Leon-Mercado Luis, Menendez-Montes Ivan, Tao Jonathan, Chen Bandy, Olson David P, Mackaaij C, Cleypool C G J, Gautron Laurent
Center for Hypothalamic Research and Department of Internal medicine, UT Southwestern Medical Center, Dallas, TX, USA.
Division of Cardiology, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA.
Mol Metab. 2025 Feb;92:102095. doi: 10.1016/j.molmet.2025.102095. Epub 2025 Jan 8.
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.
刺鼠相关肽（AgRP）是一种公认的强效促食欲肽，主要在下丘脑神经元中表达。然而，下丘脑外AgRP的表达及其功能意义仍知之甚少。在本研究中，我们利用组织学和分子生物学技术，在小鼠颈动脉体（CB）的I型球细胞中鉴定出Agrp mRNA的显著表达和AgRP肽的产生。此外，我们还发现了支持AgRP受体黑皮质素受体3（Mc3r）在相邻交感神经元中表达的证据，这表明AgRP在CB中可能具有局部旁分泌作用。重要的是，在人CB的I型球细胞中也鉴定出了AgRP免疫反应性。鉴于在专门负责氧感应的化学感受细胞I型球细胞中意外发现大量AgRP，我们进而研究CB中Agrp的表达是否受低氧血症调节以及相关的氧感应分子机制。体外荧光素酶测定显示，低氧以缺氧诱导因子（HIF1/2）依赖的方式刺激人和小鼠的Agrp启动子。我们的体内实验进一步证明，暴露于环境低氧（1０%）会强烈诱导小鼠I型球细胞中Agrp的表达。此外，这些发现共同突出了小鼠和人I型球细胞中迄今未知的AgRP来源，并强调了HIF信号对Agrp转录的直接控制。
