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Deriving functional beige fat from capillaries

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发表于 2016-3-4 12:17:07 | 显示全部楼层 |阅读模式
An exciting and potentially safe strategy proposed for the improvement of insulin sensitivity and glucose homeostasis is to promote controlled energy dissipation and fuel utilization through the activation of brown adipose tissue (BAT). BAT is a key organ that controls nonshivering thermogenesis in small mammals by converting nutrients such as lipids into heat. Promoting BAT thermogenesis in mice works as a therapeutic approach for obesity and diabetes. Given that active brown fat has been found in lean human subjects, its induction could also potentially be a valid anti-obesity and glucose-tolerance therapeutic strategy in humans1. At least two embryologically and anatomically distinct types of BAT have been identified so far in humans and rodents. Canonical brown fat is anatomically organized as distinct small depots, whereas the alternative 'beige' or 'brite' (also known as 'beige/brite') cellular type is organized as dispersed cells within the white adipose tissue (WAT). Although this notion is still controversial, BAT in humans seems to be molecularly and structurally closer to that of beige fat than to that of the canonical brown depot2. Hence, there is interest in finding ways to increase the 'beigeing' or 'browning' cell mass in humans
最近提出了一个改善胰岛素敏感性和葡萄糖稳态的新治疗策略,通过激活棕色脂肪组织(BAT)是促进控制的能量消耗和燃料利用率。BAT是一个重要的器官,控制非颤抖性产热小哺乳动物如脂类营养转换成热。促进小鼠BAT产热作为肥胖和糖尿病的治疗方法。由于活跃的棕色脂肪一直在精益人发现,其感应也可能是一个有效的抗肥胖和葡萄糖耐受性的对人的治疗策略。至少两胚胎学和解剖学上的不同种类的BAT一直在人类和啮齿类动物的鉴定。典型的棕色脂肪的解剖组织不同的小仓库,而替代的米黄'或'亮点'(也被称为“米色/布里特”)细胞型组织细胞分散在白色脂肪组织(WAT)。虽然这个概念仍然是有争议的,BAT在人类似乎是分子结构接近的米色脂肪比,典型的棕色储存。因此,在寻找增加'开始'或'褐变的细胞团在人类利益的方式

The main challenges of using browning to alleviate insulin insensitivity are that brown fat is scarce in people with obesity and diabetes, and that it needs to be activated. One approach to overcoming this challenge aims to increase the amount of functional beige cells to promote WAT browning by first recruiting adipose progenitor cells and then promoting their commitment to beige cells that are thermogenically competent in response to environmental and pharmacological activators. In this issue of Nature Medicine, Min et al.3 demonstrate that human functional beige adipocytes can be developed from capillary-derived adipocyte progenitors of human subcutaneous WAT and then induced to function as a regulator of blood glucose in mice (Fig. 1).
使用褐变减轻胰岛素不敏感的主要挑战是,肥胖和糖尿病的人缺少棕色脂肪,它需要被激活。为了克服这一挑战的目的是增加功能的米色细胞数量促进WAT褐变的首次招募脂肪祖细胞并促进其承诺的米色细胞应对环境和药理活化剂是温和主管的方法之一。在这个问题上的自然医学,Min等人3证实人类功能的米色脂肪细胞可以从毛细管衍生的脂肪前体细胞并诱导人体皮下WAT功能小鼠调节血糖(图1)。

Both brown and beige adipocytes arise from a two-step process of differentiation. First, the adipogenic precursor cells commit to brown/beige fates, and then they differentiate into mature adipocytes. Concomitantly, angiogenesis within the tissue occurs to extend the vasculature to provide the appropriate perfusion, oxygenation and nutrition of the growing BAT. Both angiogenesis and adipogenesis occur in close temporal-spatial association, which is ensured by cross-talks between endothelial cells and other vascular cells, such as pericytes and/or adipocytes4, 5.
棕色和褐色脂肪细胞都来自一个两步分化的过程。首先,脂肪细胞的前体细胞向棕色/米色犯的命运,然后他们向成熟脂肪细胞的分化。同时,延长血管提供适当的灌注发生组织内血管生成,氧和营养生长的BAT。血管生成和脂肪形成密切的时空发生关联,这是由血管内皮细胞及血管细胞之间的交叉对话的保证,如周细胞和/或脂肪细胞4,5。

The authors first derived adipogenic progenitors. On the basis of a previously developed ex vivo model, the authors exposed subcutaneous fat biopsies, which had been obtained from patients undergoing panniculectomy surgery, to angiogenic growth factors (hFGF-B, hEGF, R3-IGF1 and VEGF) to induce vascular sprouting on Matrigel3. The authors rationalized that vascular sprouting from these tissue explants reflects the ability of adipose cells to proliferate, migrate and interact with vascular structures5. Min et al.3 made the unexpected observation that the capillary networks contained, in addition to endothelial cells, adipose progenitors with the ability to give rise to adipocytes when submitted to a well-established adipogenic cocktail of growth factors. This supports previous work reporting that microvascular fragment–derived cells display higher adipogenic potential than do classical adipose-derived stem cells6. Furthermore, the authors found that capillary-derived precursors committed to a beige fate in vitro upon the activation of β-adrenergic–dependent pathways after stimulation with forskolin. The induced pathways increased the levels of cyclic adenosine monophosphate (cAMP) and promoted the activation of the thermogenic program in beige adipocytes7. These progenitors displayed all the structural and functional features of a beige/brite cell in vitro, including high expression of endogenous uncoupling protein 1 (UCP1), and they regulated uncoupled cellular respiration. This result confirmed the key role of the vasculature in promoting adipogenesis, as initially suggested in lineage-tracing studies5.
作者首先分离成脂细胞。在以前开发的体外模型的基础上,作者暴露皮下脂肪活检,已接受手术的患者得到panniculectomy,对血管生长因子(hfgf-b,hEGF,r3-igf1和VEGF诱导血管发芽能力)。作者认为,这些组织外植体的血管发芽反映了脂肪细胞增殖,迁移和互动的血管结构的能力。Min等使毛细血管网中意外的观察,除内皮细胞、脂肪细胞和引起脂肪细胞向成熟脂肪细胞在生长因子混合物的能力。这支持了以前的工作报告,微血管片段–细胞显示比经典的脂肪干细胞成脂分化潜能高。此外,作者发现毛细管来源的前体致力于米色的命运在体外对β-激活肾上腺素能–依赖途径刺激后与福斯克林。诱导途径增加环磷酸腺苷(cAMP)水平和促进在米色脂肪细胞的产热程序激活。显示所有这些祖细胞体外米色/该细胞的结构和功能特性,包括内源性解偶联蛋白1(UCP1)高表达,并调节耦合细胞呼吸。这个结果证实了血管促进脂肪细胞的关键作用,与最初建议在谱系追踪研究一致。

全文链接:http://www.nature.com/nm/journal/v22/n3/full/nm.4056.html
中文翻译参考:百度翻译

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