Glucocorticoids regulate pivotal processes such as metabolism and inflammation via the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). In the present study we investigated the metabolic role of MR by using the synthetic glucocorticoid dexamethasone (DEX). DEX strongly binds to GR, but not MR, and thereby completely suppresses endogenous glucocorticoid production and thereby depletes the MR of its ligand. To reactivate the MR, a low dose of corticosterone (CORT) can be used as add-on therapy. Male C57BL/6J mice received a high-fat diet (HFD) in combination with 10% fructose water for 24 days. DEX (1 mg/kg/day) or vehicle was administered via diet-supplementation and CORT or vehicle via subcutaneous implantation of slow-release pellets. DEX fully prevented HFD-induced body weight gain, which was partially rescued by CORT add-on therapy. In line with this, DEX but not DEX+CORT treatment reduced fat mass and white adipose tissue (WAT) weight. DEX induced the expression of rate-limiting lipolysis enzyme Atgl in WAT, which was diminished by CORT add-on therapy. To investigate the peripheral triglyceride uptake, mice were intravenously injected with glycerol tri[³H]oleate-labelled lipoprotein-like emulsion particles. 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 Atgl, while this was (partially) lost upon CORT add-on therapy. Our data suggest that MR depletion leads to weight loss, which may partially be caused by increased BAT activity and increased flux of fatty acids from the WAT towards other peripheral tissues. MR reactivation via CORT add-on therapy could partially counteracts these effects. It is currently unknown whether the adipose MRs mediate the observed effects, or whether brain MRs also play a role.