尽管科学家们早已知道在小鼠中一些免疫细胞可能有助于防止肥胖的发生，新研究结果却是首次表明在人体中亦是这种情况。研究人员发现，相比瘦人，肥胖成人腹部脂肪中不大常见一种称作为ILC2s的免疫细胞。并且在一些小鼠实验中，他们发现ILC2s似乎促进了“米色”(beige)脂肪细胞形成，众所周知后者可以提高身体的卡路里燃烧。项目高级研究员、威尔康乃尔医学院（Weill Cornell
Medical College）的免疫学教授David Artis说，似乎这些ILC2细胞无法在肥胖者中正常地工作。Artis说，目前尚不清楚发生这种情况的确切原因或机制，但这些都是未来研究的关键问题。他希望最终能够开发出一些新方法来解决肥胖问题。
Group 2 innate lymphoid cells promote beiging of white
adipose tissue and limit obesity
Obesity is an
increasingly prevalent disease regulated by genetic and environmental factors.
Emerging studies indicate that immune cells, including monocytes, granulocytes
and lymphocytes, regulate metabolic homeostasis and are dysregulated in
obesity1, 2. Group 2 innate lymphoid cells (ILC2s) can regulate adaptive
immunity3, 4 and eosinophil and alternatively activated macrophage responses5,
and were recently identified in murine white adipose tissue (WAT)5 where they
may act to limit the development of obesity6. However, ILC2s have not been
identified in human adipose tissue, and the mechanisms by which ILC2s regulate
metabolic homeostasis remain unknown. Here we identify ILC2s in human WAT and
demonstrate that decreased ILC2 responses in WAT are a conserved characteristic
of obesity in humans and mice. Interleukin (IL)-33 was found to be critical for
the maintenance of ILC2s in WAT and in limiting adiposity in mice by increasing
caloric expenditure. This was associated with recruitment of uncoupling protein
1 (UCP1)+ beige adipocytes in WAT, a process known as beiging or browning that
regulates caloric expenditure7, 8, 9. IL-33-induced beiging was dependent on
ILC2s, and IL-33 treatment or transfer of IL-33-elicited ILC2s was sufficient
to drive beiging independently of the adaptive immune system, eosinophils or
IL-4 receptor signalling. We found that ILC2s produce methionine-enkephalin
peptides that can act directly on adipocytes to upregulate Ucp1 expression in
vitro and that promote beiging in vivo. Collectively, these studies indicate
that, in addition to responding to infection or tissue damage, ILC2s can
regulate adipose function and metabolic homeostasis in part via production of
enkephalin peptides that elicit beiging.
Nature头条：控制体重的免疫细胞
发布时间：2014-12-29 00:00 文章来源： 作者：
来自美国的研究人员在一项早期研究证实，某些免疫系统细胞有可能在体重控制中发挥了重要的作用。这一研究发现发表在12月22日的《自然》（Nature）杂志上，并被选为了Nature网站的新闻头条。
尽管科学家们早已知道在小鼠中一些免疫细胞可能有助于防止肥胖的发生，新研究结果却是首次表明在人体中亦是这种情况。研究人员发现，相比瘦人，肥胖成人腹部脂肪中不大常见一种称作为ILC2s的免疫细胞。并且在一些小鼠实验中，他们发现ILC2s似乎促进了“米色”(beige)脂肪细胞形成，众所周知后者可以提高身体的卡路里燃烧。项目高级研究员、威尔康乃尔医学院（Weill Cornell Medical College）的免疫学教授David Artis说，似乎这些ILC2细胞无法在肥胖者中正常地工作。Artis说，目前尚不清楚发生这种情况的确切原因或机制，但这些都是未来研究的关键问题。他希望最终能够开发出一些新方法来解决肥胖问题。
根据Artis所说，只在过去的几年里研究人员才开始了解免疫系统影响代谢和体重控制的机制。这听起来或许令人意外，因为免疫系统最为人所知的功能就是帮助机体抵御感染。但从进化的角度来讲这是有道理的。
尽管免疫系统的直接任务是对抗感染，可以想象其中的一些元件进化至具备了在逆境中与脂肪组织“沟通”，从而改变机体代谢的能力。“你可以想象，它实际上告诉了脂肪组织，‘我们将会在一段时间内营养不良，让我们适应它，’”Artis说。一位未参与该项研究的肥胖研究人员说，这项新研究添加了证据证实免疫系统在体重控制中起作用。
明尼苏达大学内分泌学家、美国肥胖协会发言人Charles Billington博士说：“这真的很有趣。免疫功能和代谢之间存在关联并非是一个新概念。当人们受伤或产生一种过敏反应时，机体往往会进入“代谢亢进”状态，加速卡路里的燃烧。
Billington说，但这项研究和近期的其他一些研究揭示了免疫系统影响代谢，及有可能影响长期体重控制的机制。但他也强调还有许多的未知之处。“免疫系统和代谢之间存在一些重叠，我们还没有真正地理解它。”
人们将ILC2s视作是一组可帮助对抗感染，并在过敏中起作用的免疫细胞。Artis和同事们想知道，这些细胞是否还承担了其他的工作。研究人员从来自肥胖和正常体重成人的腹部脂肪样本着手研究，结果证实了来自肥胖人群的脂肪具有较少的ILC2s——就像实验室中的肥胖小鼠一样。
随后，研究人员测试了注入白介素-33（IL-33）对实验室小鼠的影响。IL-33是一种免疫系统蛋白，其充当了细胞间的“化学信使”。研究作者们发现，这一处理可提高动物白色脂肪中的ILC2s，转而增进了卡路里燃烧。Billington解释说，白色脂肪是一种能够储存多余卡路里的脂肪类型，其常表现为啤酒肚或腰间赘肉。而另一种叫做棕色脂肪的脂肪类型，只占据身体很小的空间，可以燃烧卡路里产热。
Artis说，科学家们长期以来都在寻找一种能够上调棕色脂肪的途径。但机体除了白色脂肪和棕色脂肪外，还有第三种脂肪类型——即所谓的米色脂肪。像棕色脂肪一样，米色脂肪能够燃烧卡路里并生成热量。Artis说，更重要的是，它有可能在防止肥胖中发挥了重要的作用。在其研究小组的一些实验中，ILC2细胞似乎通过促进动物储存米色脂肪而提高了卡路里燃烧。
这对于人类意味着什么？
Artis说：“很明显，我们还处在这项研究的初期阶段，仍有大量的工作要做。而我们的目标是通过更好地了解免疫系统和身体脂肪之间的通讯，来开发出一些新方法治疗肥胖。”但Billington认为，这将是一条漫漫长路。他指出了一个大问题：既然一些免疫系统细胞承担了多项工作，你如何能够让它们只增加米色脂肪，而不会做些你不想发生的事情——例如刺激过敏反应？
在更大的图景中，肥胖研究已明确了一件事情：代谢和体重控制是复杂的。“不太可能有任何的‘灵丹妙药’来对抗肥胖，”Billington说。
原文摘要
Group 2 innate lymphoid cells promote beiging of white adipose tissue and limit obesity
Obesity is an increasingly prevalent disease regulated by genetic and environmental factors. Emerging studies indicate that immune cells, including monocytes, granulocytes and lymphocytes, regulate metabolic homeostasis and are dysregulated in obesity1, 2. Group 2 innate lymphoid cells (ILC2s) can regulate adaptive immunity3, 4 and eosinophil and alternatively activated macrophage responses5, and were recently identified in murine white adipose tissue (WAT)5 where they may act to limit the development of obesity6. However, ILC2s have not been identified in human adipose tissue, and the mechanisms by which ILC2s regulate metabolic homeostasis remain unknown. Here we identify ILC2s in human WAT and demonstrate that decreased ILC2 responses in WAT are a conserved characteristic of obesity in humans and mice. Interleukin (IL)-33 was found to be critical for the maintenance of ILC2s in WAT and in limiting adiposity in mice by increasing caloric expenditure. This was associated with recruitment of uncoupling protein 1 (UCP1)+ beige adipocytes in WAT, a process known as beiging or browning that regulates caloric expenditure7, 8, 9. IL-33-induced beiging was dependent on ILC2s, and IL-33 treatment or transfer of IL-33-elicited ILC2s was sufficient to drive beiging independently of the adaptive immune system, eosinophils or IL-4 receptor signalling. We found that ILC2s produce methionine-enkephalin peptides that can act directly on adipocytes to upregulate Ucp1 expression in vitro and that promote beiging in vivo. Collectively, these studies indicate that, in addition to responding to infection or tissue damage, ILC2s can regulate adipose function and metabolic homeostasis in part via production of enkephalin peptides that elicit beiging.
http://www.nature.com/nature/journal/vaop/ncurrent/full/nature14115.html