{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Ghrelin (GHRL) is a multifunctional peptide hormone predominantly secreted by the stomach that plays a central role in linking nutritional status to diverse physiological processes. In its acylated form, ghrelin stimulates appetite and promotes growth hormone release via the growth hormone secretagogue receptor (GHS‐R1a), with its bioactivity dependent on a unique octanoylation reaction mediated by the ghrelin O‐acyltransferase (GOAT) enzyme."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " Moreover, alternative peptides derived from the same preproghrelin gene, such as obestatin, exert opposing anorexigenic effects, thereby suggesting a complex intragene regulatory network in energy balance."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " Beyond its well‐established orexigenic and endocrine actions, ghrelin modulates insulin secretion and pancreatic β‐cell function, contributing to glucose homeostasis"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "; it also exerts anti‐inflammatory effects in vascular and immune cells."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " In the brain, ghrelin crosses the blood–brain barrier, where it enhances synaptic plasticity and cognitive functions by promoting dendritic spine formation and long‐term potentiation, particularly in the hippocampus"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": ", and activates hypothalamic circuits that coordinate feeding behavior via mitochondrial signaling pathways in key orexigenic neurons."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " Genetic deletion and pharmacologic studies further demonstrate that the endogenous ghrelin system contributes to energy substrate utilization and overall metabolic balance under various nutritional challenges."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Finally, investigations into the constitutive activity of the ghrelin receptor and mutations that selectively impair this activity reveal a complex regulatory mechanism by which ghrelin signaling integrates metabolic, trophic, and anti‐inflammatory responses."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Jing Yang, Michael S Brown, Guosheng Liang, et al. 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