Bone marrow adipose tissue as a novel regulator of metabolic homeostasis

骨髓脂肪组织作为代谢稳态的新型调节剂

• 批准号: MR/M021394/1
• 负责人: William Cawthorn
• 金额: $ 141.73万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FM021394%2F1
• 关键词: Bone; marrow; adipose; tissue; novel

Stop and think about your bones; what images come to mind? Perhaps a skull with grinning jaws, or the strong white limbs stretching from your hips to your toes. You might even think of the bone marrow within them, producing the blood that courses through your veins. But this is not the whole picture, for your skeleton hides a secret: it is full of fat, and no one knows why.This unsolved mystery is surprising. Scientists first noticed that our bone marrow contains fat-storing cells, called adipocytes, over a century ago. Having fat in our bones might strike you as unusual, but it is not: bone marrow adipose tissue (MAT) makes up to 70% of bone marrow volume in healthy adults, suggesting that MAT has a role in normal human physiology. MAT further increases in conditions of altered bone formation or metabolic health. For example, increased MAT occurs in osteoporosis, suggesting that MAT might contribute to the bone fragility that defines this disease. Perhaps most bizarrely, MAT formation increases in starvation states, such as during caloric restriction in animals or in human patients with anorexia nervosa. This is in stark contrast to adipose tissue elsewhere in the body, called white adipose tissue (WAT), which is broken down during starvation to be used as fuel. Caloric restriction has numerous health benefits, including increased lifespan, decreased risk of cancer and cardiovascular disease, and metabolic benefits such as enhanced fat breakdown and insulin sensitivity. MAT also increases in response to treatment with anti-diabetic drugs, which, like caloric restriction, enhance insulin sensitivity. These clinical observations raise the possibility that MAT directly promotes insulin sensitivity and metabolic health. But unlike WAT, almost nothing is known about the biological function of MAT. The possibility that MAT exerts metabolic benefits could have enormous implications for human health. Metabolic diseases such as diabetes currently place a huge burden on public health, both in the UK and around the globe. One in seventeen adults in the UK, or 3.2 million people, now has diabetes, and this is expected to rise to 4.6 million people by 2030. This is causing a major strain on the economy, costing the NHS over £1.5 million an hour, or 10% of the NHS budget for England and Wales. In total, an estimated £14 billion is spent a year on treating diabetes and its complications in the UK. Globally, diabetes cost £232 billion in 2010, and this is projected to increase to over £300 billion by 2030. Identifying new treatments for diabetes and its complications would therefore provide a massive benefit to human health worldwide. However, developing such treatments requires improved understanding of the factors that regulate insulin sensitivity and metabolic health. This leads us back to MAT. What controls MAT formation, and does MAT benefit metabolic health?A team of scientists at the University of Edinburgh is now working to answer these key questions. Members of this research team recently found that, during caloric restriction, MAT is a key source of adiponectin, a hormone that helps to maintain insulin sensitivity and fat breakdown, and which is linked to decreased risk of obesity-associated cancers, cardiovascular disease and diabetes. The University of Edinburgh team will now build on this research by studying why MAT expands during caloric restriction and investigating if MAT affects our metabolic health. Finally, these researchers will study samples of MAT and WAT provided by human donors to determine precisely how MAT differs to WAT in humans.These studies will help to unravel the mystery of MAT. In doing so, this research might allow the development of new treatments for diabetes and its complications, as well as other diseases including osteoporosis, cardiovascular disease and some cancers. This will be vital if we are to reduce the public health impact of these globally relevant health problems.

停下来想想你的骨头，你会想到什么？也许是一个咧着嘴笑的头骨，或者是从臀部延伸到脚趾的强壮的白色四肢。你甚至可以想到它们里面的骨髓，产生通过你的静脉的血液。但这并不是全貌，因为你的骨架隐藏着一个秘密：它充满了脂肪，没有人知道为什么。这个未解之谜令人惊讶。早在世纪前，科学家们就首次发现我们的骨髓中含有储存脂肪的细胞，称为脂肪细胞。我们的骨骼中含有脂肪可能会让你觉得不寻常，但事实并非如此：健康成年人的骨髓脂肪组织（MAT）占骨髓体积的70%，这表明MAT在正常的人体生理学中发挥作用。MAT在骨形成或代谢健康改变的情况下进一步增加。例如，MAT增加发生在骨质疏松症中，这表明MAT可能有助于定义这种疾病的骨脆性。也许最奇怪的是，MAT形成在饥饿状态下增加，例如在动物或患有神经性厌食症的人类患者的热量限制期间。这与身体其他部位的脂肪组织形成鲜明对比，称为白色脂肪组织（WAT），在饥饿期间被分解用作燃料。热量限制有许多健康益处，包括延长寿命，降低癌症和心血管疾病的风险，以及代谢益处，如增强脂肪分解和胰岛素敏感性。MAT也会随着抗糖尿病药物的治疗而增加，这些药物与热量限制一样，会增强胰岛素敏感性。这些临床观察提高了MAT直接促进胰岛素敏感性和代谢健康的可能性。但与WAT不同的是，人们对MAT的生物学功能几乎一无所知。MAT发挥代谢益处的可能性可能对人类健康产生巨大影响。代谢性疾病如糖尿病目前给英国和地球仪的公共卫生带来巨大负担。在英国，每17个成年人中就有一个，即320万人患有糖尿病，预计到2030年将增加到460万人。这对经济造成了重大压力，NHS每小时的成本超过150万英镑，占英格兰和威尔士NHS预算的10%。英国每年用于治疗糖尿病及其并发症的费用估计为140亿英镑。在全球范围内，糖尿病在2010年花费了2320亿英镑，预计到2030年将增加到3000亿英镑以上。因此，确定糖尿病及其并发症的新疗法将为全世界的人类健康带来巨大益处。然而，开发这种治疗方法需要更好地了解调节胰岛素敏感性和代谢健康的因素。这让我们回到MAT。什么控制MAT的形成，MAT有益于代谢健康？爱丁堡大学的一个科学家小组正在努力回答这些关键问题。该研究小组的成员最近发现，在热量限制期间，MAT是脂联素的关键来源，脂联素是一种有助于维持胰岛素敏感性和脂肪分解的激素，与降低肥胖相关癌症，心血管疾病和糖尿病的风险有关。爱丁堡大学的研究小组现在将在这项研究的基础上，研究为什么MAT在热量限制期间会膨胀，并调查MAT是否会影响我们的代谢健康。最后，这些研究人员将研究由人类捐赠者提供的MAT和WAT样本，以精确确定MAT与WAT在人类中的差异。这些研究将有助于解开MAT之谜。通过这样做，这项研究可能会开发新的治疗糖尿病及其并发症的方法，以及其他疾病，包括骨质疏松症，心血管疾病和一些癌症。如果我们要减少这些全球相关健康问题对公共健康的影响，这将是至关重要的。

项目成果

Fat cell progenitors get singled out.

脂肪细胞祖细胞被挑选出来。

• DOI: 10.1126/science.aax2967
• 发表时间: 2019
• 期刊: Science (New York, N.Y.)
• 作者: Chau YY

Adipocytes disrupt the translational programme of acute lymphoblastic leukaemia to favour tumour survival and persistence.

• DOI: 10.1038/s41467-021-25540-4
• 发表时间: 2021-09-17
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Heydt Q;Xintaropoulou C;Clear A;Austin M;Pislariu I;Miraki-Moud F;Cutillas P;Korfi K;Calaminici M;Cawthorn W;Suchacki K;Nagano A;Gribben JG;Smith M;Cavenagh JD;Oakervee H;Castleton A;Taussig D;Peck B;Wilczynska A;McNaughton L;Bonnet D;Mardakheh F;Patel B
• 通讯作者: Patel B

Ablation of Enpp6 Results in Transient Bone Hypomineralization.

• DOI: 10.1002/jbm4.10439
• 发表时间: 2021-03
• 期刊: JBMR plus
• 影响因子: 3.8
• 作者: Dillon S;Suchacki K;Hsu SN;Stephen LA;Wang R;Cawthorn WP;Stewart AJ;Nudelman F;Morton NM;Farquharson C
• 通讯作者: Farquharson C

Turning the spotlight on bone marrow adipocytes in haematological malignancy and non‐malignant conditions

• DOI: 10.1111/bjh.18748
• 发表时间: 2023-04
• 期刊: British Journal of Haematology
• 影响因子: 6.5
• 作者: M. Austin;Foteini Kalampalika;W. Cawthorn;B. Patel