Chronic Dexamethasone Treatment Leads to Less Weight Gain and Ameliorated Glucose Tolerance in Mice; Role of the Cytoprotective Nrf2 Pathway

Introduction: Chronic glucocorticoid administration is necessary in a variety of conditions including but not limited to autoimmune, inflammatory and cancer-related diseases in order to relieve symptoms and sustain disease progression. However, there are adverse effects that include increase in glucose levels and others whose severity depends on the dose and duration of glucocorticoid exposure. It has been described that dexamethasone induces oxidative stress in cells by increasing reactive oxygen species (ROS) and this is one of the causes of insulin resistance at the cellular level. Nrf2 is a transcription factor which co-ordinates the antioxidant response and its activation has been shown to ameliorate insulin resistance in murine models. Hypothesis: We hypothesized that deletion of Nrf2 will lead to a more glucose intolerant insulin resistant phenotype in mice chronically treated with dexamethasone as cells would be exposed to higher ROS levels. Methods: To this end, 3-months old wild-type (WT) and Nrf2 knockout (KO) C57BL6J mice were treated intraperitoneally with 2 mg/kg dexamethasone or saline 3 times per week for 3 months. 5-10 mice were included per genotype per treatment and both male and female mice were used. Weekly measurements of body weights were performed and intraperitoneal glucose tolerance tests were done on the second and third month of treatment. Mice were sacrificed 24 hours after the last dose of dexamethasone and blood, white adipose tissue, soleus muscle and liver were collected for RNA preparation and quantitative RT-PCR analysis. Quantitative analysis of trabecular bone parameters was performed by micro-CT. Results: Both male and female mice treated with dexamethasone gained less weight over time and surprisingly were more glucose tolerant than the control group. Absence of Nrf2 did not seem to considerably affect the body weight but KO mice tended to have lower body weights after dexamethasone treatment in both genders with the effect on male mice being statistically significant (25% lower, p<0.05). Surprisingly, both WT and KO mice of both genders showed lower fasting blood glucose levels after 3 months of treatment and better glucose tolerance. Livers of KO mice showed lower levels (~50%) of the cytoprotective genes Nqo1 and Gclc as expected but no difference was observed after dexamethasone treatment. Sarcopenia muscle markers Mafbx1 and Murf1 showed no significant changes. Male mice showed increased expression of Pnpla3 in white adipose tissue indicating increased lipolysis upon dexamethasone exposure. Micro-CT showed minor changes in the bone parameters without difference between male WT and Nrf2KO mice. Conclusions: Dexamethasone unexpectedly led to better glucose tolerance and lower body weight which is uncommon in humans but it has been described previously in mouse models. More analyses are in progress to fully elucidate this phenotype.