Mifepristone Improves Adipose Tissue Insulin Sensitivity in Insulin Resistant Individuals

Gubbi, Sriram; Muniyappa, Ranganath; Sharma, Susmeeta T.; Grewal, Shivraj; McGlotten, Raven; Nieman, Lynnette K.

doi:10.1210/clinem/dgab046

Cited by 17 publications

(13 citation statements)

References 60 publications

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“…The ability of mifepristone to increase life span of virgin females on HFD reported here further extends the similarities between mifepristone effects in flies and mammals. Mifepristone improved insulin sensitivity and adiponectin levels in mice fed a HFD ( Hashimoto et al, 2013 ), and mifepristone is reported to have anti-diabetes and anti-obesity effects in humans and mice ( Gross et al, 2010 ; Bernal-Sore et al, 2018 ; Diaz-Castro et al, 2020 ; Gubbi et al, 2021 ). The female sex-specificity of mifepristone life span effects in Drosophila , and the implication of midgut as a relevant target, also suggests some similarities to human health.…”

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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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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“…More recently, mifepristone has become of additional interest due to its anti-cancer, anti-obesity, and anti-diabetes effects in human and rodent models [ 3–5 ]. For example, short-term inhibition of the GR with mifepristone was reported to improve insulin sensitivity in overweight and pre-diabetic subjects [ 5 ]. Mifepristone is also a mammalian PPARγ agonist that activates expression of PPARγ target genes [ 6 , 7 ].…”

Section: Introductionmentioning

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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“…Mifepristone is a drug with a long record of safe use in humans for birth control and for the treatment of Cushing's disease, and it has recently become of additional interest because of its anticancer, antiobesity, and antidiabetic effects (Gubbi et al, 2021;Llaguno-Munive et al, 2021). Mifepristone also shows beneficial metabolic effects in female Drosophila, including decreased lipid levels and increased life span on normal and high-fat diets (Landis et al, 2021a;Landis et al, 2021b).…”

Section: Discussionmentioning

confidence: 99%

“…Mifepristone also shows promising results in the treatment of depression (Block et al, 2018). Several studies report antiobesity and antidiabetic effects of mifepristone in humans and mice (Gross et al, 2010;Bernal-Sore et al, 2018;Gubbi et al, 2021). For example, mifepristone improved insulin sensitivity and adiponectin levels in mice fed with a high-fat diet and caused adiponectin release from cultured adipocytes that was dependent upon PPARγ (Hashimoto et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Mifepristone Increases Life Span in Female Drosophila Without Detectable Antibacterial Activity

et al. 2022

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Mifepristone dramatically increases the life span of mated female Drosophila while reducing the expression of innate immune response genes. Previous results indicated that mifepristone also reduced the load of aero-tolerant bacteria in mated females. Experiments were conducted to further investigate the possible role of bacteria in mifepristone life span effects. Life span was assayed in flies grown from sterilized eggs on autoclaved media and in normally cultured controls in two independent assays. Sterilization increased mated female life span (+8.3% and +57%, respectively), and the effect of mifepristone was additive (+53% and +93%, respectively). High-throughput sequencing of 16S sequences revealed that sterilization reduced the abundance of multiple species and the classes Bacteroidia, Bacilli, Actinobacteria, and Cytophagia. By contrast, mifepristone caused no decreases and instead increased the abundance of three species. Five aero-tolerant bacterial species were cultured from extracts of mated female flies, including both Gram-positive and Gram-negative species (Acetobacter sicerae, Enterococcus faecalis, Lactobacillus plantarum, Serratia rubidea, and Paenibacillus glucanolyticus). There was no detectable effect of mifepristone on the growth of these bacteria in vitro, indicating that mifepristone does not have a direct antibiotic effect. To test if antibiotics could mimic the effects of mifepristone in vivo, mated female flies were treated throughout adult life span with high concentrations of the individual antibiotics doxycycline, ampicillin, kanamycin, and streptomycin, in replicate experiments. No significant effect on life span was observed for ampicillin, kanamycin, or streptomycin, and an inconsistent benefit was observed for doxycycline. Finally, supplementation of media with Enterococcus faecalis did not alter adult female life span in the presence or absence of mifepristone. Taken together, the results indicate the life span benefits of mifepristone are not due to an antibiotic effect.

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Mifepristone Improves Adipose Tissue Insulin Sensitivity in Insulin Resistant Individuals

Cited by 17 publications

References 60 publications

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

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

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

Mifepristone Increases Life Span in Female Drosophila Without Detectable Antibacterial Activity

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