Dexamethasone-associated metabolic effects in male mice are partially caused by depletion of endogenous corticosterone

Abstract

Synthetic glucocorticoids are clinically used to treat auto-immune and inflammatory disease. Despite the high efficacy, glucocorticoid treatments causes side effects such as obesity and insulin resistance in many patients. Via their pharmacological target, the glucocorticoid receptor (GR), glucocorticoids suppress endogenous glucocorticoid secretion. Endogenous, but not synthetic, glucocorticoids activate the mineralocorticoid receptor (MR) and side effects of synthetic glucocorticoids may thus not only result from GR hyperactivation but also from MR hypoactivation. Here, we tested the hypothesis that reactivation of MR with corticosterone add-on treatment can attenuate the metabolic effects of the synthetic glucocorticoid dexamethasone. Male 8-week-old C57Bl/6J mice received a high-fat diet supplemented with dexamethasone or vehicle, and were subcutaneously implanted with low-dose corticosterone- or vehicle-containing pellets. Dexamethasone strongly reduced body weight and fat mass gain, while corticosterone add-on partially normalized this. Dexamethasone-induced hyperglycemia and hyperinsulinemia were exacerbated by corticosterone add-on, which was prevented by MR antagonism. In subcutaneous white adipose tissue, corticosterone add-on prevented the dexamethasone-induced expression of intracellular lipolysis genes. In brown adipose tissue, dexamethasone also upregulated gene expression of brown adipose tissue identity markers, lipid transporters and lipolysis enzymes, which was prevented by corticosterone add-on. In conclusion, corticosterone add-on treatment prevents several, while exacerbating other metabolic effects of dexamethasone. While the exact role of MR remains elusive, this study suggests that corticosterone suppression by dexamethasone contributes to its effects in mice.

Modulation of the dynamics and cellularity of adipose tissues in different fat depots in broilers by dietary dexamethasone

“…Such a dose-related outcome is possibly connected to lipolysis resulting from prolonged treatment with a high dose of DEX [ 32 , 33 ]. A similar observation was reported in the rat model, where a significant reduction in fat mass gain in response to DEX treatment [ 31 ]. Prolonged treatment with DEX increases the expression of the lipolytic genes in the fat depots, which justifies the current study findings [ 31 ].…”

“…A similar observation was reported in the rat model, where a significant reduction in fat mass gain in response to DEX treatment [ 31 ]. Prolonged treatment with DEX increases the expression of the lipolytic genes in the fat depots, which justifies the current study findings [ 31 ]. In this study, we noticed the tendency of fat accumulation toward the abdominal region of the broiler, which agrees with the previous report [ 25 ].…”

“…The increased deposition of body fat mostly happens in the liver of both human and avian species, and the insulin resistance resulting from the prolonged DEX therapy might be a potential reason for the increased deposition of body fat [ 16 ]. However, DEX’s effects are primarily determined by its dose and the type of fat depot [ 30 , 31 ]. The fat depot weight was much lower in the groups that received high DEX doses, indicating that DEX has a dose-dependent effect on fat accumulation.…”

“…GCs like DEX are frequently prescribed for treating different diseases in humans [ 36 ]. However, excess exposure to GC leads to augmented lipid accumulation in the visceral fat depots connected to insulin resistance, obesity, cardiovascular disorders, and different metabolic dysfunctions in either sex [ 31 , 37 ]. Therefore, the current findings might give a deep insight into the multi-dimensional relationship between the DEX dose, duration of DEX treatment, and fat depot weight as well as adipocyte cellularity.…”