Cholecystokinin

From Gallbladder to Cognition and Beyond

1st Edition - March 10, 2025
Editors: Christine Feinle-Bisset, Jens F Rehfeld
Language: English
Paperback ISBN:
9 7 8 - 0 - 4 4 3 - 2 3 7 2 0 - 1
eBook ISBN:
9 7 8 - 0 - 4 4 3 - 2 3 7 2 1 - 8

Cholecystokinin: From Gallbladder to Cognition and Beyond covers the biology, physiology, and pathophysiological roles of cholecystokinin (CCK) peptides. The book begins with a… Read more

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Cholecystokinin: From Gallbladder to Cognition and Beyond covers the biology, physiology, and pathophysiological roles of cholecystokinin (CCK) peptides. The book begins with a historical overview before providing in-depth chapters on the biology of CCK, from biogenesis to cell expression, including intestinal and extraintestinal endocrine cells, the central and peripheral nervous system, and receptor function. CCK phylogenesis is explored across various species, including fish, birds, insects and amphibians. The physiology of CCK covers intestinal CCK secretion, the gallbladder and pancreas, and the role of CCK in the gut-brain axis, gastrointestinal motor function, appetite regulation, and cardiovascular function.

Methods used for CCK research are also discussed. A number of chapters then covers the roles of CCK in various diseases, including metabolic diseases, tumors, psychiatric illness, the immune system and nociception, as well as potential therapeutic approaches targeting CCK receptors.

Cholecystokinin
Cover image
Title page
Table of Contents
Front Matter
Copyright
Contributors
Preface
Series preface
Part I: History
Chapter 1 Milestones in the history of cholecystokinin
Abstract
Introduction
Milestones
Premonitions
The physiological identification of CCK
The structural identifications as CCK-33
CCK and satiation signaling
CCK expression in central and peripheral neurons
ProCCK and its processing products
CCK in “classic” endocrine cells, germ cells, immune cells, cardiac myocytes, and tumor cells
Reliable plasma measurements
The molecular receptor identification
Concluding comments
References
Part II: Biology of cholecystokinin
Chapter 2 Evolutionarily conserved roles of cholecystokinin signaling
Abstract
Introduction
CCK signaling in mammals, a brief overview
CCK signaling in nonmammalian vertebrates
Elasmobranchs (cartilaginous fishes)
Teleost fish
Amphibians and reptiles
Birds
Skin-derived CCKs (caeruleins) in frogs
CCK signaling in invertebrates
CCK/SK peptides and their precursors in invertebrates
CCK/SK receptors in invertebrates
Distribution of CCK/SK peptides and receptors in invertebrates
Functional roles of SK signaling in invertebrates
Identified neurons and functional roles of CCK/SK signaling in Drosophila
Nociception in Drosophila
Aggression and courtship behavior in Drosophila
SK, food attraction, feeding, and satiation in Drosophila
CCK/SK signaling to regulate food intake differs mechanistically in invertebrates and mammals
Conclusions and future perspectives
References
Chapter 3 The biogenesis and cell-specific expression of cholecystokinin peptides
Abstract
Acknowledgment
Introduction
The CCK gene, transcription, and translation
PreproCCK
ProCCK processing, general aspects
ProCCK processing in gut endocrine cells
ProCCK processing in central and peripheral neurons
ProCCK processing in extraintestinal endocrine cells
ProCCK processing in spermatogenic cells
ProCCK processing in cardiac myocytes
ProCCK processing in immune cells
ProCCK processing in tumor cells
Conclusion
References
Chapter 4 Cholecystokinin in intestinal and extraintestinal endocrine cells
Abstract
Introduction
Receptors
CCK in the intestine
CCK secretion and GPCRs involved in I-cell signaling
CCK in peripheral extraintestinal cells
Extraintestinal endocrine cells
CCK in the pancreas
Spermatogenic cells
Myocardial myocytes
Kidney cells
Conclusion
References
Chapter 5 Cholecystokinin in the central and peripheral nervous system
Abstract
Acknowledgments
Introduction
Methods to study the distribution of the CCK systems
Anti-CCK antisera used in immunohistochemistry
The in situ hybridization era
CCK: A coexisting neuropeptide and features of peptide signaling
CCK in the brain
Ontogeny
Overall distribution studies
Cortex
The hippocampal formation
Other brain regions/nuclei
CCK pathways
CCK circuitries
CCK-dopamine coexistence in neurons in the ventral mesencephalon
CCK projections to striatum (caudate nucleus, caudatus putamen), nucleus accumbens, and olfactory tubercles
CCK neuronal cell bodies in the medulla oblongata and spinal cord
CCK in dorsal root ganglion neurons and their afferent projections
CCK in the vagus system
CCK in the gastrointestinal tract and associated ganglia
Concluding remarks
References
Chapter 6 Cholecystokinin 1 and 2 receptors
Abstract
Acknowledgment
Introduction
Discovery of CCK receptors
Characterization of CCK receptors
Localization of CCK1R and CCK2R
Signaling at CCK1R and CCK2R
Physiologic effects of CCK1R activation
Physiologic effects of CCK2R activation
Drugs targeting CCK1R
Drugs targeting CCK2R
Conclusions
References
Chapter 7 The relationship between cholecystokinin and gastrin
Abstract
Introduction
The common structure
The evolutionary relationship
The sulfation homology of cholecystokinins and gastrins
The cell-specificity of CCK versus gastrin expression
The cholecystokinin/gastrin receptors
The secretory patterns of cholecystokinin and gastrin
The specificity of assay measurements
The distinction between gastrinomas and CCKomas
CCK versus gastrin peptides as drug targets
Conclusion
References
Part III: Physiology of cholecystokinin
Chapter 8 Intestinal cholecystokinin secretion
Abstract
Introduction
CCK peptide
CCK-secreting I-cells—Location and anatomy
CCK secretion
A comment on CCK assays
Nutrient stimulation
Protein-mediated regulation of CCK secretion
Regulation of CCK secretion by fat
Carbohydrate-mediated regulation of intestinal CCK
Neuronal connections
CCK receptors
Physiological functions of CCK
Exocrine pancreas
Gallbladder
Gastric emptying
Gastric secretion and growth
Food intake
Regulation of the endocrine pancreas
CCK and other actions
Future considerations
References
Chapter 9 Cholecystokinin and the gut-brain axis
Abstract
Introduction
Gut-brain axis
Sensory signaling from the gastrointestinal tract
Gastric vagal afferents
Small intestinal vagal afferents
CCK signaling in vagal afferent neurons
Plasticity
Central inputs of vagal afferents
Effects of CCK to modulate central vagal afferent transmission
Effects of CCK to modulate NTS neuronal activity
Effects of CCK to modulate DMV neuronal activity
Modulation of central CCK responses
CCK effects in pathophysiological conditions
Conclusion
References
Chapter 10 CCK and the gallbladder
Abstract
Acknowledgment
Introduction
Cholecystokinin
The gallbladder
The sphincter of Oddi
Assessment of gallbladder motor function
Gallbladder motor function and CCK: Interdigestive and digestive states
Interdigestive state
Digestive state
Effect of age and sex
Pathophysiology: CCK secretion and gallbladder motility in various gastrointestinal conditions
Upper gastrointestinal surgery
Celiac disease
Exocrine pancreas insufficiency
Pancreatic surgery
Colonic dysfunction and postcolectomy
Total parenteral nutrition
Total enteral nutrition
Gallstone formation and gallstone disease
Medication that affects CCK secretion
Bile acid sequestrants
Somatostatin and somatostatin analogs
CCK receptor antagonists
Conclusion
References
Chapter 11 Cholecystokinin and the exocrine pancreas
Abstract
Introduction
Stimulation of pancreatic enzyme secretion by CCK (Fig. 1)
Comparative aspects of CCK regulation of pancreatic secretion
Fish
Amphibians
Reptiles
Birds
Other actions of CCK on the pancreas
Stimulation of pancreatic growth by CCK
Stimulation of pancreatic protein synthesis by CCK
Stimulation or potentiation of pancreatic ductal secretion by CCK
Regulation of acinar cell metabolism by CCK
Actions of CCK on pancreatic acinar cells at the molecular level (Table 1)
PLC—IP3—Ca2+ pathway
DAG—PKC pathway
mTOR pathway
Other pathways activated by CCK
Cholecystokinin and pancreatitis
Conclusion
References
Chapter 12 Islet effects of cholecystokinin and exploitation in diabetes
Abstract
Introduction
Diabetes and obesity
Peptide therapeutics
Cholecystokinin, tissue distribution, molecular forms, and analogs
Key milestones in relation to CCK and pancreatic islets
CCK stimulates insulin secretion in rodents
CCK is essential for maintenance of islet function and survival
CCK signaling pathways within islet beta-cells
Impact of CCK on human islet function
In vitro effects of CCK on human islets
In vivo effects of CCK on human islets
Combining CCK with other hormones for islet benefits
CCK and GLP-1
CCK and GIP
CCK and peptides beyond incretins
Safety concerns with CCK peptides
Concluding remarks
References
Chapter 13 Cholecystokinin and gastrointestinal motor function
Abstract
Introduction
GI motility patterns
Fasting GI motility
Postprandial GI motility
Role of CCK in the regulation of GI motility
Effects of CCK on esophageal motility
Effects of CCK on gastric motility
Effects of CCK on small intestinal motility
Effects of CCK on colonic motility
Roles of CCK in disordered GI motility and its therapeutic potential
Achalasia and diffuse esophageal spasm
Gastroesophageal reflux disease (GERD)
Impaired gastric emptying
Disorders of gut-brain interaction
Constipation
Conclusion
References
Chapter 14 Effect of cholecystokinin on food intake and appetite
Abstract
Introduction
Impact of exogenous CCK on food intake
Role of endogenous CCK on food intake
Role of vagal gut-brain signaling in CCK action
Interaction of CCK signaling with other metabolic signals
Role of the enteric nervous system in CCK action on food intake
Conclusion
References
Chapter 15 Cholecystokinin, nutrient preference, and taste aversion
Abstract
Acknowledgments
Preamble
Introduction
On feeding, preference, and aversion
CCK receptors
The vagus: main mediator of intestinal CCK effects on feeding
Modulation of CCK-8 effectiveness by nutritional status
CCK signaling and nutrient preference
CCK in the CNS
CCK and bariatric surgery
Conclusion
References
Chapter 16 Cholecystokinin in peripheral and central cardiovascular control
Abstract
Introduction
Cholecystokinin and blood pressure
Peripheral actions of CCK on the circulation
Central and peripheral cardiorespiratory responses to CCK
CCK and postprandial gastrointestinal hyperaemia
Vagal afferent neurons and the actions of CCK on the circulation
Cardiovascular responses to CCK in obesity
Does endogenously released CCK modulate the vasomotor system?
Conclusion
References
Chapter 17 Cholecystokinin in cardiac myocytes
Abstract
Introduction
A notion of the endocrine cardiovascular system
Early clues of cardiac cholecystokinin expression
Identification of cardiac CCK peptide expression
Cardiac localization of CCK peptide expression
Endothelial CCK gene expression
Lack of CCK or its receptor in relation to cardiovascular effects
CCK and cardiovascular disease
Distinguishing cardiac CCK from gut and brain CCK
Conclusions
References
Part IV: Methods used for cholecystokinin research
Chapter 18 Measurement of cholecystokinin in biological fluids
Abstract
Introduction
Methodological principles for measurement of cholecystokinin
The bioassay
The radioimmunoassay (RIA)
The enzyme-linked immunosorbent assay
Mass-spectrometry approaches
The processing-independent analysis
The CCK radioimmunoassay
Antibodies
The tracer
Additional RIA comments
Molecular CCK pattern in tissue extracts, blood plasma, and cerebrospinal fluid
Tissue extracts
Plasma extracts
The specific issue about CCK-58 in plasma
Cerebrospinal fluid
Concentration levels in plasma
Levels of bioactive CCK in healthy subjects
Levels of bioactive CCK in obesity
Conclusion
References
Chapter 19 Cholecystokinin knockout mice: peripheral and central phenotypes
Abstract
Physiological function of cholecystokinin
Generation of CCK knockout mice
Evaluation of physiological functions of CCK using CCK-KO models
Food intake in CCK-KO mice
Digestion and absorption in CCK-KO mice
Energy homeostasis in CCK-KO mice
Glucoregulatory functions and leptin in CCK-KO mice
Cognitive behaviors in CCK-KO mice
Concluding remarks
References
Part V: Cholecystokinin in disease
Chapter 20 Cholecystokinin in obesity and other disorders of eating
Abstract
Introduction
CCK receptor subtypes
CCK1 receptors and feeding regulation
Metabolic consequences of the absence of CCK or CCK1 receptors
Nutritional status modulates CCK effectiveness
CCK in obesity
CCK in eating disorders
Anorexia nervosa
Anorexia of aging
Bulimia nervosa
Binge eating disorder
Conclusions
References
Chapter 21 Cholecystokinin in tumors
Abstract
Introduction
Cholecystokinin expression in tumors
CCKomas and the CCKoma syndrome
Gastroenteropancreatic carcinomas
Bronchial carcinomas
Neuroendocrine tumors
Pediatric tumors
Cerebral tumors
Cholecystokinin as a tumor growth factor
Diagnostic methods for measurement of cholecystokinin from tumors
Perspectives
Conclusion
References
Chapter 22 Cholecystokinin and panic disorder
Abstract
Acknowledgments
Introduction
Investigating the effects of CCK in humans
Confirming the panicogenic property of CCK-4
Identifying neurotransmitter systems involved in the panicogenic effects of CCK-4
Psychological mechanisms in the panicogenic effects of CCK-4
The site of action of the panicogenic effects of CCK-4
Effect of CCK2R agonists in other psychiatric disorders
Genetic variants of the CCK system and panic disorder
Animal research supporting the role of the CCK system in anxiety
Evaluation of CCK receptor antagonists as antipanic agents
Summary
References
Chapter 23 Cholecystokinin and the immune system
Abstract
Introduction
CCK-releasing enteroendocrine cells as innate immune cells
Indirect CCK immune modulation
Immunoglobulin A
Tight junctions
Modulation of feeding by CCK during infection: An immunomodulatory axis
Epithelial damage and the reserve stem cell niche
CCK as a cytokine
Innate immunity
Professional antigen-presenting cells
Adaptive immunity
Conclusion
References
Chapter 24 Cholecystokinin in nociception and pain
Abstract
Introduction
Nociception
CCK signaling pathways
Canonical CCK signaling pathways linked to nociception
Downstream CCK Gαq signaling pathways linked to nociception
Downstream CCK Gᵦᵧ signaling pathways linked to nociception
Other signaling mechanisms
Tools to study CCK signaling in nociception
Rodent pain models
Transgenic and reporter mice
Otsuka Long Evans Tokushima fatty rat
Drosophila CCK pathway
Roles of CCK, CCK1R, and CCK2R in nociception and pain
CCK
CCK1R
CCK2R
CCK2R and opioid receptor interactions
CCK in peripheral neuropathy
Comorbidities associated with chronic pain
CCK drug discovery and therapeutics for pain
Pharmaceuticals to CCK1R
Pharmaceuticals to CCK2R
Conclusions
References
Part VI: Cholecystokinin-based novel therapeutic approaches
Chapter 25 Potential therapeutics targeting cholecystokinin 1 receptors
Abstract
Acknowledgments
Introduction
Partial agonists/biased agonists
Positive allosteric modulators
Membrane cholesterol sensitivity of the CCK1 receptor
Conclusions
References
Chapter 26 Reflections on cholecystokinin research: Past, present, and future
Abstract
A century of CCK research—And beyond
Index

Christine Feinle-Bisset

Professor Christine Feinle-Bisset has a PhD in Nutrition and GI Physiology from the University of Stuttgart-Hohenheim, Germany. After gaining research experience at the University of Sheffield, UK and the University of Zurich, Switzerland, she joined the University of Adelaide in 2000, where she is currently a Professorial Research Fellow and a lead investigator in the Centre of Research Excellence in Translating Nutritional Science to Good Health. Her research is clinical and relates to the impact of nutrients on appetite, GI motor and hormone function and perception, in health, obesity and functional dyspepsia. Her work has contributed significantly to current concepts of the role of gastrointestinal mechanisms, including gut hormones and gastrointestinal motor activity, in the regulation of energy intake in health and obesity, and symptom generation in functional dyspepsia. She has published more than 220 publications, with over 15,000 citations.

Affiliations and expertise

Professorial Research Fellow, Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Australia

Jens F Rehfeld

Professor Jens F. Rehfeld has an MD from the University of Aarhus, and later DMSc and DSc in Clinical Biochemistry from the University of Copenhagen. He became professor in Medical Biochemistry at University of Aarhus in 1975, and of Clinical Biochemistry, University of Copenhagen, in 1981. He was also administrative head of the Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, until 2010. His main research theme is bioactive peptides (in particular gastrin, cholecystokinin, and insulin), their biosynthesis, methods for measurement, and clinical relevance. He has published approximately 1100 publications, including 650 original articles, 90 review articles, 55 textbook chapters, and 8 books, and has more than 43,000 citations.

Affiliations and expertise

Professor, Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, Denmark

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