞在另一个下丘脑脑区域，弓状核。随后发现，在这些细胞中产生的NPY并不是饥饿的主要驱动因素。因此，大脑其他区域的NPY很可能在很大程度上有助于其对食欲的重要影响。其中，下丘脑外侧的一组NPY细胞（LHA(NPY)）特别有趣，因为这些细胞能够检测到局部环境中糖（葡萄糖）水平的变化。这种检测葡萄糖的能力很可能有助于大脑评估我们是否需要食物并做出相应的反应。在这个项目中，我将测试NPY是否是控制饥饿和体重的重要途径，NPY是一种主要的饥饿刺激剂，产生于饥饿大脑的关键区域LHA。该项目旨在回答以下问题：(1)LHA（NPY）细胞是如何调控的？先前的研究和试点数据提供了令人信服的证据，证明LHA（NPY）细胞检测并响应糖的波动。我将研究LHA（NPY）细胞如何对营养物质和不同的食物线索做出反应，以及这些信号如何直接塑造LHA（NPY）细胞的活性。(2) LHA（NPY）细胞是否能够驱动食物摄入并促进肥胖？有证据表明，人类和动物的NPY对食欲和体重至关重要，但LHA（NPY）细胞的具体作用尚不清楚。为了回答这个问题，我将通过实验激活LHA（NPY）细胞，并研究这是否会导致短期和/或长期的食物摄入增加，以及LHA（NPY）过度活跃是否会导致肥胖。(3)是否有可能通过灭活LHA（NPY）细胞来预防肥胖？由于NPY能有效地刺激食欲，因此有可能通过选择性地灭活LHA中制造这种蛋白质的细胞来预防肥胖。初步研究表明，情况确实如此。进一步的实验将证实和扩展这些初步研究，以评估LHA（NPY）失活在预防肥胖方面的有效性。这个项目旨在发现大脑如何控制我们选择吃的食物类型，我们吃多少，以及这是如何影响体重的。在发现这一点的过程中，它将使我们更接近于能够找到新的药物来抑制我们过度饮食的冲动，从而减轻我们的卫生系统和社会日益增长的肥胖负担。

In recent decades obesity has become increasingly common around the world and this has led to significant and growing problems for health systems and societies globally. In terms of physical health, obesity increases the risk of heart disease, diabetes, cancer and associated complications. The main driver for obesity is eating more food than our bodies require, and the extra calories get stored as body fat. Thus, to be able to tackle obesity and its complications it is essential to understand how hunger and fullness are sensed in the brain. More than half a century ago, researchers discovered a part of the brain that is essential for controlling hunger, a region called the lateral hypothalamus. Despite this long-standing knowledge, it still is not known how this brain region fundamentally controls appetite and body weight. Thus far, the majority of attention has focused on brain chemicals made in this region called orexin-hypocretin and melanin concentrating hormone (MCH). However, what has not yet been investigated is a principal regulator of hunger called neuropeptide Y (NPY). This small protein made in several regions of our brain produces a profound increase in hunger, much greater than orexin-hypocretin or MCH. Historically, efforts have focussed on a subset of NPY, agouti-related protein and GABA co-expressing cells in another hypothalamic brain region, the arcuate nucleus. It has been subsequently revealed that NPY made in these cells is not the main driver of hunger. Thus, it is likely that NPY in other brain regions largely contributes to its vital effect on appetite. Of these, a group of NPY cells in the lateral hypothalamus (LHA(NPY)) is particularly interesting because these cells are able to detect changes in sugar (glucose) levels in their local environment. It is likely that this ability to detect glucose helps the brain evaluate whether we need food and react accordingly.In this project I will test whether NPY, a major hunger stimulator made in the key hunger brain region the LHA, is an important way that hunger and body weight are controlled. The project aims to answer these questions:(1) How are LHA(NPY) cells regulated? Previous research and pilot data provide compelling evidence that LHA(NPY) cells detect and respond to fluctuations in sugar. I will investigate how LHA(NPY) cells respond to nutrients and to different food cues, and how these signals directly shape the activity of LHA(NPY) cells.(2) Are LHA(NPY) cells able to drive food intake and promote obesity? There is evidence in humans and in animals that NPY is critical for appetite and body weight, but it is less clear what the particular contribution from LHA(NPY) cells is. To answer this question, I will experimentally activate LHA(NPY) cells and investigate if this leads to short term and/or long term increase in food intake, and whether LHA(NPY) overactivity leads to obesity.(3) Is it possible to prevent obesity by inactivating LHA(NPY) cells? Because NPY potently stimulates appetite, it is likely that obesity can be prevented by selectively inactivating the cells in the LHA that make this protein. Pilot studies indicate that this is indeed the case. Additional experiments will confirm and expand these initial studies to evaluate how effective is LHA(NPY) inactivation at preventing obesity.This project aims to discover how the brain controls the types of food that we choose to eat, how much we eat, and how that affects body weight. In discovering this, it will bring us closer to being able to find new medications to dampen our urge to over-eat and thus reduce the growing burden of obesity on our health systems and societies.