Landis Gary N, Hilsabeck Tyler A U, Bell Hans S, Ronnen-Oron Tal, Wang Lu, Doherty Devon V, Tejawinata Felicia I, Erickson Katherine, Vu William, Promislow Daniel E L, Kapahi Pankaj, Tower John
Molecular and Computational Biology Section, Department of Biological Sciences, Dornsife College of Letters, Arts, and Sciences, University of Southern California, Los Angeles, CA, United States.
Buck Institute for Research on Aging, Novato, CA, United States.
Front Genet. 2021 Sep 24;12:751647. doi: 10.3389/fgene.2021.751647. eCollection 2021.
The synthetic steroid mifepristone is reported to have anti-obesity and anti-diabetic effects in mammals on normal and high-fat diets (HFD). We previously reported that mifepristone blocks the negative effect on life span caused by mating in female . Here we asked if mifepristone could protect virgin females from the life span-shortening effect of HFD. Mifepristone was assayed for effects on life span in virgin females, in repeated assays, on regular media and on media supplemented with coconut oil (HFD). The excrement quantification (EX-Q) assay was used to measure food intake of the flies after 12 days mifepristone treatment. In addition, experiments were conducted to compare the effects of mifepristone in virgin and mated females, and to identify candidate mifepristone targets and mechanisms. Mifepristone increased life span of virgin females on regular media, as well as on media supplemented with either 2.5 or 5% coconut oil. Food intake was not reduced in any assay, and was significantly increased by mifepristone in half of the assays. To ask if mifepristone might rescue virgin females from all life span-shortening stresses, the oxidative stressor paraquat was tested, and mifepristone produced little to no rescue. Analysis of extant metabolomics and transcriptomics data suggested similarities between effects of mifepristone in virgin and mated females, including reduced tryptophan breakdown and similarities to dietary restriction. Bioinformatics analysis identified candidate mifepristone targets, including transcription factors Paired and Extra-extra. In addition to shortening life span, mating also causes midgut hypertrophy and activation of the lipid metabolism regulatory factor SREBP. Mifepristone blocked the increase in midgut size caused by mating, but did not detectably affect midgut size in virgins. Finally, mating increased activity of a SREBP reporter in abdominal tissues, as expected, but reporter activity was not detectably reduced by mifepristone in either mated or virgin females. Mifepristone increases life span of virgin females on regular and HFD without reducing food intake. Metabolomics and transcriptomics analyses suggest some similar effects of mifepristone between virgin and mated females, however reduced midgut size was observed only in mated females. The results are discussed regarding possible mifepristone mechanisms and targets.
据报道，合成类固醇米非司酮对正常饮食和高脂饮食（HFD）的哺乳动物具有抗肥胖和抗糖尿病作用。我们之前报道过米非司酮可消除交配对雌性寿命产生的负面影响。在此，我们探究米非司酮是否能保护未交配雌性免受高脂饮食导致的寿命缩短影响。我们在重复试验中，对正常培养基以及添加了椰子油的培养基（高脂饮食）上的未交配雌性进行了米非司酮对寿命影响的测定。在米非司酮处理12天后，采用粪便定量（EX-Q）试验来测量果蝇的食物摄入量。此外，还进行了实验以比较米非司酮对未交配和已交配雌性的影响，并确定米非司酮的候选靶点和作用机制。米非司酮延长了正常培养基上以及添加了2.5%或5%椰子油培养基上未交配雌性的寿命。在任何试验中食物摄入量均未减少，并且在一半的试验中米非司酮显著增加了食物摄入量。为了探究米非司酮是否能使未交配雌性免受所有缩短寿命的应激影响，我们测试了氧化应激剂百草枯，结果发现米非司酮几乎没有起到挽救作用。对现有代谢组学和转录组学数据的分析表明，米非司酮对未交配和已交配雌性的影响存在相似之处，包括色氨酸分解减少以及与饮食限制的相似性。生物信息学分析确定了米非司酮的候选靶点，包括转录因子Paired和Extra-extra。除了缩短寿命外，交配还会导致中肠肥大以及脂质代谢调节因子SREBP的激活。米非司酮可阻止交配引起的中肠大小增加，但未检测到对未交配雌性中肠大小有明显影响。最后，正如预期的那样，交配增加了腹部组织中SREBP报告基因的活性，但在已交配或未交配雌性中，米非司酮均未检测到对报告基因活性有明显降低作用。米非司酮可延长正常饮食和高脂饮食条件下未交配雌性的寿命，且不减少食物摄入量。代谢组学和转录组学分析表明米非司酮对未交配和已交配雌性有一些相似的影响，然而仅在已交配雌性中观察到中肠大小减小。我们对米非司酮可能的作用机制和靶点进行了讨论。
