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

双侧 BBSRC-SFI：下丘脑神经肽网络在响应饮食能量含量和成分调节组织大小中的作用

• 批准号: BB/P009875/1
• 负责人: John Speakman
• 金额: $ 70.17万
• 依托单位: University of Aberdeen
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FP009875%2F1
• 关键词: Bilateral; BBSRC; SFI; role; hypothalamic

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.

如果你通过节食来减肥，那么你减掉的不仅仅是身体脂肪。你的肌肉质量也会减少，肝脏、心脏和大脑等重要器官也会萎缩一些。然而，如果您体重增加，您通常会增加不成比例的更多脂肪组织，但您也可能会将脂肪沉积到肝脏和肌肉中。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也患上 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，如果您不幸心脏病发作或患上慢性肾病或癌症等严重疾病。对于某些人来说，这些情况的一个不幸的副作用是您可能会失去食欲，在这种情况下，当您减肥时，您会失去大量肌肉并缩小重要器官的大小。这些变化会对慢性病患者的生活质量产生重大影响，并大大增加死亡风险。最后，随着年龄的增长，一些人会进入负能量平衡状态，他们也会在较长时间内失去肌肉质量，从而导致虚弱并导致衰弱，这是晚年死亡的主要风险因素。目前，我们对调节身体成分变化的系统实际上是如何运作的知之甚少。我们有一些证据表明，大脑中负责调节饥饿程度的一小块区域（称为下丘脑）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着重要作用。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。这样做的第一步是探索当我们以不同的方式扰乱系统时——给予不同的饮食和限制不同数量的能量供应——该大脑区域的基因表达的整体模式如何变化。然后我们将能够将大脑的变化与组织使用的模式联系起来。为了证明基因与组织大小变化存在因果关系，我们将直接操纵基因，然后看看它如何改变对能量平衡变化的反应。例如，从相关性中我们可能会发现，当我们处于负能量平衡时，基因“x”的表达与骨骼肌的使用增加密切相关。因此，我们将敲除该基因，然后看看没有该基因如何影响肌肉的使用。如果当我们敲除该基因时，没有肌肉损失，那么我们就会知道我们操纵的基因对系统的那部分有直接影响。我们拨款的主要目的是找到参与调节系统的关键基因。这些基因可能会成为药物开发的目标，从而影响我们的组织利用模式。例如，可以利用这些信息来开发药物，为患有癌症等慢性病的患者提供预防体重减轻的药物。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，由于我们将通过控制饮食来了解该系统的工作原理，这也可能使我们能够提出饮食建议以达到相同的目的，无论是针对慢性病患者还是针对采用减肥策略来减轻肥胖的人。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并最大限度地减少其他组织的损失，并在节食结束时相反地防止脂肪增加并最大限度地恢复组织。这笔赠款将为实现这一目标迈出第一步。

项目成果

Fur removal promotes an earlier expression of involution-related genes in mammary gland of lactating mice.

• DOI: 10.1007/s00360-023-01474-9
• 发表时间: 2023-03
• 期刊: Journal of comparative physiology. B, Biochemical, systemic, and environmental physiology

Whey protein effects on energy balance link the intestinal mechanisms of energy absorption with adiposity and hypothalamic neuropeptide gene expression.

乳清蛋白对能量平衡的影响将肠道能量吸收机制与肥胖和下丘脑神经肽基因表达联系起来。

• DOI: 10.1152/ajpendo.00356.2016
• 发表时间: 2017
• 期刊: American journal of physiology. Endocrinology and metabolism
• 作者: Nilaweera KN

Oral Delivery of Nisin in Resistant Starch Based Matrices Alters the Gut Microbiota in Mice.

• DOI: 10.3389/fmicb.2018.01186
• 发表时间: 2018
• 期刊: Frontiers in microbiology
• 影响因子: 5.2
• 作者: Gough R;Cabrera Rubio R;O'Connor PM;Crispie F;Brodkorb A;Miao S;Hill C;Ross RP;Cotter PD;Nilaweera KN;Rea MC
• 通讯作者: Rea MC

The Effects of Graded Levels of Calorie Restriction: XIV. Global Metabolomics Screen Reveals Brown Adipose Tissue Changes in Amino Acids, Catecholamines, and Antioxidants After Short-Term Restriction in C57BL/6 Mice.

• DOI: 10.1093/gerona/glz023
• 发表时间: 2020-01-20
• 期刊: The journals of gerontology. Series A, Biological sciences and medical sciences
• 作者: Green CL;Mitchell SE;Derous D;Wang Y;Chen L;Han JJ;Promislow DEL;Lusseau D;Douglas A;Speakman JR
• 通讯作者: Speakman JR

Depletion of the gut microbiota differentially affects the impact of whey protein on high-fat diet-induced obesity and intestinal permeability.

• DOI: 10.14814/phy2.14867
• 发表时间: 2021-06
• 期刊: Physiological reports
• 影响因子: 2.5
• 作者: Boscaini S;Cabrera-Rubio R;Golubeva A;Nychyk O;Fülling C;Speakman JR;Cotter PD;Cryan JF;Nilaweera KN
• 通讯作者: Nilaweera KN