Understand the contribution of yolk sac-derived macrophage progenitors to the generation of adipose tissue macrophages and the development of insulin resistance
了解卵黄囊来源的巨噬细胞祖细胞对脂肪组织巨噬细胞的生成和胰岛素抵抗的发展的贡献
基本信息
- 批准号:277878931
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:德国
- 项目类别:Research Grants
- 财政年份:2015
- 资助国家:德国
- 起止时间:2014-12-31 至 2019-12-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Insulin resistance (IR) is a non-curable metabolic disease, which is reaching pandemic proportions and it is predicted to emerge a leading worldwide morbidity by 2030. Immune cells, the so-called adipose tissue macrophages (ATMs) have key roles in the development of IR. Modulation of ATM development is considered as a straightforward approach to abrogate IR. This project was initiated to understand the origin and replenishment mechanism of ATMs, which should provide new opportunities to prevent or combat IR. The project has already delivered key concepts on ATM development. We have found that (a) ATM progenitors develop before birth from yolk sac (YS) hematopoietic stem cells, (b) and are maintained by self-renewal in adulthood, with minor contribution from blood monocytes. We have found that increasing self-renewal of ATMs improves AT health and reduces IR. Moreover, we have found that (c) AT-specific cues determine the replenishment of ATMs. Our yet unpublished data show that YS-derived ATMs (YS-ATMs) have an unexpected, active metabolic role: they convert breast milk-derived lipid signals into ether lipids which maintain a thermogenic, “fat burning”, beige AT phenotype in the neonate. Moreover, our preliminary data show that this mechanism can be used to reduce IR in adulthood. Our project has developed to a crucial point, which strongly suggests that AT health is critically dependent on YS-ATMs, and physiological AT function can be restored by YS-ATMs in IR. This mechanism can provide alternative of the life-long medication of patients with IR, and has the potential to change the therapeutic concept of IR.
胰岛素抵抗(IR)是一种不可治愈的代谢性疾病,它正在达到大流行的程度,预计到2030年将成为全球领先的发病率。免疫细胞,即所谓的脂肪组织巨噬细胞,在胰岛素抵抗的发生发展中起着关键作用。调整ATM发展被认为是废除IR的一种直接方法。这个项目是为了了解自动取款机的来源和补给机制,这将为预防或打击IR提供新的机会。该项目已经提出了自动取款机开发的关键概念。我们发现:(A)ATM祖细胞在出生前由卵黄囊(YS)造血干细胞发育,(B)成年期通过自我更新维持,仅有少量单核细胞的贡献。我们发现,增加自动取款机的自我更新可以改善AT的健康状况,降低IR。此外,我们还发现(C)AT特有的线索决定了自动取款机的补给。我们尚未发表的数据表明,YS来源的ATM(YS-ATM)具有意想不到的、活跃的代谢作用:它们将母乳来源的脂肪信号转化为乙醚脂肪,从而在新生儿中保持产热、脂肪燃烧、米色的AT表型。此外,我们的初步数据表明,这一机制可以用于减少成年后的IR。我们的项目已经发展到了一个关键时刻,这有力地表明AT的健康严重依赖YS-ATM,在IR中YS-ATM可以恢复生理AT功能。这一机制可以替代IR患者的终生用药,并有可能改变IR的治疗理念。
项目成果
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Privatdozent Dr. Tamás Röszer, Ph.D.其他文献
Privatdozent Dr. Tamás Röszer, Ph.D.的其他文献
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