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[ADA2015]众所瞩目:Banting科学成就奖关注脂肪组织的多重角色
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作者:P.Scherer 2015/6/10 16:07:00    加入收藏
内容概要:这是个非常好的问题,近期观察发现,人体除了具有白色脂肪、棕色脂肪外,还有另一种脂肪即所谓的米色脂肪组织。鉴于米色脂肪组织及棕色脂肪组织都在机体的热量产生中发挥了特定作用

   <International Diabetes>:So, Dr. Scherer, in recent years, many studies focused on brown adipocytes. So what do you think of the role of the regulation of brown adipose tissue in the development of diabetes and obesity?

 
  Dr. Phillip Scherer: An excellent question. The realization that humans have both white and brown or – there’s actually a third kind, the so-called beige adipocyte. It’s a relatively recent observation and everybody’s excited about the potential that this might have, therapeutically on the long-term. The reason why there is a lot of excitement about this is the fact that these beige and brown adipocytes have specialized roles in terms of generating heat in a futile cycle so we can waste calories, so to speak. And by doing so the hope is that we can effectively lower body weight, reduce fat mass and thereby improve insulin sensitivity and inflammation.
 
  您如何看待棕色脂肪组织在糖尿病及肥胖发病中的作用?
 
  这是个非常好的问题,近期观察发现,人体除了具有白色脂肪、棕色脂肪外,还有另一种脂肪即所谓的米色脂肪组织。鉴于米色脂肪组织及棕色脂肪组织都在机体的热量产生中发挥了特定作用,有助于消耗热量,故人们对这类脂肪的长期潜在治疗意义倍感兴奋。通过这类脂肪的作用,我们可以有效减轻体重、减少脂肪含量,从而改善胰岛素敏感性及炎症反应。
 
   <International Diabetes>:The second question, compared with white adipose tissue, what special adipokines did brown adipocytes secrete that influence the glucose homeostasis? Please elaborate on this your answer please.
 
  Dr. Phillip Scherer: The brown and beige adipocyte does not necessarily secrete a unique set of proteins even though people are looking for these specialized adipokines that come from the brown adipocyte. I think their major role is their ability to respond to factors from other parts of our body that can be central, from the brain, as well as from a host of other cells that will tell the white adipose tissue to induce spacing and when they do that there is a special protein that is being induced that is called the uncoupling protein one and that seems to be the key mediator for these futile cycles of uncoupling that generates heat and the beneficial effects on diabetes is primarily on the basis of consuming that excess energy and thereby lowering issues like hepatic steatosis, lipid accumulation in the liver that causes insulin resistance. So it’s this fat burning ability which people appreciate to a very high degree.
 
  与白色脂肪组织相比,棕色脂肪细胞可分泌哪些特别的脂肪因子来影响葡萄糖代谢?
 
  尽管人们一直在寻找来源于棕色脂肪细胞的特定脂肪因子,但棕色脂肪细胞及米色脂肪细胞并不一定会分泌一系列独特的蛋白质。我认为,它们的主要作用是对来自机体其他部分如大脑中枢及其他大量细胞的因子作出反应,这时候就诱导一种特定蛋白即所谓的解偶联蛋白。
 
 
   <International Diabetes>: Okay, thank you. So if activation of brown fat or increasing the amount of brown fat has the potential to reverse obesity, what are the pathways that should be chosen for the activation of brown fat?
 
  Dr. Phillip Scherer: Well there is a very old-fashioned way of inducing brown fat and that’s simply cold exposure. So if you turn the temperature down inside in the winter, lower it by a few degrees - that will in fact induce beige and brown fat cells. But there is of course also the hope that pharmacologically there will be ways of stimulating that process more selectively. We can see some hints of that in existing antidiabetic regiments. For instance, you know the PPAR gamma agonists of which there are a couple of different ones out there – thiazolidinediones. They have the ability to induce browning and beigeing. There are several other molecules in development, FGF21 is another one which you will hear about most certainly in the future. And then there’s a well-described list of additional factors, probably half a dozen of them that various labs, in the lab have been shown to induce beigeing and the hope is to be able to take some of these molecules and funnel them into an actual pharmacological regime that allows us to induce higher levels of brown adipose tissue. Perhaps in combination with some other existing medications or simply cold exposure.
 
  如果激活棕色脂肪或增加棕色脂肪含量具有逆转肥胖的潜能,应选择哪些通路来激活棕色脂肪?
 
  有一种非常传统的诱导棕色脂肪的方式,那就是暴露于寒冷。如果在冬天将室内温度降低几度,实际上就对机体的米色及棕色脂肪细胞产生诱导作用。当然,药物治疗也可能有望能够激活棕色脂肪组织,使我们具有更多的选择性。目前,我们已经发现有的一些降糖药物似乎具有激活棕色脂肪组织的潜力。例如PPARγ受体激动剂噻唑烷二酮类药物具有诱导白色脂肪棕色化及米色化的能力。目前,还有几个其他分子在研发中,其中FGF21可能是未来最有潜力的一个。另外,还有一些其他因素,其中很多已被各实验室的研究显示可诱导脂肪米色化。我们希望能够利用这些分子,真正研发出能够诱导高水平棕色脂肪组织的药物制剂。也许其与现有的一些药物联合应用或仅仅是寒冷暴露即可用来激活棕色脂肪组织。
 
 
   <International Diabetes>:Okay, thank you. So besides TZD, in your lecture, you also introduced some other treatment targets of adipose tissue in obesity and diabetes. So as you know, will these findings be used in the design of new therapeutic agents? If yes, what do you think of its prospect in the treatment of obesity and diabetes?
 
  Dr. Phillip Scherer: Well I touched upon at least 3 different areas in my lecture, each one of which I believe has the potential to actually be developed into an individual therapeutic area and, in fact, is already an actively – an area of active research in that area. So the first part was the focus on so-called adipokines and there was one particular adipokine that some of you may have heard about. It’s called adiponectin. Now adiponectin has many beneficial roles, this is a protein that adipocytes produce and release and it is associated with insulin sensitization. Now like any other good protein out there adiponectin has a receptor and from a pharmacological point of view, these receptors, adiponectin receptors, r1 and r2, are now prime targets to design molecules, to find molecules that will activate these receptors, and on the basis of that, improve insulin sensitivity. Downstream of these receptors is an area that I covered as well, that was the second topic that I covered in the lecture, was the manipulation of specific lipid species. They are relatively esoteric lipids, we called them sphingolipids, and there’s a subclass of those which are called ceramides. Now these ceramides have a complicated structure, which is not relevant. But the fact is that when you have type 2 diabetes or the metabolic syndrome, your plasma levels with ceramides will be elevated. Your tissue levels of ceramides will be elevated. And it turns out if you manage to lower ceramide levels you effectively improve insulin sensitivity. These adiponectin receptors that I mentioned are, in fact, excellent modulators of these ceramide species so activation of the adiponectin receptors will effectively lower ceramide levels and thereby improve insulin sensitivity. There are other drugs that do this effectively. The existing PPAR gamma agonists, the thiazolidinediones, lower ceramides but they do this, actually, with the help of adiponectin. FGF21, which is another important emerging target, does the same thing and effectively lowers ceramide species. So this seems to be a new therapeutic area that is emerging and that a lot of companies and academic labs are starting to focus on, trying to manipulate these ceramide levels and thereby improve insulin sensitivity. And then the last area that I spent a little bit of time on were novel biochemical pathways that your textbook would not suggest to be present in the adipocytes, specifically. Yet they’re very important. I talked a fair amount about one particular building block which is called uridine. And this uridine is very important for many different reactions in the system. But what the key point of my lecture was that the adipocyte can produce very high levels of uridine and, by doing that, can actually undergo a futile cycle just like uncoupling in brown adipose tissue does, except the uncoupling in brown adipose tissue will generate heat whereas here we will produce something which we can put into the system and then lose it. And, on the basis of that, we hope we can coax this process into an effective weight loss approach and of course with anytime you lose weight you will improve insulin sensitivity almost across the board.
 

  除了噻唑烷二酮类药物外,在您的讲座中也还介绍了脂肪组织中肥胖及糖尿病治疗的其他一些靶点。据您所知,这些研究结果能否被用于设计未来的新型治疗药物?如果能的话,您认为其前景如何?
 
  我的讲座至少涉及了三个不同的领域,我认为每一个都具有研发为个体化治疗药物的潜力,事实上已经成为相应研究领域的热点。
 
  第一部分关注的是所谓的脂肪因子,其中有一种脂肪因子有些人可能已经听说过,那就是脂联素。现在研究发现,脂联素是一种由脂肪细胞产生和释放的、与胰岛素增敏有关的蛋白,具有很多有益作用。与其他好的蛋白质一样,脂联素具有相应的受体。从药理学角度讲,脂联素受体1及2是发现新型治疗药物的主要靶标,新型治疗药物的研发应该从能够激活这些受体的分子入手来改善胰岛素敏感性。
 
  调控特殊脂质的上述脂联素受体的下游是我在演讲中所提到的第二个领域。这些脂质都是相对比较特殊的脂质,我们称之为鞘磷脂。神经酰胺是鞘磷脂中的一个亚类,其结构较为复杂。研究发现,2型糖尿病或代谢综合征患者的神经酰胺水平增加。如果能够降低神经酰胺的水平,则能有效改善胰岛素敏感性。实际上,我所提到的脂联素受体是神经酰胺的调节器,因此激活脂联素受体可有效降低神经酰胺的水平,从而改善胰岛素敏感性。有些药物也可以有效降低神经酰胺水平。现有的PPARγ受体激动剂噻唑烷二酮类药物就可以降低神经酰胺水平,但是其发挥上述作用需要有赖于脂联素的帮助。FGF21则是另一种非常重要的新兴治疗靶标,能以同样方式有效降低神经酰胺的水平。因此,这成为一个新的药物治疗开发靶点,已经有很多制药公司及科学实验室关注并进行了相关研究,以期通过降低神经酰胺的水平来改善胰岛素敏感性。
 
  我演讲中所提到的第三个领域就是教科书上未提到的存在于脂肪组织中的非常重要的新生化通路,其中我重点谈到的就是尿苷,它对机体系统的很多不同反应而言都是非常重要的。但是,我在演讲中强调的重点脂肪细胞可产生大量的尿苷,从而像棕色脂肪组织解偶联那样使脂肪细胞燃烧热量,进而有效减轻体重,改善胰岛素敏感性。
 
 
   <International Diabetes>: Okay, thank you very much. Congratulations on winning the banting award. I couldn’t help myself feeling proud when I see there’s a few Chinese scientists that’s in your team. Would you like to comment on that?
 
  Dr. Phillip Scherer: Absolutely. The – I have been privileged to host a very large number of Chinese scientists in the lab at every level. Be it as a student, be it as a post-doctoral fellow, be it, in fact, as a visiting faculty member. Too many to mention here basically. But two names certainly that are directly relevant to the data that I presented today in the banting lecture are Ying Fang Ding and Zao Wang , both of which have been absolutely instrumental in establishing many of the research areas that we are working on now. Effectively Ying Fang Ding is still, fortunately, part of my lab. And they both have contributed through intellectual contributions but also have generated a lot of the reagents that we are using. So I’m very proud of them in terms of what they’ve been able to do and contribute to the community at large and I hope I’ve been able to offer them a playground, an intellectual playground where they can actually fulfill their dreams and there conceptualize their scientific ideas.
 
  我对您的研究团队中有一些中国科学家而情不自禁地感到骄傲和自豪。您对此作何评论?
 
  绝对是这样的。我非常有幸能够在不同级别实验室中拥有大量的中国科学家加入到自己的团队,这其中有学生、有博士后、有交流访问者。需要提到和感谢的人有太多太多。其中Ying Fang Ding和Zao Wang两人对我今天在Banting奖获奖讲座中发布的数据有着直接贡献,他们对我们现在所研究的研究领域的确立作出了绝对的贡献。非常幸运的是,Ying Fang Ding是我实验室的成员。他们的贡献既有知识方面的贡献,也为我们提供了很多所应用的试剂。我对他们所作出的努力及贡献感到非常自豪,也希望能够给他们提供一个非常好的平台让其真正实现自己的梦想和科学理想。
 
   <International Diabetes>: Thank you very much.
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