Bone marrow adipose tissue as a novel regulator of metabolic homeostasis

停下来想想自己的骨头；你会想到什么画面？也许是一个咧嘴而笑的头骨，或者是从臀部伸展到脚趾的强壮的白色四肢。你甚至可能会想到它们里面的骨髓，产生流经血管的血液。但这还不是全部，因为你的骨骼隐藏着一个秘密：它充满了脂肪，没有人知道为什么。这个未解之谜令人惊讶。一个多世纪前，科学家首次注意到我们的骨髓中含有脂肪储存细胞，称为脂肪细胞。骨骼中有脂肪可能会让你觉得不寻常，但事实并非如此：在健康成人中，骨髓脂肪组织（MAT）占骨髓体积的70%，这表明MAT在正常的人体生理中起着重要作用。在骨形成改变或代谢健康的情况下，MAT进一步增加。例如，骨质疏松症中MAT增加，表明MAT可能导致骨质脆弱，而骨质脆弱正是骨质疏松症的特征。也许最奇怪的是，MAT的形成在饥饿状态下增加，比如在动物的热量限制或人类神经性厌食症患者中。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），白色脂肪组织在饥饿时被分解，用作燃料。限制热量摄入对健康有很多好处，包括延长寿命，降低癌症和心血管疾病的风险，以及促进脂肪分解和胰岛素敏感性等代谢益处。与限制热量一样，抗糖尿病药物治疗也会增加胰岛素敏感性。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。像糖尿病这样的代谢性疾病目前给英国和全球的公共卫生带来了巨大的负担。在英国，每17个成年人中就有一个患有糖尿病，即320万人，预计到2030年这一数字将上升到460万。这给经济造成了巨大压力，NHS每小时花费超过150万英镑，占英格兰和威尔士NHS预算的10%。据估计，英国每年总共花费140亿英镑用于治疗糖尿病及其并发症。在全球范围内，2010年糖尿病的成本为2320亿英镑，预计到2030年将增加到3000多亿英镑。因此，确定糖尿病及其并发症的新治疗方法将为全世界的人类健康带来巨大利益。然而，开发这样的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。是什么控制了MAT的形成，MAT对代谢健康有益吗？爱丁堡大学的一组科学家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是脂联素的主要来源，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，与降低与肥胖相关的癌症、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，研究为什么在热量限制期间MAT会扩张，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人类供体提供的MAT和WAT样本，以准确确定MAT与人类WAT有何不同。这些研究将有助于揭开MAT的奥秘。在这样做的过程中，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与全球相关的卫生问题对公共卫生的影响，这一点至关重要。

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.