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Loss of function in the Drosophila clock gene period results in altered intermediary lipid metabolism and increased susceptibility to starvation.
Cellular and Molecular Life Sciences ( IF 6.2 ) Pub Date : 2020-01-20 , DOI: 10.1007/s00018-019-03441-6
Stefan Schäbler 1 , Kelechi M Amatobi 1 , Melanie Horn 2 , Dirk Rieger 2 , Charlotte Helfrich-Förster 2 , Martin J Mueller 1 , Christian Wegener 2 , Agnes Fekete 1
Affiliation  

The fruit fly Drosophila is a prime model in circadian research, but still little is known about its circadian regulation of metabolism. Daily rhythmicity in levels of several metabolites has been found, but knowledge about hydrophobic metabolites is limited. We here compared metabolite levels including lipids between period01 (per01) clock mutants and Canton-S wildtype (WTCS) flies in an isogenic and non-isogenic background using LC–MS. In the non-isogenic background, metabolites with differing levels comprised essential amino acids, kynurenines, pterinates, glycero(phospho)lipids, and fatty acid esters. Notably, detectable diacylglycerols (DAG) and acylcarnitines (AC), involved in lipid metabolism, showed lower levels in per01 mutants. Most of these differences disappeared in the isogenic background, yet the level differences for AC as well as DAG were consistent for fly bodies. AC levels were dependent on the time of day in WTCS in phase with food consumption under LD conditions, while DAGs showed weak daily oscillations. Two short-chain ACs continued to cycle even in constant darkness. per01 mutants in LD showed no or very weak diel AC oscillations out of phase with feeding activity. The low levels of DAGs and ACs in per01 did not correlate with lower total food consumption, body mass or weight. Clock mutant flies showed higher sensitivity to starvation independent of their background-dependent activity level. Our results suggest that neither feeding, energy storage nor mobilisation is significantly affected in per01 mutants, but point towards impaired mitochondrial activity, supported by upregulation of the mitochondrial stress marker 4EBP in the clock mutants.



中文翻译:


果蝇时钟基因周期的功能丧失会导致中间脂质代谢改变并增加饥饿的易感性。



果蝇是昼夜节律研究的主要模型,但人们对其代谢的昼夜节律调节仍知之甚少。已发现几种代谢物水平的每日节律性,但有关疏水性代谢物的知识有限。我们在这里使用 LC-MS 在等基因和非等基因背景下比较了01( per 01 ) 时钟突变体和 Canton-S 野生型 (WT CS ) 果蝇之间的代谢水平,包括脂质。在非等基因背景中,不同水平的代谢物包括必需氨基酸、犬尿氨酸、蝶呤、甘油(磷酸)脂质和脂肪酸酯。值得注意的是,在per 01突变体中,可检测到的参与脂质代谢的二酰基甘油 (DAG) 和酰基肉碱 (AC) 水平较低。大多数这些差异在同基因背景中消失,但对于果蝇体来说,AC 和 DAG 的水平差异是一致的。 AC 水平取决于 WT CS中一天中的时间,与 LD 条件下的食物消耗同步,而 DAG 显示出微弱的每日振荡。即使在持续的黑暗中,两台短链空调仍继续循环。 LD 中的per 01突变体没有表现出或表现出非常弱的与摄食活动异相的昼夜交流振荡。01中 DAG 和 AC 水平较低与较低的总食物消耗量、体重或体重无关。时钟突变果蝇对饥饿表现出更高的敏感性,与其背景依赖性活动水平无关。 我们的结果表明, per 01突变体的摄食、能量储存和动员均未受到显着影响,但表明线粒体活性受损,这受到时钟突变体中线粒体应激标记 4EBP 上调的支持。

更新日期:2020-01-20
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