Limiting glucocorticoid secretion increases the anorexigenic property of Exendin-4
Objective: Glucagon-like peptide-1 (GLP-1) analogs are attractive options for the treatment of type II diabetes and obesity because of their incretin and anorexigenic effects. Peripheral administration of the GLP-1R agonist Exendin-4 (Ex-4) also increases glucocorticoid secretion in rodents and huma...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2016-07-01
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| Series: | Molecular Metabolism |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877816300321 |
| _version_ | 1828228382170546176 |
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| author | Shin J. Lee Katharina Diener Sharon Kaufman Jean-Philippe Krieger Klaus G. Pettersen Nino Jejelava Myrtha Arnold Alan G. Watts Wolfgang Langhans |
| author_facet | Shin J. Lee Katharina Diener Sharon Kaufman Jean-Philippe Krieger Klaus G. Pettersen Nino Jejelava Myrtha Arnold Alan G. Watts Wolfgang Langhans |
| author_sort | Shin J. Lee |
| collection | DOAJ |
| description | Objective: Glucagon-like peptide-1 (GLP-1) analogs are attractive options for the treatment of type II diabetes and obesity because of their incretin and anorexigenic effects. Peripheral administration of the GLP-1R agonist Exendin-4 (Ex-4) also increases glucocorticoid secretion in rodents and humans, but whether the released glucocorticoids interact with Ex-4's anorexigenic effect remains unclear. Methods: To test this, we used two experimental approaches that suppress corticosterone secretion and then assessed Ex-4 effects on eating in adult male rats. First, we combined acute and chronic low dose dexamethasone treatment with Ex-4. Second, we ablated hindbrain catecholamine neurons projecting to the hypothalamus with anti-dopamine-β-hydroxylase-saporin (DSAP) to block Ex-4-induced corticosterone secretion. Results: Combining dexamethasone and Ex-4 produced a larger acute anorexigenic effect than Ex-4 alone. Likewise, chronic dexamethasone and Ex-4 co-treatment produced a synergistic effect on eating and greater body weight loss in diet-induced obese rats than Ex-4 alone. DSAP lesions not only blunted Ex-4's ability to increase corticosterone secretion, but potentiated the anorexigenic effect of Ex-4, indicating that Ex-4-dependent corticosterone secretion opposes Ex-4's actions. Consistent with the enhancement of Ex-4's anorexigenic effect, DSAP lesion altered Ex-4-dependent changes in neuropeptide Y, preproglucagon, and corticotropin releasing hormone gene expression involved in glucocorticoid feedback. Conclusions: Our findings demonstrate that limiting glucocorticoid secretion and actions with low dose dexamethasone or DSAP lesion increases Ex-4's ability to reduce food intake and body weight. Novel glucocorticoid receptor based mechanisms, therefore, may help enhance GLP-1-based obesity therapies. Author Video: Author Video Watch what authors say about their articles Keywords: GLP-1, Exendin-4, Corticosterone, Anti-dopamine-β-hydroxylase-saporin, Hypothalamus, Neuropeptide Y |
| first_indexed | 2024-04-12T18:19:55Z |
| format | Article |
| id | doaj.art-a6c071dc906049c38d0b9863fc7803e0 |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-04-12T18:19:55Z |
| publishDate | 2016-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-a6c071dc906049c38d0b9863fc7803e02022-12-22T03:21:28ZengElsevierMolecular Metabolism2212-87782016-07-0157552565Limiting glucocorticoid secretion increases the anorexigenic property of Exendin-4Shin J. Lee0Katharina Diener1Sharon Kaufman2Jean-Philippe Krieger3Klaus G. Pettersen4Nino Jejelava5Myrtha Arnold6Alan G. Watts7Wolfgang Langhans8Physiology and Behavior Laboratory, ETH Zürich, 8603 Schwerzenbach, Switzerland; Corresponding author. Tel.: +41 44 655 7263.Physiology and Behavior Laboratory, ETH Zürich, 8603 Schwerzenbach, SwitzerlandPhysiology and Behavior Laboratory, ETH Zürich, 8603 Schwerzenbach, SwitzerlandPhysiology and Behavior Laboratory, ETH Zürich, 8603 Schwerzenbach, SwitzerlandPhysiology and Behavior Laboratory, ETH Zürich, 8603 Schwerzenbach, SwitzerlandPhysiology and Behavior Laboratory, ETH Zürich, 8603 Schwerzenbach, SwitzerlandPhysiology and Behavior Laboratory, ETH Zürich, 8603 Schwerzenbach, SwitzerlandDepartment of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USAPhysiology and Behavior Laboratory, ETH Zürich, 8603 Schwerzenbach, SwitzerlandObjective: Glucagon-like peptide-1 (GLP-1) analogs are attractive options for the treatment of type II diabetes and obesity because of their incretin and anorexigenic effects. Peripheral administration of the GLP-1R agonist Exendin-4 (Ex-4) also increases glucocorticoid secretion in rodents and humans, but whether the released glucocorticoids interact with Ex-4's anorexigenic effect remains unclear. Methods: To test this, we used two experimental approaches that suppress corticosterone secretion and then assessed Ex-4 effects on eating in adult male rats. First, we combined acute and chronic low dose dexamethasone treatment with Ex-4. Second, we ablated hindbrain catecholamine neurons projecting to the hypothalamus with anti-dopamine-β-hydroxylase-saporin (DSAP) to block Ex-4-induced corticosterone secretion. Results: Combining dexamethasone and Ex-4 produced a larger acute anorexigenic effect than Ex-4 alone. Likewise, chronic dexamethasone and Ex-4 co-treatment produced a synergistic effect on eating and greater body weight loss in diet-induced obese rats than Ex-4 alone. DSAP lesions not only blunted Ex-4's ability to increase corticosterone secretion, but potentiated the anorexigenic effect of Ex-4, indicating that Ex-4-dependent corticosterone secretion opposes Ex-4's actions. Consistent with the enhancement of Ex-4's anorexigenic effect, DSAP lesion altered Ex-4-dependent changes in neuropeptide Y, preproglucagon, and corticotropin releasing hormone gene expression involved in glucocorticoid feedback. Conclusions: Our findings demonstrate that limiting glucocorticoid secretion and actions with low dose dexamethasone or DSAP lesion increases Ex-4's ability to reduce food intake and body weight. Novel glucocorticoid receptor based mechanisms, therefore, may help enhance GLP-1-based obesity therapies. Author Video: Author Video Watch what authors say about their articles Keywords: GLP-1, Exendin-4, Corticosterone, Anti-dopamine-β-hydroxylase-saporin, Hypothalamus, Neuropeptide Yhttp://www.sciencedirect.com/science/article/pii/S2212877816300321 |
| spellingShingle | Shin J. Lee Katharina Diener Sharon Kaufman Jean-Philippe Krieger Klaus G. Pettersen Nino Jejelava Myrtha Arnold Alan G. Watts Wolfgang Langhans Limiting glucocorticoid secretion increases the anorexigenic property of Exendin-4 Molecular Metabolism |
| title | Limiting glucocorticoid secretion increases the anorexigenic property of Exendin-4 |
| title_full | Limiting glucocorticoid secretion increases the anorexigenic property of Exendin-4 |
| title_fullStr | Limiting glucocorticoid secretion increases the anorexigenic property of Exendin-4 |
| title_full_unstemmed | Limiting glucocorticoid secretion increases the anorexigenic property of Exendin-4 |
| title_short | Limiting glucocorticoid secretion increases the anorexigenic property of Exendin-4 |
| title_sort | limiting glucocorticoid secretion increases the anorexigenic property of exendin 4 |
| url | http://www.sciencedirect.com/science/article/pii/S2212877816300321 |
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