Hypoxia inducible factor-dependent upregulation of Agrp in glomus type I cells of the carotid body
Agouti-related peptide (AgRP) is a well-established potent orexigenic peptide primarily expressed in hypothalamic neurons. Nevertheless, the expression and functional significance of extrahypothalamic AgRP remain poorly understood. In this study, utilizing histological and molecular biology techniqu...
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Elsevier
2025-02-01
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| Series: | Molecular Metabolism |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S221287782500002X |
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| author | Luis Leon-Mercado Ivan Menendez-Montes Jonathan Tao Bandy Chen David P. Olson C. Mackaaij C.G.J. Cleypool Laurent Gautron |
| author_facet | Luis Leon-Mercado Ivan Menendez-Montes Jonathan Tao Bandy Chen David P. Olson C. Mackaaij C.G.J. Cleypool Laurent Gautron |
| author_sort | Luis Leon-Mercado |
| collection | DOAJ |
| description | Agouti-related peptide (AgRP) is a well-established potent orexigenic peptide primarily expressed in hypothalamic neurons. Nevertheless, the expression and functional significance of extrahypothalamic AgRP remain poorly understood. In this study, utilizing histological and molecular biology techniques, we have identified a significant expression of Agrp mRNA and AgRP peptide production in glomus type I cells within the mouse carotid body (CB). Furthermore, we have uncovered evidence supporting the expression of the AgRP receptor melanocortin receptor 3 (Mc3r) in adjacent sympathetic neurons, suggesting a potential local paracrine role for AgRP within the CB. Importantly, AgRP immunoreactivity was also identified in glomus type I cells of the human CB. Given the unexpected abundance of AgRP in glomus type I cells, a chemoreceptor cell specialized in oxygen sensing, we proceeded to investigate whether Agrp expression in the CB is regulated by hypoxemia and associated oxygen-sensing molecular mechanisms. In vitro luciferase assays reveal that hypoxia stimulates the human and mouse Agrp promoters in a Hypoxia Inducible Factor (HIF1/2)-dependent manner. Our in vivo experiments further demonstrate that exposure to environmental hypoxia (10%) robustly induces Agrp expression in type I glomus cells of mice. Furthermore, these findings collectively highlight the hitherto unknown source of AgRP in murine and human type I glomus cells and underscore the direct control of Agrp transcription by HIF signaling. |
| format | Article |
| id | doaj-art-8136909bf941442589237008c4460926 |
| institution | Kabale University |
| issn | 2212-8778 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj-art-8136909bf941442589237008c44609262025-02-01T04:11:59ZengElsevierMolecular Metabolism2212-87782025-02-0192102095Hypoxia inducible factor-dependent upregulation of Agrp in glomus type I cells of the carotid bodyLuis Leon-Mercado0Ivan Menendez-Montes1Jonathan Tao2Bandy Chen3David P. Olson4C. Mackaaij5C.G.J. Cleypool6Laurent Gautron7Center for Hypothalamic Research and Department of Internal medicine, UT Southwestern Medical Center, Dallas, TX, USADivision of Cardiology, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USACenter for Hypothalamic Research and Department of Internal medicine, UT Southwestern Medical Center, Dallas, TX, USACenter for Hypothalamic Research and Department of Internal medicine, UT Southwestern Medical Center, Dallas, TX, USADepartment of Pediatrics, University of Michigan Medical School, Ann Arbor, MI, USADivision of Surgical Specialties, Department of Anatomy, University Medical Center, Utrecht, the NetherlandsDivision of Surgical Specialties, Department of Anatomy, University Medical Center, Utrecht, the NetherlandsCenter for Hypothalamic Research and Department of Internal medicine, UT Southwestern Medical Center, Dallas, TX, USA; Corresponding author.Agouti-related peptide (AgRP) is a well-established potent orexigenic peptide primarily expressed in hypothalamic neurons. Nevertheless, the expression and functional significance of extrahypothalamic AgRP remain poorly understood. In this study, utilizing histological and molecular biology techniques, we have identified a significant expression of Agrp mRNA and AgRP peptide production in glomus type I cells within the mouse carotid body (CB). Furthermore, we have uncovered evidence supporting the expression of the AgRP receptor melanocortin receptor 3 (Mc3r) in adjacent sympathetic neurons, suggesting a potential local paracrine role for AgRP within the CB. Importantly, AgRP immunoreactivity was also identified in glomus type I cells of the human CB. Given the unexpected abundance of AgRP in glomus type I cells, a chemoreceptor cell specialized in oxygen sensing, we proceeded to investigate whether Agrp expression in the CB is regulated by hypoxemia and associated oxygen-sensing molecular mechanisms. In vitro luciferase assays reveal that hypoxia stimulates the human and mouse Agrp promoters in a Hypoxia Inducible Factor (HIF1/2)-dependent manner. Our in vivo experiments further demonstrate that exposure to environmental hypoxia (10%) robustly induces Agrp expression in type I glomus cells of mice. Furthermore, these findings collectively highlight the hitherto unknown source of AgRP in murine and human type I glomus cells and underscore the direct control of Agrp transcription by HIF signaling.http://www.sciencedirect.com/science/article/pii/S221287782500002XNeuropeptideTranscriptionCardiovascular adaptationHypoxiaMelanocortins |
| spellingShingle | Luis Leon-Mercado Ivan Menendez-Montes Jonathan Tao Bandy Chen David P. Olson C. Mackaaij C.G.J. Cleypool Laurent Gautron Hypoxia inducible factor-dependent upregulation of Agrp in glomus type I cells of the carotid body Molecular Metabolism Neuropeptide Transcription Cardiovascular adaptation Hypoxia Melanocortins |
| title | Hypoxia inducible factor-dependent upregulation of Agrp in glomus type I cells of the carotid body |
| title_full | Hypoxia inducible factor-dependent upregulation of Agrp in glomus type I cells of the carotid body |
| title_fullStr | Hypoxia inducible factor-dependent upregulation of Agrp in glomus type I cells of the carotid body |
| title_full_unstemmed | Hypoxia inducible factor-dependent upregulation of Agrp in glomus type I cells of the carotid body |
| title_short | Hypoxia inducible factor-dependent upregulation of Agrp in glomus type I cells of the carotid body |
| title_sort | hypoxia inducible factor dependent upregulation of agrp in glomus type i cells of the carotid body |
| topic | Neuropeptide Transcription Cardiovascular adaptation Hypoxia Melanocortins |
| url | http://www.sciencedirect.com/science/article/pii/S221287782500002X |
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