Abstract
Background: 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 Drosophila melanogaster. Methods: 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. Results: 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. Conclusion: 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.
Highlights
Mifepristone (RU486) is a synthetic steroid that antagonizes the activities of human glucocorticoids and progesterone by binding to type II glucocorticoid receptor and progestin receptor, enabling it’s use as a treatment for Cushing’s disease and for birth control (Baulieu, 1997; Chen et al, 2014)
Virgin female flies were assayed for life span and food consumption when cultured on regular media, media supplemented to 2.5% CO, and media supplemented to 5% CO, in replicate assays
ANOVA for the combined excreta quantification (EX-Q) assays confirmed significant effect of mifepristone for control media and the 2.5% CO media, and the lack of effect on 5% CO media (Supplementary Table S2). These results show that mifepristone can increase life span of virgin females on high-fat diet (HFD) without decreasing food intake
Summary
Mifepristone (RU486) is a synthetic steroid that antagonizes the activities of human glucocorticoids and progesterone by binding to type II glucocorticoid receptor and progestin receptor, enabling it’s use as a treatment for Cushing’s disease and for birth control (Baulieu, 1997; Chen et al, 2014). Mifepristone improved insulin sensitivity and adiponectin levels in mice fed a high-fat diet (HFD), and caused adiponectin release from cultured adipocytes that was dependent upon PPARγ (Hashimoto et al, 2013). Consistent with those observations, mifepristone is a mammalian PPARγ agonist that activates expression of PPARγ target genes (Lin et al, 2012; Wu et al, 2018). We previously reported that mifepristone blocks the negative effect on life span caused by mating in female Drosophila melanogaster
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