Endocrine Abstracts

Drospirenone (DRSP) is a potent antimineralocorticoid with progestative and moderate antiandrogenic properties. We have previously shown that DRSP exerts a potent antiadipogenic activity in murine and human preadipocytes through specific antagonism of the MR. In the present study responses to DRSP were investigated in a model of diet-induced obesity for 12 weeks. Female 10-week-old C57bl6 mice were fed with normal chow or a high fat diet (HF, containing 45% fat by calories). Mice were concomitantly treated for 12 weeks with either vehicle, DRSP (3 and 30 mg/kg per day) or the MR antagonist Potassium Canrenoate (kCan 20 mg/kg per day). Glucose tolerance tests were performed after 3 and 12 weeks of treatment. High levels of MR mRNA were detected in all examined depots of adipose tissue. Mice fed HF showed significantly increased body weight and fat mass, increased expression of MCP-1 and adipogenic markers and a reduced glucose tolerance. DRSP (3 mg/kg per day) significantly improved glucose tolerance and reduced gonadal, renal and subcutaneous fat mass in mice fed HF; similar responses were observed with KCan, though to a lesser extent. Importantly, DRSP reversed HF-induced up-regulation of leptin, LPL, AcetilCoA and MCP-1 mRNA expression. HF diet-induced increase in adipocyte size was also completely reversed by DRSP, and to a lesser extent by kCan. Finally, DRSP induced the appearance of paucilocular UCP1 positive adipocytes in gonadal and subcutaneous adipose tissue of mice fed HF.

In conclusion, we show that DRSP can reverse adipocyte dysfunction induced by HF in an MR-dependent manner. Finally, DRSP treatment caused a dramatic morphological switch of white to brown adipocytes. This could explain the improvement in the metabolic profile of treated mice, suggesting a novel role for MR in controlling fat metabolism and white to brown transdifferentiation. MR blockade therefore has promise as a novel therapeutic option for the prevention of metabolic syndrome.

Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.

Funding: This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.