Dexamethasone Administration in Mice Leads to Less Body Weight Gain over Time, Lower Serum Glucose, and Higher Insulin Levels Independently of NRF2.

Fotini Filippopoulou,Eleni Douni,Antonia Sophocleous,Dionysios V Chartoumpekis,George I Habeos,Gerasimos P Sykiotis,Vagelis Rinotas

doi:10.3390/antiox11010004

Abstract

Glucocorticoids are used widely on a long-term basis in autoimmune and inflammatory diseases. Their adverse effects include the development of hyperglycemia and osteoporosis, whose molecular mechanisms have been only partially studied in preclinical models. Both these glucocorticoid-induced pathologies have been shown to be mediated at least in part by oxidative stress. The transcription factor nuclear erythroid factor 2-like 2 (NRF2) is a central regulator of antioxidant and cytoprotective responses. Thus, we hypothesized that NRF2 may play a role in glucocorticoid-induced metabolic disease and osteoporosis. To this end, WT and Nrf2 knockout (Nrf2KO) mice of both genders were treated with 2 mg/kg dexamethasone or vehicle 3 times per week for 13 weeks. Dexamethasone treatment led to less weight gain during the treatment period without affecting food consumption, as well as to lower glucose levels and high insulin levels compared to vehicle-treated mice. Dexamethasone also reduced cortical bone volume and density. All these effects of dexamethasone were similar between male and female mice, as well as between WT and Nrf2KO mice. Hepatic NRF2 signaling and gluconeogenic gene expression were not affected by dexamethasone. A 2-day dexamethasone treatment was also sufficient to increase insulin levels without affecting body weight and glucose levels. Hence, dexamethasone induces hyperinsulinemia, which potentially leads to decreased glucose levels, as well as osteoporosis, both independently of NRF2.

Highlights

Chronic glucocorticoid administration is widely used in a variety of clinical settings, such as autoimmune and inflammatory diseases, with the purpose of symptomatic relief and prevention of disease progression
We examined the effect of dexamethasone on glucose metabolism and osteoporosis under a standard diet in two genotypes (WT and Nrf2 knockout (Nrf2KO))
We showed that chronic dexamethasone treatment in mice under a standard diet led to less body weight gain over time and, surprisingly, to lower glucose levels

Summary

Introduction

Chronic glucocorticoid administration is widely used in a variety of clinical settings, such as autoimmune and inflammatory diseases, with the purpose of symptomatic relief and prevention of disease progression. 1% of all adults and 3% of adults older than 50 in the USA receive glucocorticoids [1]. Such use is associated with several adverse effects that include diabetes [2] and osteoporosis [3], and whose severity depends on the dose and duration of glucocorticoid exposure. Diabetes has been linked to oxidative stress as increased reactive oxygen species (ROS) are found in the plasma and adipose tissue of diabetic subjects [4], and hyperglycemia itself has been shown to lead to increased oxidative stress [5]. Glucocorticoids have the potential to increase ROS generation and cause insulin resistance [6] and osteoporosis [7].

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Results

Conclusion