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A growing body of research indicates that cortisol, the glucocorticoid product of the activation of the hypothalamic-pituitary-adrenal axis, plays a role in the pathophysiology of metabolic syndrome. In this regard, chronic exposure to cortisol is associated with risk factors related to metabolic syndrome like weight gain, type 2 diabetes, hypertension, among others. Mifepristone also have been shown positive effects in rodents models of diabetes and patients with obesity due to antipsychotic treatment. However, the underlying molecular mechanisms are not fully understood. In this perspective, we summarized the literature regarding the beneficial effects of mifepristone in metabolic syndrome from animal studies to clinical research. Also, we propose a potential mechanism for the beneficial effects in insulin sensitivity which involved the regulation of mitochondrial function in muscle cells. This drug is a synthetic hormone with antiprogestogen receptor blocker and glucocorticoid receptor GR antagonism activity. However, their first and most common use is as an emergency contraceptive or abortion-inducing pill during the first month of pregnancy Rodger and Baird, ; Silvestre et al. Mifepristone had also demonstrated to display antiproliferative and antimetastasis effects in several cancer cell lines such as breast, endometrium, cervix, prostate, gastrointestinal tract, brain, bone, and ovary Chen et al. Regarding the antiglucocorticoid properties, mifepristone has three and 10 times higher relative binding affinity for the GR than dexamethasone and cortisol, respectively Castinetti et al. Due to the several effects caused by chronic glucocorticoids exposure, mifepristone is being investigated as a potential therapeutic drug for the treatment of psychiatric disorders such as psychotic depression, alcohol and cocaine dependence, schizophrenia, and bipolar disorder Howland, Due to the favorable results found in glycaemia control in these patients, the U. Moreover, since to date several studies in rodents and humans with metabolic syndrome had shown beneficial effects of mifepristone see Table 1. Despite the accumulative evidence, little is known about the mechanisms involved in the hypoglycemic effects of mifepristone. This deregulation may be produced by endogenous or exogenous factors. The less common is the endogenous CS, which is usually caused by a tumor that produces an excess of cortisol or ACTH depending on its anatomical location adrenal or pituitary gland Allolio and Fassnacht, The most common cause for CS is the treatment with exogenous glucocorticoids, such as prednisone, for asthma, rheumatoid arthritis, and immunosuppression organ transplantation Lacroix et al. This study enrolled 50 patients for 24 weeks with endogenous CS. Before that, other works reported benefits of mifepristone use in patients with CS. In , Neiman et al. The patient improved somatic features as buffalo hump, central obesity and moon face, and sensitive glucocorticoid parameters such as fasting blood glucose Nieman et al. Other cases of patients with CS treated with mifepristone have been summarized in a previous retrospective study. The authors concluded that treatment with mifepristone produced a reduction in signs of hypercortisolism, half-reduced blood pressure and half of the patients with diabetes improved blood glucose levels Castinetti et al. In this report, the weight loss achieved during the treatment of week in SEISMIC, persisted for two additional years in patients who remained on therapy Fein et al. In addition, to the beneficial effects on glycaemia control in patients with CS, several works have reported beneficial effects of mifepristone in metabolic syndrome see Table 1. The metabolic syndrome is a group of physiologic, biochemical and metabolic factors that lead to increased risk for type 2 diabetes, stroke and cardiovascular diseases Eckel et al. These factors visceral obesity, dyslipidemia, hyperglycemia and hypertension are associated with changes in lifestyle, mainly in dietary preferences and sedentary behavior Dalle Grave et al. Insulin resistance is a major underlying mechanism of metabolic syndrome, which affects different organs such as the brain, liver, pancreas, vascular endothelium, adipose tissue, heart and skeletal muscle, which contribute to development of metabolic syndrome Guo, People with metabolic syndrome may have abnormal levels of cortisol, as in Cushing patients, but without developing CS Pasquali and Vicennati, Whereby the deregulation of cortisol action could have an important role in the development of metabolic syndrome, but this is still uncertain Paredes and Ribeiro, Mifepristone, being the only antiglucocorticoid drug clinically available, has been used to investigate this hypothesis and has promise as a potential insulin sensitizer see Table 1. In , Kusunoki et al. Moreover, mifepristone enhances insulin-dependent glucose uptake, improving insulin sensitivity in obese animals Hashimoto et al. Moreover, mifepristone ameliorates obesity and metabolic perturbations in patients with antipsychotic medication Gross et al. All of these reports pointed that mifepristone could be useful in the treatment of metabolic syndrome not associated with CS, however the mechanisms of the beneficial action of mifepristone in metabolic syndrome are far from being elucidated. Skeletal muscle insulin response is one of the mayor processes altered in metabolic syndrome, thus leading to high plasmatic levels of glucose and insulin resistance Guo, In this regard, we recently reported a potential mechanism the beneficial effects of mifepristone associated with skeletal muscle physiology. We demonstrated that mifepristone increases insulin-dependent glucose uptake through a mitochondrial-AMPK pathway Bernal-Sore et al. Mitochondrial function and response to stimuli are highly dependent on their structure and dynamics. Mitochondria can modulate their morphology in response to stressors to create an elongated mitochondrial network or fragmented mitochondria depending on energy demands Eisner et al. Mitochondrial dysfunction has gained attention as an important player in the development of type 2 diabetes, obesity, dyslipidemia, and cardiovascular diseases. Excess in ROS production or nutrient supply led to a decrease of mitochondrial protein levels, changes in substrate oxidation and modifications on the shape and size of the mitochondria Joseph et al. In addition, changes on the expression of mitochondrial dynamics related proteins in type 2 diabetes have been reported, particularly a downregulation of MFN2 and an increase on DRP1, favoring mitochondrial fission Joseph et al. Our recent research demonstrated that mifepristone enhances insulin-stimulated glucose uptake on L6 skeletal muscle cells through a mechanism that reduces oxygen consumption, ROS levels and ATP production, promoting AMPK activation Bernal-Sore et al. The activation of AMPK, subsequent to the decrease of ATP production, has been previously documented as a possible mechanism of several compounds that promote insulin sensitivity Smith and Steinberg, These compounds include berberine, a herb-derived drug widely used in China for the treatment of type 2 diabetes Yin et al. In the case of mifepristone, the mechanism associated with the regulation of mitochondrial function is not yet elucidated. To gain insight into how mifepristone affects mitochondrial function, we evaluated the changes in mitochondrial morphology. Confocal images stack of the mitochondrial network were captured with a Nikon C2 Confocal microscope. The number and volume of individual mitochondria were quantified using ImageJ software NIH as described previously del Campo et al. Our results show that mifepristone induces an increase in the number and a decrease in the volume of mitochondria at 6 and 24 h of treatment when compared to control cells, which determine a fragmented phenotype Figure 1A. These results suggest that mifepristone regulates mitochondrial morphology toward a fragmented state, which correlates with the decrease in mitochondrial function that we previously reported Bernal-Sore et al. Fusion and fission processes are part of the mitochondria life cycle, which allow the mitochondria to respond to cell stressors adapting ATP production efficiency Liesa and Shirihai, To further elucidate whether changes in mitochondrial morphology correlate with mitochondrial function, we examined the modification in OXPHOS proteins levels. Our results show that mifepristone reduces the protein levels of mitochondrial respiratory chain complexes III and V Figure 1B. However, how mifepristone is affecting mitochondria is still unknown, the aforementioned results point this could be through a direct effect on mitochondria, just as metformin or resveratrol, without discarding the effects of its antagonist activity over the GR. Regarding the latter, it is known that glucocorticoids regulate mitochondrial RNA synthesis Mansour and Nass, The above, open the possibility that mifepristone may regulate mitochondrial function through the control of mitochondrial gene expression. Figure 1 Mifepristone targets mitochondria. A Time course of mifepristone on mitochondrial morphology. Cells were incubated with mifepristone 10 uM at indicated times and then loaded with MitoTracker Orange. Multislice imaging reconstitution was obtained by confocal microscopy. The individual mitochondrial volume and number of mitochondria per cell were determined. The beneficial effects of mifepristone in the control of glycaemia in patients with CS had been proven. In addition, several clinical and basic research works have reported its potential use as an insulin sensitizer in different models of metabolic syndrome Table 1. However, the mechanisms of these beneficial effects are not completely elucidated. Here, we propose a new perspective to explore the mechanism of mifepristone-induced insulin sensitization based on the regulation of OXPHOS and mitochondrial dynamics, which could explain the reduction in ATP levels and the activation of AMPK. In this regard, mifepristone improves glycemic control through the regulation of mitochondrial function in skeletal muscle, but its feasible to propose that mifepristone also could control insulin resistance in other organs. Moreover, in patients with CS mifepristone decreases body weight, fasting glucose and blood pressure which suggests that other tissues, like brain, liver and endothelium could be involved in the beneficial effects of mifepristone Fleseriu et al. It is important to note, that the consequences of mifepristone in glycemic control are similar to approved drug for diabetes such as pioglitazone and metformin, which mechanism of action also is related in regulation of AMPK activity and mitochondrial function, but mifepristone may have a subtly different mechanism of action or side-effects profile that could be helpful in pool of patients with different base pathology, risk factors or response to treatment. Nonetheless, the first use of mifepristone was as a contraceptive drug. Therefore, the use of this drug should be restricted in some populations, including pregnant women and women who wish to get pregnant. Furthermore, effects in fertility and endocrine system after a short and long-term treatment should be studied to determine the potential patients of this drug and thus be able to determine the potential advantages of mifepristone or mifepristone-derived drugs over currently available treatments for metabolic disorders. The datasets generated for this study are available on request to the corresponding author. FD-C performed experiments, data analysis, and contributed to the manuscript writing. LR and AC designed experiments and contributed to the manuscript writing. RT outlined the manuscript, overviewed the experiments, analyzed data, and wrote the manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Allolio, B. Clinical review: Adrenocortical carcinoma: clinical update. Bernal-Sore, I. Mifepristone enhances insulin-stimulated Akt phosphorylation and glucose uptake in skeletal muscle cells. Cell Endocrinol. Brunmair, B. Thiazolidinediones, like metformin, inhibit respiratory complex I: a common mechanism contributing to their antidiabetic actions? Diabetes 53, — Castinetti, F. Neuroendocrinology 92 Suppl 1, — Diabetes Obes. Chen, J. The unique pharmacological characteristics of mifepristone RU : from terminating pregnancy to preventing cancer metastasis. Dalle Grave, R. Lifestyle modification in the management of the metabolic syndrome: achievements and challenges. Diabetes Metab. Eckel, R. The metabolic syndrome. Lancet , — Eisner, V. Mitochondrial dynamics in adaptive and maladaptive cellular stress responses. Cell Biol. Fein, H. BMC Endocr. Finkel, T. The Krebs cycle meets the cell cycle: mitochondria and the G1-S transition. Fleseriu, M. Gettys, T. Goldenthal, M. Cell Biochem. Gross, C. Mifepristone treatment of olanzapine-induced weight gain in healthy men. Mifepristone reduces weight gain and improves metabolic abnormalities associated with risperidone treatment in normal men. Silver Spring 18, — Guo, S. Insulin signaling, resistance, and the metabolic syndrome: insights from mouse models into disease mechanisms. Hashimoto, T. Mifepristone promotes adiponectin production and improves insulin sensitivity in a mouse model of diet-induced-obesity. PloS One 8, e Howland, R. Mifepristone as a therapeutic agent in psychiatry. Health Serv. Joseph, A. Mitochondrial dysregulation in the pathogenesis of diabetes: potential for mitochondrial biogenesis-mediated interventions. Diabetes Res. Kusunoki, M. Amelioration of high-fat feeding-induced insulin resistance in skeletal muscle with the antiglucocorticoid RU Diabetes 44, — Lacroix, A. Liesa, M. Mitochondrial dynamics in the regulation of nutrient utilization and energy expenditure. Cell Metab. Mansour, A. In vivo cortisol action on RNA synthesis in rat liver nuclei and mitochondria. Nature , — Martineau, L. Large enhancement of skeletal muscle cell glucose uptake and suppression of hepatocyte glucosephosphatase activity by weak uncouplers of oxidative phosphorylation. Acta , — Newell-Price, J. Nieman, L. Nikolic, I. The role of endogenous glucocorticoids in glucose metabolism and immune status of MIF-deficient mice. Orrenius, S. Mitochondrial oxidative stress: implications for cell death. Otto Buczkowska, E. Przemiany Mater. Wieku Rozw 9, 93— Paredes, S. Cortisol: the villain in metabolic syndrome? Bras 60, 84— Pasquali, R. The abdominal obesity phenotype and insulin resistance are associated with abnormalities of the hypothalamic-pituitary-adrenal axis in humans. Priyadarshini, E. Diabetes 41, 41— Psarra, A. Glucocorticoids induce mitochondrial gene transcription in HepG2 cells: role of the mitochondrial glucocorticoid receptor. Ramamoorthy, S. Maghnie, M. Basel: S. Rodger, M. Induction of therapeutic abortion in early pregnancy with mifepristone in combination with prostaglandin pessary. Lancet 2, — Mechanisms involved in the side effects of glucocorticoids. Trends Mol. Senior, A. ATP synthesis by oxidative phosphorylation. Silvestre, L. Voluntary interruption of pregnancy with mifepristone RU and a prostaglandin analogue. A large-scale French experience. Smith, B. AMP-activated protein kinase, fatty acid metabolism, and insulin sensitivity. Care 20, — Spitz, I. Mifepristone: where do we come from and where are we going? Clinical development over a quarter of a century. Contraception 82, — Taylor, A. Effect of RU on hepatic and adipocyte gene expression improves diabetes control in obesity-type 2 diabetes. Stoffwechselforschung Hom. Toyama, E. AMP-activated protein kinase mediates mitochondrial fission in response to energy stress. Science , — Identification of a selective glucocorticoid receptor modulator that prevents both diet-induced obesity and inflammation. Xiong, S. Mitochondria-mediated apoptosis in mammals. Protein Cell 5, — Yin, J. Berberine improves glucose metabolism through induction of glycolysis. Zang, M. Polyphenols stimulate AMP-activated protein kinase, lower lipids, and inhibit accelerated atherosclerosis in diabetic LDL receptor-deficient mice. Diabetes 55, — The use, distribution or reproduction in other forums is permitted, provided the original author s and the copyright owner s are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. Top bar navigation. About us About us. Sections Sections. About journal About journal. Article types Author guidelines Editor guidelines Publishing fees Submission checklist Contact editorial office. Table 1 Mifepristone effects in model of metabolic syndrome. Edited by: Gonzalo E. Yevenes , University of Concepcion, Chile.

Frontiers | Mifepristone for Treatment of Metabolic Syndrome: Beyond Cushing’s Syndrome

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Ovariectomized mice on a high fat diet represent a model of diet-induced obesity during estrogen deficiency. Here, we tested the hypothesis that sensitivity to centrally administered leptin in ovariectomized mice with diet-induced obesity could be restored by estrogen supplementation. Ovariectomized mice on a high fat diet developed extreme obesity and hyperleptinemia and moderate hyperinsulinemia compared to those on a standard diet. Notice: The text was changed in accordance with the erratum by January 21th, The correct values are: Year Archive Download PDF. Further Information Publication History received Also available at. Key words leptin - estrogen deficiency - obesity - adipokines. Google Scholar.

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