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The effects of combined glucocorticoid/mineralocorticoid receptor modulation (CORT118335) on energy balance, adiposity, and lipid metabolism in male rats.

Psychological stress and excess glucocorticoids are associated with metabolic and cardiovascular diseases. Glucocorticoids primarily act through mineralocorticoid (MR) and glucocorticoid receptors (GR), and compounds modulating these receptors show promise in mitigating metabolic and cardiovascular-related phenotypes. CORT118335 (GR/MR modulator) prevents high fat diet-induced weight gain and adiposity in mice, but the ability of this compound to reverse obesity-related symptoms is unknown. Adult male rats were subcutaneously administered CORT118335 (3mg/kg, 10mg/kg, or 30mg/kg) or vehicle once daily. A five-day treatment with CORT118335 at 30mg/kg induced weight loss on a chow diet by decreasing food intake. However, lower doses of the compound attenuated body weight gain primarily due to decreased calorific efficiency, as there were no significant differences in food intake compared to vehicle. Notably, the body weight effects of CORT118335 persisted during a 2-week treatment hiatus, suggesting prolonged effects of the compound. To our knowledge, we are the first to demonstrate a sustained effect of combined GR/MR modulation on body weight gain. These findings suggest that CORT118335 may have long-lasting effects, likely due to GR/MR-induced transcriptional changes. Prolonged (18-days) treatment of CORT118335 (10mg/kg) reversed body weight gain and adiposity in animals fed a high fat diet for 13 weeks. Surprisingly, this occurred despite a worsening of the lipid profile and glucose homeostasis, as well as a disrupted diurnal corticosterone rhythm, suggesting GR agonistic effects in the periphery. We conclude that species and tissue specific targeting may result in promising leads for exploiting the metabolically beneficial aspects of GR/MR modulation.