Dataset Information

Mifepristone Reduces Food Palatability and Affects Drosophila Feeding and Lifespan.

ABSTRACT: The Drosophila GeneSwitch system facilitates the spatial and temporal control of gene expression through dietary supplementation of mifepristone (RU486). Because experimental and control groups differ only by treatment with RU486, confounding results from using flies of different genetic backgrounds are eliminated, making GeneSwitch especially useful in studies of aging. However, the effect of RU486 itself on longevity has not been well characterized, particularly in relation to nutritional states known to affect lifespan. Here, we show that RU486 has dose- and diet-dependent effects on longevity in both sexes. On low nutrient diets, RU486 supplementation reduces total food consumption, perhaps exacerbating undernutrition to shorten life. RU486 also inhibits proboscis extension responses to low nutrient diets, suggesting that RU486 has an aversive taste which leads to decreased food consumption and diminished longevity. RU486 is not detrimental to fly lifespan on high nutrient food, correlating with reduced effects of the drug on palatability and total consumption on rich diets. Our results highlight the critical importance of considering how food palatability and nutrient intake might be altered by dietary or drug manipulations in studies of aging and behavior.

SUBMITTER: Yamada R

PROVIDER: S-EPMC5233908 | biostudies-other | 2017 Feb

REPOSITORIES: biostudies-other

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Mifepristone Reduces Food Palatability and Affects Drosophila Feeding and Lifespan.

Yamada Ryuichi R Deshpande Sonali A SA Keebaugh Erin S ES Ehrlich Margaux R MR Soto Obando Alina A Ja William W WW

The journals of gerontology. Series A, Biological sciences and medical sciences 20160419 2

The Drosophila GeneSwitch system facilitates the spatial and temporal control of gene expression through dietary supplementation of mifepristone (RU486). Because experimental and control groups differ only by treatment with RU486, confounding results from using flies of different genetic backgrounds are eliminated, making GeneSwitch especially useful in studies of aging. However, the effect of RU486 itself on longevity has not been well characterized, particularly in relation to nutritional stat ...[more]

PMID: 27093874

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Project description: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.

Dataset Information

Mifepristone Reduces Food Palatability and Affects Drosophila Feeding and Lifespan.

Publications

Mifepristone Reduces Food Palatability and Affects Drosophila Feeding and Lifespan.

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