{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nCortistatin, a neuropeptide sharing structural similarities with somatostatin yet acting through distinct receptor mechanisms (e.g. via the ghrelin receptor GHS-R1a), plays a central role in the regulation of endocrine and metabolic functions. Evidence from transgenic and knockout mouse models indicates that endogenous cortistatin modulates pituitary hormone release—including prolactin, growth hormone, and adrenocorticotropic hormone—in a gender‐ and metabolic state–dependent manner. In addition, cortistatin influences glucose–insulin homeostasis and governs the expression and activity of the ghrelin system in endocrine tissues such as the pancreas, underscoring its role in metabolic regulation and obesity‐associated adaptations."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the central nervous system, cortistatin is expressed by specific cortical and hippocampal GABAergic interneurons where it contributes both to sleep homeostasis and to the maintenance of excitatory/inhibitory balance. Brain-derived neurotrophic factor (BDNF) signaling via TrkB receptors on these cortistatin-containing cells is essential for promoting excitatory drive, thereby preventing hyperexcitability and epileptogenesis. These mechanisms not only sustain normal sleep architecture and slow-wave activity but also provide a safeguard against seizure development."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its endocrine and neural roles, cortistatin exerts potent anti-inflammatory and analgesic effects in both the peripheral and central nervous systems. It modulates vascular smooth muscle cell proliferation and calcification, contributes to pain control by acting on peripheral nociceptive terminals and spinal mechanisms (including NF‑κB, protein kinase A, calcium, and Akt/ERK signaling), and limits airway inflammation in models of asthma through interactions with chemokines like CCL2. Furthermore, cortistatin’s involvement in tumor-related processes and the protection of brain endothelial cells under neuroinflammatory conditions highlights its diverse therapeutic potential."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Raphaëlle Winsky-Sommerer, Avron D Spier, Véronique Fabre, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Obesity- and gender-dependent role of endogenous somatostatin and cortistatin in the regulation of endocrine and metabolic homeostasis in mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Rep (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/srep37992"}], "href": "https://doi.org/10.1038/srep37992"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27901064"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27901064"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Keri Martinowich, Robert J Schloesser, Dennisse V Jimenez, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Activity-dependent brain-derived neurotrophic factor expression regulates cortistatin-interneurons and sleep behavior."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Brain (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/1756-6606-4-11"}], "href": "https://doi.org/10.1186/1756-6606-4-11"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21388527"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21388527"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Julia L Hill, Dennisse V Jimenez, Yishan Mai, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cortistatin-expressing interneurons require TrkB signaling to suppress neural hyper-excitability."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Brain Struct Funct (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00429-018-1783-1"}], "href": "https://doi.org/10.1007/s00429-018-1783-1"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30377803"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30377803"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Mario Duran-Prado, Maria Morell, Virginia Delgado-Maroto, et al. 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