Mifepristone (RU486) inhibits dietary lipid digestion by antagonizing the role of glucocorticoid receptor on lipase transcription

Ma, Peng; Zhang, Yao; Liang, Qiying; Yin, Youjie; Wang, Saifei; Han, Ruolei; Huo, Chunyu; Deng, Hansong

doi:10.1016/j.isci.2021.102507

Cited by 15 publications

(14 citation statements)

References 79 publications

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“…In addition, mifepristone partially rescued the negative life span effects of a high-fat diet (HFD) in both virgin and mated females [ 27 ]. Finally, mifepristone was reported to reduce lipid uptake in flies of undefined sex [ 41 ]. Etomoxir is an irreversible inhibitor of carnitine palmitoyltransferase I (CPT I), the rate-limiting enzyme for transport of long-chain FAs into the mitochondria [ 42 ].…”

Section: Resultsmentioning

confidence: 99%

A screen of small molecule and genetic modulators of life span in female Drosophila identifies etomoxir, RH5849 and unanticipated temperature effects

Landis

Peng

et al. 2022

Fly

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Mifepristone increases life span in female Drosophila melanogaster , and its molecular target(s) remain unclear. Here small molecule and genetic interventions were tested for ability to mimic mifepristone, or to decrease life span in a way that can be rescued by mifepristone. Etomoxir inhibits lipid metabolism, and significantly increased life span in virgin and mated females, but not males, at 50 µM concentration. Pioglitazone is reported to activate both mammalian PPARγ and its Drosophila homolog Eip75B. Pioglitazone produced minor and inconsistent benefits for female Drosophila life span, and only at the lowest concentrations tested. Ecdysone is a Drosophila steroid hormone reported to regulate responses to mating, and RH5849 is a potent mimic of ecdysone. RH5849 reduced virgin female life span, and this was partly rescued by mifepristone. Mifepristone did not compete with RH5849 for activation of an ecdysone receptor (EcR)-responsive transgenic reporter, indicating that the relevant target for mifepristone is not EcR. The conditional GAL4/GAL80ts system was used in attempt to test the effect of an Eip75B RNAi construct on female life span. However, the 29°C temperature used for induction reduced or eliminated mating-induced midgut hypertrophy, the negative life span effects of mating, and the positive life span effects of mifepristone. Even when applied after mating was complete, a shift to 29°C temperature reduced mating-induced midgut hypertrophy by half, and the life span effects of mating by 4.8-fold. Taken together, these results identify promising small molecules for further analysis, and inform the design of experiments involving the GAL4/GAL80ts system.

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Section: Resultsmentioning

confidence: 99%

A screen of small molecule and genetic modulators of life span in female Drosophila identifies etomoxir, RH5849 and unanticipated temperature effects

Landis

Peng

et al. 2022

Fly

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“…Feeding 200 μM RU486, the concentration frequently used for adult flies, caused higher developmental lethality even for the control flies in our laboratory conditions. RU486 is known to have side-effects on the physiology and lifespan of flies, depending on various factors, such as sex, mating, diet, genetic background and dose of the drug ( Landis et al, 2015 ; Ma et al, 2021 ; Robles-Murguia et al, 2019 ; Yamada et al, 2017 ). Therefore, we optimised the dosage carefully by checking the control animals.…”

Section: Resultsmentioning

confidence: 99%

Activation of innate immunity during development induces unresolved dysbiotic inflammatory gut and shortens lifespan

Yamashita

Kosakamoto

et al. 2021

Disease Models &Amp; Mechanisms

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An early-life inflammatory response is associated with risks of age-related pathologies. How transient immune signalling activity during animal development influences life-long fitness is not well understood. Using Drosophila as a model, we find that activation of innate immune pathway Immune deficiency (Imd) signalling in the developing larvae increases adult starvation resistance, decreases food intake and shortens organismal lifespan. Interestingly, lifespan is shortened by Imd activation in the larval gut and fat body, whereas starvation resistance and food intake are altered by that in neurons. The adult flies that developed with Imd activation show sustained Imd activity in the gut, despite complete tissue renewal during metamorphosis. The larval Imd activation increases an immunostimulative bacterial species, Gluconobacter sp., in the gut microbiome, and this dysbiosis is persistent to adulthood. Removal of gut microbiota by antibiotics in the adult fly mitigates intestinal immune activation and rescues the shortened lifespan. This study demonstrates that early-life immune activation triggers long-term physiological changes, highlighted as an irreversible alteration in gut microbiota, prolonged inflammatory intestine and concomitant shortening of the organismal lifespan.

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“…These results suggest that mifepristone does not act by direct inhibition of SREBP activation, however the reduction in size of midgut tissue expressing SREBP may still be a contributing factor to the life span increase caused by mifepristone in mated females. Recently, Ma et al reported that mifepristone inhibited Estrogen-related receptor (ERR) reporter activity in adult Drosophila , and reduced lipid content and magro lipase gene expression in the adult midgut, suggesting the possibility that ERR might be a mifepristone target ( Ma et al, 2021 ). However, fly sex was not defined in that study, so it is not clear if the observed effects occurred in males or females, or might reflect variation in the ratio of male and female flies in the samples.…”

Section: Discussionmentioning

confidence: 99%

Mifepristone Increases Life Span of Virgin Female Drosophila on Regular and High-fat Diet Without Reducing Food Intake

et al. 2021

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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.

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Mifepristone (RU486) inhibits dietary lipid digestion by antagonizing the role of glucocorticoid receptor on lipase transcription

Cited by 15 publications

References 79 publications

A screen of small molecule and genetic modulators of life span in female Drosophila identifies etomoxir, RH5849 and unanticipated temperature effects

A screen of small molecule and genetic modulators of life span in female Drosophila identifies etomoxir, RH5849 and unanticipated temperature effects

Activation of innate immunity during development induces unresolved dysbiotic inflammatory gut and shortens lifespan

Mifepristone Increases Life Span of Virgin Female Drosophila on Regular and High-fat Diet Without Reducing Food Intake

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