Dexamethasone Administration in Mice Leads to Less Body Weight Gain over Time, Lower Serum Glucose, and Higher Insulin Levels Independently of NRF2
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 patholog...
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| Format: | Article |
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MDPI AG
2021-12-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/11/1/4 |
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| author | Fotini Filippopoulou George I. Habeos Vagelis Rinotas Antonia Sophocleous Gerasimos P. Sykiotis Eleni Douni Dionysios V. Chartoumpekis |
| author_facet | Fotini Filippopoulou George I. Habeos Vagelis Rinotas Antonia Sophocleous Gerasimos P. Sykiotis Eleni Douni Dionysios V. Chartoumpekis |
| author_sort | Fotini Filippopoulou |
| collection | DOAJ |
| description | 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 <i>Nrf2</i> knockout (<i>Nrf2</i>KO) 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 <i>Nrf2</i>KO 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. |
| first_indexed | 2024-03-10T03:02:11Z |
| format | Article |
| id | doaj.art-d40adf3d64a6491e988829598f21ac1a |
| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-10T03:02:11Z |
| publishDate | 2021-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-d40adf3d64a6491e988829598f21ac1a2023-11-23T12:45:48ZengMDPI AGAntioxidants2076-39212021-12-01111410.3390/antiox11010004Dexamethasone Administration in Mice Leads to Less Body Weight Gain over Time, Lower Serum Glucose, and Higher Insulin Levels Independently of NRF2Fotini Filippopoulou0George I. Habeos1Vagelis Rinotas2Antonia Sophocleous3Gerasimos P. Sykiotis4Eleni Douni5Dionysios V. Chartoumpekis6Division of Endocrinology, Department of Internal Medicine, School of Medicine, University of Patras, 26504 Patras, GreeceDivision of Endocrinology, Department of Internal Medicine, School of Medicine, University of Patras, 26504 Patras, GreeceLaboratory of Genetics, Department of Biotechnology, Agricultural University of Athens, 11855 Athens, GreeceDepartment of Life Sciences, School of Sciences, European University Cyprus, Nicosia 2404, CyprusService of Endocrinology, Diabetology and Metabolism, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, SwitzerlandLaboratory of Genetics, Department of Biotechnology, Agricultural University of Athens, 11855 Athens, GreeceDivision of Endocrinology, Department of Internal Medicine, School of Medicine, University of Patras, 26504 Patras, GreeceGlucocorticoids 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 <i>Nrf2</i> knockout (<i>Nrf2</i>KO) 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 <i>Nrf2</i>KO 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.https://www.mdpi.com/2076-3921/11/1/4KEAP1diabetesglucocorticoidsosteoporosisinsulin resistancegluconeogenesis |
| spellingShingle | Fotini Filippopoulou George I. Habeos Vagelis Rinotas Antonia Sophocleous Gerasimos P. Sykiotis Eleni Douni Dionysios V. Chartoumpekis Dexamethasone Administration in Mice Leads to Less Body Weight Gain over Time, Lower Serum Glucose, and Higher Insulin Levels Independently of NRF2 Antioxidants KEAP1 diabetes glucocorticoids osteoporosis insulin resistance gluconeogenesis |
| title | Dexamethasone Administration in Mice Leads to Less Body Weight Gain over Time, Lower Serum Glucose, and Higher Insulin Levels Independently of NRF2 |
| title_full | Dexamethasone Administration in Mice Leads to Less Body Weight Gain over Time, Lower Serum Glucose, and Higher Insulin Levels Independently of NRF2 |
| title_fullStr | Dexamethasone Administration in Mice Leads to Less Body Weight Gain over Time, Lower Serum Glucose, and Higher Insulin Levels Independently of NRF2 |
| title_full_unstemmed | Dexamethasone Administration in Mice Leads to Less Body Weight Gain over Time, Lower Serum Glucose, and Higher Insulin Levels Independently of NRF2 |
| title_short | Dexamethasone Administration in Mice Leads to Less Body Weight Gain over Time, Lower Serum Glucose, and Higher Insulin Levels Independently of NRF2 |
| title_sort | dexamethasone administration in mice leads to less body weight gain over time lower serum glucose and higher insulin levels independently of nrf2 |
| topic | KEAP1 diabetes glucocorticoids osteoporosis insulin resistance gluconeogenesis |
| url | https://www.mdpi.com/2076-3921/11/1/4 |
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