Germline signals deploy NHR-49 to modulate fatty-acid β-oxidation and desaturation in somatic tissues of C. elegans.
Germline signals deploy NHR-49 to modulate fatty-acid β-oxidation and desaturation in somatic tissues of C. elegans.
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DOI：
10.1371/journal.pgen.1004829
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发表时间：
2014-12
期刊：
影响因子：
4.5
通讯作者：
Ghazi A
中科院分区：
文献类型：
--
作者：
Ratnappan R;Amrit FR;Chen SW;Gill H;Holden K;Ward J;Yamamoto KR;Olsen CP;Ghazi A
在线虫中，生殖系的移除显著延长了寿命。我们证明，核激素受体NHR-49能够通过增加参与线粒体β氧化和脂肪酸去饱和的基因的表达来对这种生理变化做出反应。这些过程的协同增强对于无生殖系动物在成年期维持其脂肪储存和维持从头合成脂肪至关重要。生殖系切除后，NHR-49在体细胞中被保守的长寿决定基因DAF-16/FOXO和TCER-1/TCERG1上调。因此，NHR-49在可育动物中的过度表达可以适度延长它们的寿命。在有生育能力的成人中，NHR-49的表达与DAF-16/FOXO和TCER-1/TCERG1无关，尽管它的缺失会导致与年龄相关的脂质异常。我们的数据提供了关于生殖刺激如何整合到全球新陈代谢变化中以改变动物寿命的分子见解。他们认为，NHR-49可能通过同步增强脂肪酸氧化和去饱和度来促进对生殖潜力丧失的适应，从而分解一些注定用于生殖的脂肪，并协调有利于躯体维持和长寿的脂质谱。关于年龄增长如何损害生育能力，我们知道的很多，但我们对生殖如何影响动物的老龄化速度知之甚少。对蠕虫和苍蝇等模式生物的研究已经开始揭示这种关系。在蠕虫中，去除产生精子和卵母细胞的生殖细胞可以延长寿命，增加耐力，并增加脂肪。脂肪代谢和荷尔蒙信号在这种寿命延长中扮演着主要角色，但其中涉及的遗传机制尚不清楚。我们发现了一种名为NHR-49的基因，它可以在去除生殖细胞后延长蠕虫的寿命。在缺乏生殖细胞的动物中，NHR-49通过保守的长寿蛋白DAF-16和TCER-1而增加。反过来，NHR-49又增加了有助于燃烧脂肪并将饱和脂肪转化为不饱和形式的基因水平。通过这些过程的同步增强，NHR-49有助于消除委托给生殖的多余脂肪，并将脂质转化为有利于长寿的形式。NHR-49在正常动物的衰老过程中也会影响这些过程，但使用不同的调节机制。我们的数据有助于理解如何利用正常的脂肪代谢过程来适应动物生殖状态变化带来的生理波动。
In C. elegans, removal of the germline extends lifespan significantly. We demonstrate that the nuclear hormone receptor, NHR-49, enables the response to this physiological change by increasing the expression of genes involved in mitochondrial β-oxidation and fatty-acid desaturation. The coordinated augmentation of these processes is critical for germline-less animals to maintain their lipid stores and to sustain de novo fat synthesis during adulthood. Following germline ablation, NHR-49 is up-regulated in somatic cells by the conserved longevity determinants DAF-16/FOXO and TCER-1/TCERG1. Accordingly, NHR-49 overexpression in fertile animals extends their lifespan modestly. In fertile adults, nhr-49 expression is DAF-16/FOXO and TCER-1/TCERG1 independent although its depletion causes age-related lipid abnormalities. Our data provide molecular insights into how reproductive stimuli are integrated into global metabolic changes to alter the lifespan of the animal. They suggest that NHR-49 may facilitate the adaptation to loss of reproductive potential through synchronized enhancement of fatty-acid oxidation and desaturation, thus breaking down some fats ordained for reproduction and orchestrating a lipid profile conducive for somatic maintenance and longevity. Much is known about how increasing age impairs fertility but we know little about how reproduction influences rate of aging in animals. Studies in model organisms such as worms and flies have begun to shed light on this relationship. In worms, removing germ cells that give rise to sperm and oocytes extends lifespan, increases endurance and elevates fat. Fat metabolism and hormonal signals play major roles in this lifespan augmentation but the genetic mechanisms involved are poorly understood. We show that a gene, nhr-49, enhances worm lifespan following germ-cell removal. NHR-49 is increased in animals that lack germ cells by conserved longevity proteins, DAF-16 and TCER-1. NHR-49, in turn, increases levels of genes that help burn fat and convert saturated fats into unsaturated forms. Through synchronized enhancement of these processes, NHR-49 helps eliminate excess fat delegated for reproduction and converts lipids into forms that favor a long life. NHR-49 impacts these processes during aging in normal animals too, but using different regulatory mechanisms. Our data helps understand how normal lipid metabolic processes can be harnessed to adapt to physiological fluctuations brought on by changes in the reproductive status of animals.
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