Background Glucocorticoids regulate pivotal processes such as metabolism and inflammation via the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). Here we investigated the relative contribution of MR in the regulation of metabolism. To this end, we used synthetic glucocorticoid dexamethasone, which strongly binds to GR but not MR.  This completely suppresses endogenous glucocorticoid production thereby depleting MR signalling. To reactivate MR, a low dose of corticosterone was administered as add-on therapy to DEX treatment.
Materials and methods Male C57BL/6J mice received a high-fat diet (HFD) in combination with 10% fructose water for 24 days. Dexamethasone (DEX, 1 mg/kg/day) was administered via diet-supplementation and corticosterone via subcutaneous implantation of slow-release pellets. Body weight and composition were measured weekly. To investigate peripheral triglyceride uptake, mice were intravenously injected with glycerol tri[³H]oleate-labelled lipoprotein-like emulsion particles and tissues were collected for measurement of ³H-activity, histological analysis and RT-qPCR analysis.
Results DEX fully prevented HFD-induced body weight gain, which was partially rescued by CORT add-on therapy. DEX with or without CORT add-on therapy similarly increased the uptake of lipoprotein-derived triglycerides in brown adipose tissue (BAT). Interestingly, DEX increased BAT tissue weight and intracellular lipid droplet size stronger than DEX with CORT add-on therapy. In line with this, DEX upregulated expression of BAT marker genes (Prdm16, Pgc1α, Ap2), lipid transporters (Cd36, Lpl) and rate-limiting lipolysis enzyme Atgl, while this was (partially) lost upon CORT add-on therapy.
Conclusion Our data suggest that MR depletion in the context of high GR via DEX treatment leads to weight loss, partially caused by increased BAT activity. MR reactivation via CORT add-on therapy partially counteracts this. Where MRs act to counteract GR-mediated metabolic effects is for now unknown.