Bilateral BBSRC-SFI: The role of hypothalamic neuropeptide network in regulating tissue sizes in response to diet energy content and composition

如果你通过节食来减肥，那么你不仅减掉了体内的脂肪。你还会失去肌肉质量，你的重要器官，如肝脏、心脏和大脑也会缩小一点。如果你体重增加，你通常会增加不成比例的脂肪组织，但你也可能会在肝脏和肌肉中沉积脂肪。一些科学家认为，脂肪沉积到肝脏和肌肉中可能是一些肥胖者患上2型糖尿病的主要原因。另一种涉及身体成分变化的情况是，如果你不幸患了心脏病，或者患上了慢性肾病或癌症等严重疾病。对一些人来说，这些情况的一个不幸的副作用是你可能会失去食欲，在这种情况下，当你减肥的时候，你会失去很多肌肉，以及减少重要器官的大小。这些变化会对慢性病患者的生活质量产生重大影响，并大大增加死亡的风险。最后，随着年龄的增长，有些人会进入负能量平衡状态，他们也会在很长一段时间内失去肌肉质量，导致身体虚弱，从而导致身体虚弱，这是晚年死亡的主要风险因素。目前，我们对调节我们身体成分变化的系统是如何工作的知之甚少。我们有一些证据表明，大脑中有一个被称为下丘脑的小区域，可以调节我们的饥饿感，它可能在协调各个组织对能量平衡整体变化的反应方面发挥重要作用。这项工作的目的是找出下丘脑中可能参与这种调节的关键基因。做这个的第一步是探索当我们以不同的方式扰乱系统时——给予不同的饮食和以不同的量限制能量供应——这个大脑区域的基因表达的整体模式是如何变化的。然后我们就能将大脑的变化与组织使用模式联系起来。为了证明这些基因与组织大小的变化是有因果关系的我们将直接操纵这些基因，然后看看它是如何改变对能量平衡变化的反应的。例如，从相关性中我们可能会发现，当我们处于负能量平衡状态时，基因“x”的表达与骨骼肌的使用增加密切相关。所以我们将把这个基因敲除，然后看看没有这个基因是如何影响肌肉使用的。如果，当我们敲除基因时，没有肌肉损失，那么我们就知道我们操纵的基因对系统的那部分有直接影响。我们赠款的主要目的是找到参与调节该系统的关键基因。这些基因可能会成为药物开发的目标，这些药物可能会影响我们的组织利用模式。例如，有可能利用这些信息来开发药物，这些药物可以给患有慢性疾病（如癌症）的患者，以防止他们的体重减轻。这可能会对慢性病患者的生活质量和死亡率产生重大影响。此外，由于我们将通过操纵饮食来发现这个系统是如何工作的，这也可能使我们能够提出饮食建议，以达到同样的目的，既适用于慢性病患者，也适用于从事减肥策略以减轻肥胖的人。最终，我们认为有可能设计出营养干预措施，在节食时最大限度地减少脂肪，最大限度地减少其他组织的损失，反过来，在节食结束时防止脂肪增加，最大限度地恢复组织。这项奖助金将提供实现这一目标的第一步。

If you go on a diet to lose weight then you don't only lose body fat. You also lose muscle mass and your vital organs like your liver, heart and brain also shrink a little. If you put on weight however you generally put on disproportionately more fat tissue, but you may also deposit fat into your liver and muscles. It is thought by some scientists that this deposition of fat into the liver and muscle may be a primary reason why some people with obesity also develop type 2 diabetes. Another situation involving body composition changes is if you are unlucky enough to have a heart attack or develop a serious disorder like chronic kidney disease or cancer. An unfortunate side effect of these conditions in some people is that you may lose appetite and in these situations when you lose weight you lose lots of muscle as well as reduced vital organ sizes. These changes can have a major impact on quality of life of the chronically sick patient, and they greatly increase the risk of dying. Finally as we age some people go into a negative energy balance state where they also lose muscle mass over longer periods of time which leads to weakness and contributes to frailty which is a major risk factor for mortality in later life. At present we know very little about how the system that regulates these changes in our body composition actually works. We have some evidence that a small area of the brain that is known to regulate how hungry we are, called the hypothalamus, may play an important role in co-ordinating the responses of the individual tissues to overall changes in energy balance. The aim of this work is to find out the key genes in the hypothalamus that may be involved in this regulation. The first step in doing this is to explore how the global pattern of gene expression in this brain area changes when we perturb the system in different ways - giving different diets and restricting energy supply by different amounts. We will then be able to correlate the changes in the brain to the patterns of tissue use. To show that the genes are causally related to the tissue size changes we will manipulate the genes directly and then see how that alters the response to a change in energy balance. For example, from the correlations we may find that the expression of gene 'x' is strongly linked to the increased use of skeletal muscle when we are in negative energy balance. So we will knock that gene out and then see how not having this gene affects the muscle use. If, when we knock out the gene, there is no muscle loss, then we will know that the gene we manipulated has a direct effect on that part of the system. Our primary aim in the grant is to find the key genes that are involved in regulating the system. These genes might then become targets for the development of pharmaceuticals that might be able to affect our tissue utilisation patterns. For example it may be possible to use this information to develop drugs that can be given to patients with chronic diseases like cancer to prevent their weight loss. This would potentially have a large impact on both quality of life and mortality of chronically ill patients. Moreover, since we will be manipulating diets to find out how the system works this may also allow us to make dietary recommendations to achieve the same ends, both for chronically ill patients but also for people engaged in weight loss strategies to alleviate obesity. Ultimately we consider it may be possible to devise nutritional interventions that maximise fat loss and minimise loss of other tissues when dieting, and conversely prevent fat gain and maximise tissue recovery when a diet ends. This grant will provide the first steps towards making that happen.