Abstract
Background:
We have previously shown that antagonism of the mineralocorticoid receptor (MR) results in a potent antiadipogenic activity, in vitro and in vivo. Excessive glucocorticoid exposure is associated with obesity and related disorders in humans and mice.
Methods:
In this study, responses to a novel combined glucocorticoid receptor (GR)/MR antagonist were investigated in a model of diet-induced obesity. Female 10-week-old C57BL/6J mice were fed with normal chow or a high-fat diet (HFD) for 9 weeks. Mice fed a HFD were concomitantly treated for 9 weeks with the GR antagonist mifepristone (80 mg kg−1 per day) or the novel combined GR/MR antagonist CORT118335 (80 mg kg−1 per day). Male, juvenile 6-week-old C57BL/6J mice fed HFD were treated with CORT118335 for 4 weeks.
Results:
Mice fed a HFD showed a significant increase in total body weight and white fat mass, with impaired glucose tolerance and increased fat infiltration in livers. Interestingly, only CORT118335 completely prevented the HFD-induced weight gain and white fat deposition, whereas mifepristone showed no effect on body weight and modestly increased subcutaneous fat mass. Importantly, food intake was not affected by either treatment, and CORT118335 dramatically increased PGC-1α protein expression in adipose tissue, without any effect on UCP1. Both CORT118335 and mifepristone produced metabolic benefit, improving glucose tolerance, increasing adiponectin plasma levels, decreasing leptin and reducing mean adipocyte size. When tested in vitro, CORT118335 markedly reduced 3T3-L1 differentiation and reversed MR-mediated pro-adipogenic effects of aldosterone; differently, GR-mediated effects of dexamethasone were not antagonized by CORT118335, suggesting that it mostly acts as an antagonist of MR in cultured preadipocytes.
Conclusions:
Combined GR/MR pharmacological antagonism markedly reduced HFD-driven weight gain and fat mass expansion in mice through the increase in adipose PGC-1α, suggesting that both receptors represent strategic therapeutic targets to fight obesity. The effects of CORT118335 in adipocytes seem predominantly mediated by MR antagonism.
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Acknowledgements
We thank Dr Raffaella Pecci and Dr Rossella Bedini for precious technical assistance, Prof Silvia Migliaccio and Prof Paolo Bianco for scientific support. This work was supported by a grant from Ministero della Salute (BANDO 2011-2012 Progetti Collaborazione Ricercatori Italiani all’Estero; project grant PE-2011-02347070 to MC), and from Corcept Therapeutics. This work was presented, in part, at the COST-ADMIRE Annual Meeting, Padua, Italy, 16th–17th October 2014. We would like to acknowledge networking support by the COST Action ADMIRE BM1301. This work is dedicated to the memory of Prof Paolo Bianco, outstanding scientist, shining example of dedication to work and freedom of thought.
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Dr Hazel Hunt is employed by CORCEPT Therapeutics, which developed and provided CORT118335 and mifepristone for the experiments. All the other authors declare no conflict of interest.
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Mammi, C., Marzolla, V., Armani, A. et al. A novel combined glucocorticoid-mineralocorticoid receptor selective modulator markedly prevents weight gain and fat mass expansion in mice fed a high-fat diet. Int J Obes 40, 964–972 (2016). https://doi.org/10.1038/ijo.2016.13
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DOI: https://doi.org/10.1038/ijo.2016.13
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