{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Cholecystokinin (CCK) is a multifunctional peptide that plays critical roles in both peripheral and central systems. In the gastrointestinal tract, CCK is secreted by specialized enteroendocrine I cells in response to dietary nutrients. For instance, dietary long‐chain fatty acids and aromatic amino acids stimulate CCK release by activating specific G protein–coupled receptors—such as GPR40 and the extracellular calcium–sensing receptor (CaSR)—as well as by engaging voltage‐sensitive Ca²⁺ channels that mediate Ca²⁺ influx into I cells (See."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": " Moreover, bitter tastants can induce similar Ca²⁺–dependent CCK secretion, and many enteroendocrine cells coexpress CCK alongside other peptide hormones—suggesting a coordinated role in digestive regulation, nutrient sensing, and the maintenance of satiety (See."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition to its well‐characterized digestive functions (promoting gallbladder contraction, pancreatic enzyme secretion, and modulating gastrointestinal motility), CCK acts centrally as a neuromodulator. In the medial prefrontal cortex, stress‐related induction of the transcription factor ΔFosB leads to upregulation of CCK–B receptors; local administration of CCK in this region elicits anxiogenic and depressant‐like behaviors, highlighting a role for CCK in stress and mood regulation (See."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " Furthermore, CCK‐expressing glutamatergic neurons in limbic regions such as the basolateral amygdala appear to mediate negative reinforcement signals linked to social stress, while alterations in CCK–positive interneurons may contribute to deficits in endocannabinoid signaling implicated in neurodevelopmental disorders (See."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n At higher concentrations, as encountered under supramaximal stimulation, CCK also has pathophysiological roles. In the pancreas, excessive CCK stimulation triggers the formation of large endocytic vacuoles in acinar cells, leading to intracellular activation of trypsinogen—an early event associated with the development of pancreatitis (See."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond digestion and pancreatic function, CCK contributes to other homeostatic processes. Peripheral CCK signaling can modulate bile acid release and intestinal epithelial proliferation, thereby participating in gut regeneration. In parallel, CCK receptors on vagal afferents facilitate gut–brain communication, influencing satiety and the central integration of metabolic signals (See."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " Finally, in conditions such as oxytocin deficiency, adaptive mechanisms may involve compensatory upregulation of satiety peptides including CCK, underscoring its role in energy homeostasis (See."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these findings illustrate that CCK is a pleiotropic hormone whose actions extend from facilitating nutrient digestion and modulating gut motility to influencing neuronal circuits involved in mood, anxiety, and energy balance.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Toshiki Tanaka, Susumu Katsuma, Tetsuya Adachi, et al. 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