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López-Méndez I, Maldonado-Rojas ADC, Uribe M, Juárez-Hernández E. Hunger & satiety signals: another key mechanism involved in the NAFLD pathway. Front Endocrinol (Lausanne) 2023; 14:1213372. [PMID: 37753211 PMCID: PMC10518611 DOI: 10.3389/fendo.2023.1213372] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Accepted: 08/28/2023] [Indexed: 09/28/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent metabolic disease, although prevalence could change according to region, nowadays is considered a public health problem whose real impact on the health system is unknown. NAFLD has a multifactorial and complex pathophysiology, due to this, developing a unique and effective pharmacological treatment has not been successful in reverting or avoiding the progression of this liver disease. Even though NAFLD pathophysiology is known, all actual treatments are focused on modifying or regulating the metabolic pathways, some of which interplay with obesity. It has been known that impairments in hunger and satiety signals are associated with obesity, however, abnormalities in these signals in patients with NAFLD and obesity are not fully elucidated. To describe these mechanisms opens an additional option as a therapeutic target sharing metabolic pathways with NAFLD, therefore, this review aims to describe the hormones and peptides implicated in both hunger-satiety in NAFLD. It has been established that NAFLD pharmacological treatment cannot be focused on a single purpose; hence, identifying interplays that lead to adding or modifying current treatment options could also have an impact on another related outcome such as hunger or satiety signals.
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Affiliation(s)
- Iván López-Méndez
- Hepatology and Transplants Unit, Medica Sur Clinic & Foundation, Mexico City, Mexico
| | | | - Misael Uribe
- Gastroenterology and Obesity Unit, Medica Sur Clinic & Foundation, Mexico City, Mexico
| | - Eva Juárez-Hernández
- Translational Research Unit, Medica Sur Clinic & Foundation, Mexico City, Mexico
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Verbeure W, Deloose E, Tóth J, Rehfeld JF, Van Oudenhove L, Depoortere I, Tack J. The endocrine effects of bitter tastant administration in the gastrointestinal system: intragastric versus intraduodenal administration. Am J Physiol Endocrinol Metab 2021; 321:E1-E10. [PMID: 34029163 DOI: 10.1152/ajpendo.00636.2020] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Bitter tastants are recently introduced as potential hunger-suppressive compounds, the so-called "Bitter pill." However, the literature about bitter administration lacks consistency in methods and findings. We want to test whether hunger ratings and hormone plasma levels are affected by: 1) the site of administration: intragastrically (IG) or intraduodenally (ID), 2) the bitter tastant itself, quinine hydrochloride (QHCl) or denatonium benzoate (DB), and 3) the timing of infusion. Therefore, 14 healthy, female volunteers participated in a randomized, placebo-controlled six-visit crossover study. After an overnight fast, DB (1 µmol/kg), QHCl (10 µmol/kg), or placebo were given IG or ID via a nasogastric feeding tube. Blood samples were taken 10 min before administration and every 10 min after administration for a period of 2 h. Hunger was rated at the same time points on a visual analogue scale. ID bitter administration did not affect hunger sensations, motilin, or acyl-ghrelin release compared with its placebo infusion. IG QHCl infusion tended to suppress hunger increase, especially between 50 and 70 min after infusion, simultaneously with reduced motilin values. Here, acyl-ghrelin was not affected. IG DB did not affect hunger or motilin, however acyl-ghrelin levels were reduced 50-70 minutes after infusion. Plasma values of glucagon-like peptide 1 and cholecystokinin were too low to be properly detected or to have any physiological relevance. In conclusion, bitter tastants should be infused into the stomach to reduce hunger sensations and orexigenic gut peptides. QHCl has the best potential to reduce hunger sensations, and it should be infused 60 min before food intake.NEW & NOTEWORTHY Bitter tastants are a potential new weight-loss treatment. This is a noninvasive, easy approach, which should be received with considerable enthusiasm by the public. However, literature about bitter administration lacks consistency in methods and findings. We summarize how the compound should be given based on: the site of administration, the best bitter compound to use, and at what timing in respect to the meal. This paper is therefore a fundamental step to continue research toward the further development of the "bitter pill."
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Affiliation(s)
- Wout Verbeure
- Translational Research Center for Gastrointestinal Disorders, KU Leuven, Leuven, Belgium
| | - Eveline Deloose
- Translational Research Center for Gastrointestinal Disorders, KU Leuven, Leuven, Belgium
| | - Joran Tóth
- Translational Research Center for Gastrointestinal Disorders, KU Leuven, Leuven, Belgium
| | - Jens F Rehfeld
- Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Lukas Van Oudenhove
- Translational Research Center for Gastrointestinal Disorders, KU Leuven, Leuven, Belgium
| | - Inge Depoortere
- Translational Research Center for Gastrointestinal Disorders, KU Leuven, Leuven, Belgium
| | - Jan Tack
- Translational Research Center for Gastrointestinal Disorders, KU Leuven, Leuven, Belgium
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3
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Williams JA. Cholecystokinin (CCK) Regulation of Pancreatic Acinar Cells: Physiological Actions and Signal Transduction Mechanisms. Compr Physiol 2019; 9:535-564. [PMID: 30873601 DOI: 10.1002/cphy.c180014] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Pancreatic acinar cells synthesize and secrete about 20 digestive enzymes and ancillary proteins with the processes that match the supply of these enzymes to their need in digestion being regulated by a number of hormones (CCK, secretin and insulin), neurotransmitters (acetylcholine and VIP) and growth factors (EGF and IGF). Of these regulators, one of the most important and best studied is the gastrointestinal hormone, cholecystokinin (CCK). Furthermore, the acinar cell has become a model for seven transmembrane, heterotrimeric G protein coupled receptors to regulate multiple processes by distinct signal transduction cascades. In this review, we briefly describe the chemistry and physiology of CCK and then consider the major physiological effects of CCK on pancreatic acinar cells. The majority of the review is devoted to the physiologic signaling pathways activated by CCK receptors and heterotrimeric G proteins and the functions they affect. The pathways covered include the traditional second messenger pathways PLC-IP3-Ca2+ , DAG-PKC, and AC-cAMP-PKA/EPAC that primarily relate to secretion. Then there are the protein-protein interaction pathways Akt-mTOR-S6K, the three major MAPK pathways (ERK, JNK, and p38 MAPK), and Ca2+ -calcineurin-NFAT pathways that primarily regulate non-secretory processes including biosynthesis and growth, and several miscellaneous pathways that include the Rho family small G proteins, PKD, FAK, and Src that may regulate both secretory and nonsecretory processes but are not as well understood. © 2019 American Physiological Society. Compr Physiol 9:535-564, 2019.
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Affiliation(s)
- John A Williams
- University of Michigan, Departments of Molecular & Integrative Physiology and Internal Medicine (Gastroenterology), Ann Arbor, Michigan, USA
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4
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Abstract
Even the simplest animals possess sophisticated systems for sensing and securing nutrients. After all, ensuring adequate nutrition is essential for sustaining life. Once multicellular animals grew too large to be nourished by simple diffusion of nutrients from their environment, they required a digestive system for the absorption and digestion of food. The majority of cells in the digestive tract are enterocytes that are designed to absorb nutrients. However, the digestive tracts of animals ranging from worms to humans contain specialized cells that discriminate between nutrients and nondigestible ingestants. These cells "sense" both the environment within the gut lumen and nutrients as they cross the gut epithelium. This dual sensing is then translated into local signals that regulate the gut epithelium or distant signals through hormones or nerves. This review will discuss how sensors of the gut interact with cells of the epithelium and neurons to regulate epithelial integrity and initiate neural transmission from the gut lumen. © 2017 American Physiological Society. Compr Physiol 8:1019-1030, 2018.
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Affiliation(s)
- Rodger A Liddle
- Department of Medicine, Duke University and Durham VA Healthcare System, Durham, North Carolina, USA
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5
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D'Agostino G, Lyons DJ, Cristiano C, Burke LK, Madara JC, Campbell JN, Garcia AP, Land BB, Lowell BB, Dileone RJ, Heisler LK. Appetite controlled by a cholecystokinin nucleus of the solitary tract to hypothalamus neurocircuit. eLife 2016; 5. [PMID: 26974347 PMCID: PMC4861598 DOI: 10.7554/elife.12225] [Citation(s) in RCA: 123] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2015] [Accepted: 03/11/2016] [Indexed: 11/25/2022] Open
Abstract
The nucleus of the solitary tract (NTS) is a key gateway for meal-related signals entering the brain from the periphery. However, the chemical mediators crucial to this process have not been fully elucidated. We reveal that a subset of NTS neurons containing cholecystokinin (CCKNTS) is responsive to nutritional state and that their activation reduces appetite and body weight in mice. Cell-specific anterograde tracing revealed that CCKNTS neurons provide a distinctive innervation of the paraventricular nucleus of the hypothalamus (PVH), with fibers and varicosities in close apposition to a subset of melanocortin-4 receptor (MC4RPVH) cells, which are also responsive to CCK. Optogenetic activation of CCKNTS axon terminals within the PVH reveal the satiating function of CCKNTS neurons to be mediated by a CCKNTS→PVH pathway that also encodes positive valence. These data identify the functional significance of CCKNTS neurons and reveal a sufficient and discrete NTS to hypothalamus circuit controlling appetite. DOI:http://dx.doi.org/10.7554/eLife.12225.001 Obesity primarily results from eating more food than the body requires, the energy from which is then stored as fat. In recent years obesity has become increasingly common, with the resulting health problems presenting one of the major healthcare challenges of the twenty-first century. New ways to tackle the obesity epidemic are therefore required to improve human health on a global scale. To regulate how much food is eaten, the gut sends chemical messengers to the brain about how much food has been consumed. These messengers activate particular cells in the brain that signal to other brain regions to trigger a decision about whether we’ve had enough food to eat. This raises a question: if we can artificially activate these cells, can we ‘trick’ the brain into thinking that food has been consumed? A brain region called the nucleus of the solitary tract (NTS) is known to play a key role in receiving signals from the gut about meals. By studying mice, D’Agostino et al. found that cells in the NTS that make a brain hormone called cholecystokinin (CCK) are particularly activated by food. Further experiments then used a technique called optogenetics to activate these cells in mice that had free access to different types of food. This activation significantly reduced how hungry the mice were, causing them to eat less food and lose weight. D’Agostino et al. also showed that CCK cells relay the signal about food intake to a brain region called the hypothalamus. Overall, D’Agostino et al. have found a way to trick the brain into thinking that food has been eaten when it actually hasn’t, and for this reason mice eat less without feeling hungry and lose weight. The next step is to try and find a way to activate the CCK cells in obese humans who have health complications associated with excess body weight. DOI:http://dx.doi.org/10.7554/eLife.12225.002
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Affiliation(s)
- Giuseppe D'Agostino
- Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, United Kingdom.,Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom
| | - David J Lyons
- Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, United Kingdom
| | - Claudia Cristiano
- Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, United Kingdom
| | - Luke K Burke
- Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom
| | - Joseph C Madara
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States
| | - John N Campbell
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States
| | - Ana Paula Garcia
- Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom
| | - Benjamin B Land
- Department of Psychiatry, Yale University School of Medicine, New Haven, United States
| | - Bradford B Lowell
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States
| | - Ralph J Dileone
- Department of Psychiatry, Yale University School of Medicine, New Haven, United States
| | - Lora K Heisler
- Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, United Kingdom.,Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom
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6
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Borer KT. Counterregulation of insulin by leptin as key component of autonomic regulation of body weight. World J Diabetes 2014; 5:606-629. [PMID: 25317239 PMCID: PMC4138585 DOI: 10.4239/wjd.v5.i5.606] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2013] [Revised: 05/15/2014] [Accepted: 06/03/2014] [Indexed: 02/05/2023] Open
Abstract
A re-examination of the mechanism controlling eating, locomotion, and metabolism prompts formulation of a new explanatory model containing five features: a coordinating joint role of the (1) autonomic nervous system (ANS); (2) the suprachiasmatic (SCN) master clock in counterbalancing parasympathetic digestive and absorptive functions and feeding with sympathetic locomotor and thermogenic energy expenditure within a circadian framework; (3) interaction of the ANS/SCN command with brain substrates of reward encompassing dopaminergic projections to ventral striatum and limbic and cortical forebrain. These drive the nonhomeostatic feeding and locomotor motivated behaviors in interaction with circulating ghrelin and lateral hypothalamic neurons signaling through melanin concentrating hormone and orexin-hypocretin peptides; (4) counterregulation of insulin by leptin of both gastric and adipose tissue origin through: potentiation by leptin of cholecystokinin-mediated satiation, inhibition of insulin secretion, suppression of insulin lipogenesis by leptin lipolysis, and modulation of peripheral tissue and brain sensitivity to insulin action. Thus weight-loss induced hypoleptimia raises insulin sensitivity and promotes its parasympathetic anabolic actions while obesity-induced hyperleptinemia supresses insulin lipogenic action; and (5) inhibition by leptin of bone mineral accrual suggesting that leptin may contribute to the maintenance of stability of skeletal, lean-body, as well as adipose tissue masses.
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Abstract
Individual meals are products of a complex interaction of signals related to both short-term and long-term availability of energy stores. In addition to maintaining the metabolic demands of the individual in the short term, levels of energy intake must also maintain and defend body weight over longer periods. To accomplish this, satiety pathways are regulated by a sophisticated network of endocrine and neuroendocrine pathways. Higher brain centers modulate meal size through descending inputs to caudal brainstem regions responsible for the motor pattern generators associated with ingestion. Gastric and intestinal signals interact with central nervous system pathways to terminate food intake. These inputs can be modified as a function of internal metabolic signals, external environmental influences, and learning to regulate meal size.
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Mackie AR, Rafiee H, Malcolm P, Salt L, van Aken G. Specific food structures supress appetite through reduced gastric emptying rate. Am J Physiol Gastrointest Liver Physiol 2013; 304:G1038-43. [PMID: 23578786 PMCID: PMC3680687 DOI: 10.1152/ajpgi.00060.2013] [Citation(s) in RCA: 69] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2013] [Accepted: 04/05/2013] [Indexed: 01/31/2023]
Abstract
The aim of this study was to determine the extent to which gastric layering and retention of a meal could be used to reduce appetite using the same caloric load. Liquid (control) and semi-solid (active) meals were produced with the same protein, fat, carbohydrate, and mass. These were fed to 10 volunteers on separate days in a crossover study, and subjective appetite ratings, gastric contents, and plasma cholecystokinin (CCK) were assessed over a period of 3 h. The active meal showed food boluses in the stomach persisting for ~45 min, slower emptying rates, and lower plasma CCK levels over the first hour. After the first hour, both gastric emptying rates and plasma CCK levels were similar for both systems and slightly increased compared with the unfed situation. Despite the lower plasma CCK levels for the active meal over the first hour, this meal reduced appetite more than the control meal over the 3 h of the study. For a moderately increased plasma CCK level in the fed state, appetite was correlated with the volume of gastric contents rather than gastric emptying rates or plasma CCK. This suggests that enhanced gastric retention was the key factor in decreasing appetite and was probably mediated by a combination of intestinal nutrient sensing and increased viscosity in the stomach.
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Affiliation(s)
- Alan R Mackie
- Institute of Food Research, Norwich Research Park, Norwich, UK.
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9
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Kontos A, de Menezes RC, Ootsuka Y, Blessing W. Brown adipose tissue thermogenesis precedes food intake in genetically obese Zucker (fa/fa) rats. Physiol Behav 2013; 118:129-37. [PMID: 23685234 DOI: 10.1016/j.physbeh.2013.05.021] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2012] [Revised: 03/22/2013] [Accepted: 05/07/2013] [Indexed: 10/26/2022]
Abstract
In Sprague-Dawley rats, brown adipose tissue (BAT) thermogenesis occurs in an episodic ultradian manner (BAT on-periods) as part of the basic rest-activity cycle (BRAC). Eating occurs approximately 15min after the onset of BAT on-periods. Zucker obese (fa/fa) rats eat larger less frequent meals than control rats. In chronically instrumented conscious unrestrained Zucker obese rats we examined ultradian fluctuations in BAT, body and brain temperatures, and the relation between BAT temperature and eating. The interval between BAT temperature peaks for the 12hour dark phase was 121±3 (mean±SE) min for Zucker obese rats and 91±3min for control lean rats (p<0.01). Corresponding values for the light phase were 148±6 and 118±4min (p<0.01). Mean BAT and body temperatures were lower in Zucker obese rats, in comparison with lean controls, during both BAT on-periods and BAT off-periods. Mean brain temperatures were lower during BAT off-periods. Amplitudes of the BRAC-related increases in all 3 temperatures were greater in the Zucker obese rats. Meal onset in Zucker obese rats commenced 15±1min after the onset of a BAT on-period, not significantly different for the delay observed in lean control rats (18±1min, p>0.05). Thus periods between eating are increased in the Zucker obese rats, but the action of leptin, absent in these animals, is not crucial for the timing of eating in relation to increases in BAT and body temperature. Lack of the normal excitatory action of leptin on brain-regulated BAT sympathetic discharge could also contribute to lower BAT thermogenesis in Zucker obese rats.
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Affiliation(s)
- Anna Kontos
- Centre for Neuroscience, Department of Human Physiology, Flinders University, Adelaide, SA 5042, Australia
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10
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Nováková J, Lukačínová A, Lovásová E, Cimboláková I, Rácz O, Ništiar F. Lifetime exposure to low doses of lead in rats. Toxicol Ind Health 2013; 31:448-58. [DOI: 10.1177/0748233713475510] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
The aim of the study was to assess the effects of exposure to low doses of lead dissolved in drinking water (average daily dose of 2.2 mg kg−1 day−1) on selected carbohydrate metabolism parameters in 20 wistar rats. Animals were divided into two groups – control (C) (group drinking clear water) and experimental group (Pb; group exposed to low doses of lead acetate in a concentration of 100 μmol l−1 of drinking water). In this study, we studied the biochemical parameters (glucose, haemoglobin (Hb), glycated haemoglobin (HbA1c), lactate dehydrogenase (LDH) and amylase (AMS)) in rat blood. Glucose and Hb concentration and AMS activity decreased, LDH activity increased but HbA1c concentration levels did not change in rats exposed to lead. Our results well documented that lifetime exposure to lead affected carbohydrate metabolism of rats. Some parameters like concentration of Hb as well as activities of AMS and LDH are useful markers of intoxication of rats with lead. For the evaluation of results (e.g. AMS), not only the data at the end of the experiment should be taken into account but also the entire duration of trials (i.e. more time steps) that makes results more objective should be considered.
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Affiliation(s)
| | | | - Eva Lovásová
- Faculty of Medicine, P.J. Safarik University, Kosice, Slovakia
| | | | - Oliver Rácz
- Faculty of Medicine, P.J. Safarik University, Kosice, Slovakia
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11
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Abstract
Many peptides and other compounds that influence metabolism also influence food intake, and numerous hypotheses explaining the observed effects in terms of energy homeostasis have been suggested over the years. For example, cholecystokinin (CCK), a duodenal peptide secreted during meals that aids in digestion, also reduces ongoing food intake, thereby contributing to satiation; and insulin and leptin, hormones secreted in direct proportion to body fat, act in the brain to help control adiposity by reducing energy intake. These behavioral actions are often considered to be hard-wired, such that negative experiments, in which an administered compound fails to have its purported effect, are generally disregarded. In point of fact, failures to replicate the effects of compounds on food intake are commonplace, and this occurs both between and within laboratories. Failures to replicate have historically fueled heated debate about the efficacy and/or normal function of one or another compound, leading to confusion and ambiguity in the literature. We review these phenomena and their implications and argue that, rather than eliciting hard-wired behavioral responses in the maintenance of homeostasis, compounds that alter food intake are subjected to numerous influences that can render them completely ineffective at times and that a major reason for this variance is that food intake is not under stringent homeostatic control.
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Affiliation(s)
- Stephen C Woods
- Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, OH 45237, USA.
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12
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Teubner BJ, Bartness TJ. Cholecystokinin-33 acutely attenuates food foraging, hoarding and intake in Siberian hamsters. Peptides 2010; 31:618-24. [PMID: 20025915 PMCID: PMC2837760 DOI: 10.1016/j.peptides.2009.12.010] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2009] [Revised: 12/04/2009] [Accepted: 12/07/2009] [Indexed: 11/26/2022]
Abstract
Neurochemicals that stimulate food foraging and hoarding in Siberian hamsters are becoming more apparent, but we do not know if cessation of these behaviors is due to waning of excitatory stimuli and/or the advent of inhibitory factors. Cholecystokinin (CCK) may be such an inhibitory factor as it is the prototypic gastrointestinal satiety peptide and is physiologically important in decreasing food intake in several species including Siberian hamsters. Systemic injection of CCK-33 in laboratory rats decreases food intake, doing so to a greater extent than CCK-8. We found minimal effects of CCK-8 on food foraging and hoarding previously in Siberian hamsters, but have not tested CCK-33. Therefore, we asked: Does CCK-33 decrease normal levels or food deprivation-induced increases in food foraging, hoarding and intake? Hamsters were housed in a wheel running-based foraging system with simulated burrows to test the effects of peripheral injections of CCK-33 (13.2, 26.4, or 52.8 microg/kg body mass), with or without a preceding 56 h food deprivation. The highest dose of CCK-33 caused large baseline reductions in all three behaviors for the 1st hour post-injection compared with saline; in addition, the intermediate CCK-33 dose was sufficient to curtail food intake and foraging during the 1st hour. In food-deprived hamsters, we used a 52.8 microg/kg body mass dose of CCK-33 which decreased food intake, hoarding, and foraging almost completely compared with saline controls for 1h. Therefore, CCK-33 appears to be a potent inhibitor of food intake, hoarding, and foraging in Siberian hamsters.
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Affiliation(s)
| | - Timothy J. Bartness
- To whom correspondence should be addressed: Dr. Timothy J. Bartness, Department of Biology, Georgia State University, 24 Peachtree Center Ave. NE, Atlanta, GA 30302-4010, Fax: 404 413-5334,
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13
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Stengel A, Goebel M, Wang L, Rivier J, Kobelt P, Mönnikes H, Lambrecht NWG, Taché Y. Central nesfatin-1 reduces dark-phase food intake and gastric emptying in rats: differential role of corticotropin-releasing factor2 receptor. Endocrinology 2009; 150:4911-9. [PMID: 19797401 PMCID: PMC2775975 DOI: 10.1210/en.2009-0578] [Citation(s) in RCA: 202] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Nesfatin-1, derived from nucleobindin2, is expressed in the hypothalamus and reported in one study to reduce food intake (FI) in rats. To characterize the central anorexigenic action of nesfatin-1 and whether gastric emptying (GE) is altered, we injected nesfatin-1 into the lateral brain ventricle (intracerebroventricular, icv) or fourth ventricle (4v) in chronically cannulated rats or into the cisterna magna (intracisternal, ic) under short anesthesia and compared with ip injection. Nesfatin-1 (0.05 microg/rat, icv) decreased 2-3 h and 3-6 h dark-phase FI by 87 and 45%, respectively, whereas ip administration (2 microg/rat) had no effect. The corticotropin-releasing factor (CRF)(1)/CRF(2) antagonist astressin-B or the CRF(2) antagonist astressin(2)-B abolished icv nesfatin-1's anorexigenic action, whereas an astressin(2)-B analog, devoid of CRF-receptor binding affinity, did not. Nesfatin-1 icv induced a dose-dependent reduction of GE by 26 and 43% that was not modified by icv astressin(2)-B. Nesfatin-1 into the 4v (0.05 microg/rat) or ic (0.5 microg/rat) decreased cumulative dark-phase FI by 29 and 60% at 1 h and by 41 and 37% between 3 and 5 h, respectively. This effect was neither altered by ic astressin(2)-B nor associated with changes in GE. Cholecystokinin (ip) induced Fos expression in 43% of nesfatin-1 neurons in the paraventricular hypothalamic nucleus and 24% of those in the nucleus tractus solitarius. These data indicate that nesfatin-1 acts centrally to reduce dark phase FI through CRF(2)-receptor-dependent pathways after forebrain injection and CRF(2)-receptor-independent pathways after hindbrain injection. Activation of nesfatin-1 neurons by cholecystokinin at sites regulating food intake may suggest a role in gut peptide satiation effect.
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Affiliation(s)
- Andreas Stengel
- Center for Neurovisceral Sciences and Women's Health CURE, Building 115, Room 117, Veterans Administration Greater Los Angeles Healthcare System, 11301 Wilshire Boulevard, Los Angeles, California 90073, USA
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14
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Stengel A, Goebel M, Million M, Stenzel-Poore MP, Kobelt P, Mönnikes H, Taché Y, Wang L. Corticotropin-releasing factor-overexpressing mice exhibit reduced neuronal activation in the arcuate nucleus and food intake in response to fasting. Endocrinology 2009; 150:153-60. [PMID: 18787020 PMCID: PMC2630908 DOI: 10.1210/en.2008-0723] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Corticotropin-releasing factor (CRF) overexpressing (OE) mice are a genetic model that exhibits features of chronic stress. We investigated whether the adaptive feeding response to a hypocaloric challenge induced by food deprivation is impaired under conditions of chronic CRF overproduction. Food intake response to a 16-h overnight fast and ip injection of gut hormones regulating food intake were compared in CRF-OE and wild type (WT) littermate mice along with brain Fos expression, circulating ghrelin levels, and gastric emptying of a nonnutrient meal. CRF-OE mice injected ip with saline showed a 47 and 44% reduction of 30-min and 4-h cumulative food intake response to an overnight fast, respectively, compared with WT. However, the 30-min food intake decrease induced by ip cholecystokinin (3 microg/kg) and increase by ghrelin (300 microg/kg) were similar in CRF-OE and WT mice. Overnight fasting increased the plasma total ghrelin to similar levels in CRF-OE and WT mice, although CRF-OE mice had a 2-fold reduction of nonfasting ghrelin levels. The number of Fos-immunoreactive cells induced by fasting in the arcuate nucleus was reduced by 5.9-fold in CRF-OE compared with WT mice whereas no significant changes were observed in other hypothalamic nuclei. In contrast, fasted CRF-OE mice displayed a 5.6-fold increase in Fos-immunoreactive cell number in the dorsal motor nucleus of the vagus nerve and a 34% increase in 20-min gastric emptying. These findings indicate that sustained overproduction of hypothalamic CRF in mice interferes with fasting-induced activation of arcuate nucleus neurons and the related hyperphagic response.
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Affiliation(s)
- Andreas Stengel
- Center for Ulcer Research and Education, Digestive Diseases Research Center, Digestive Diseases Division, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90073, USA
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Sartor DM, Verberne AJ. Abdominal vagal signalling: A novel role for cholecystokinin in circulatory control? ACTA ACUST UNITED AC 2008; 59:140-54. [DOI: 10.1016/j.brainresrev.2008.07.002] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2008] [Revised: 06/24/2008] [Accepted: 07/07/2008] [Indexed: 02/07/2023]
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Chen J, Scott KA, Zhao Z, Moran TH, Bi S. Characterization of the feeding inhibition and neural activation produced by dorsomedial hypothalamic cholecystokinin administration. Neuroscience 2008; 152:178-88. [PMID: 18248910 PMCID: PMC2562916 DOI: 10.1016/j.neuroscience.2007.12.004] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2007] [Revised: 09/25/2007] [Accepted: 12/03/2007] [Indexed: 12/18/2022]
Abstract
Within the dorsomedial hypothalamus (DMH), cholecystokinin (CCK) has been proposed to modulate neuropeptide Y (NPY) signaling to affect food intake. However, the neural circuitry underlying the actions of this CCK-NPY signaling system in the controls of food intake has yet to be determined. We sought to characterize the feeding inhibition and brain neural activation produced by CCK administration into the DMH of rats. We determined the time course of feeding inhibitory effects of exogenous DMH CCK, assessed NPY gene expression in the DMH in response to DMH CCK administration, and characterized c-Fos activation in the entire brain induced by CCK injection into the DMH using c-Fos like immunohistochemistry. We found that parenchymal injection of CCK into the DMH decreased food intake during the entire 22 h observation period, with a primary effect in the first 4 h, and down-regulated NPY gene expression in the DMH. c-Fos immunohistochemistry revealed that DMH CCK increased the number of c-Fos positive cells in the paraventricular nucleus (PVN), arcuate nucleus, suprachiasmatic nucleus and retrochiasmatic area as well as in the contralateral DMH. This pattern of activity is different from that produced by peripherally administered CCK which is short acting and primarily activates neurons in the nucleus of the solitary tract and area postrema, as well as the PVN and DMH. Together, these data suggest that DMH CCK plays an important role in the control of food intake, and does so by activating different pathways from those activated by peripheral CCK.
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Affiliation(s)
- Jie Chen
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21205, USA
- Children’s Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Karen A. Scott
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21205, USA
| | - Zhengyan Zhao
- Children’s Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Timothy H. Moran
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21205, USA
| | - Sheng Bi
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21205, USA
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17
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Free fatty acids induce cholecystokinin secretion through GPR120. Naunyn Schmiedebergs Arch Pharmacol 2007; 377:523-7. [DOI: 10.1007/s00210-007-0200-8] [Citation(s) in RCA: 204] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2007] [Accepted: 10/09/2007] [Indexed: 10/22/2022]
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18
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Verbaeys I, León-Tamariz F, Buyse J, De Cuyper M, Pottel H, Van Boven M, Cokelaere M. PEGylated cholecystokinin prolongs satiation in rats: dose dependency and receptor involvement. Br J Pharmacol 2007; 152:396-403. [PMID: 17618299 PMCID: PMC2042956 DOI: 10.1038/sj.bjp.0707390] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND AND PURPOSE Acute intraperitoneal (i.p.) administration of cholecystokinin (CCK) is known to induce a significant, but short-lasting, reduction in food intake, followed by recovery within hours. Therefore, we had covalently coupled CCK to a 10 kDa polyethylene glycol and showed that this conjugate, PEG-CCK(9), produced a significantly longer anorectic effect than unmodified CCK(9). The present study assessed the dose-dependency of this response and the effect of two selective CCK(1) receptor antagonists, with different abilities to cross the blood-brain barrier (BBB), on PEG-CCK(9)-induced anorexia. EXPERIMENTAL APPROACH Food intake was measured, for up to 23 h, after i.p. administration of different doses (2, 4, 8, 16 and 32 microg kg(-1)) of CCK(9) or PEG-CCK(9) in male Wistar rats. Devazepide (100 microg kg(-1)), which penetrates the BBB or 2-NAP (3 mg kg(-1)), which does not cross the BBB, were coadministered i.p. with PEG-CCK(9) (6 microg kg(-1)) and food intake was monitored. KEY RESULTS In PEG-CCK(9)-treated rats, a clear dose-dependency was seen for both the duration and initial intensity of the anorexia whereas, for CCK(9), only the initial intensity was dose-dependent. Intraperitoneal administration of devazepide or 2-NAP, injected immediately prior to PEG-CCK(9), completely abolished the anorectic effect of PEG-CCK(9). CONCLUSIONS AND IMPLICATIONS The duration of the anorexia for PEG-CCK(9) was dose-dependent, suggesting that PEGylation of CCK(9) increases its circulation time. Both devazepide and 2-NAP completely abolished the anorectic effect of i.p. PEG-CCK(9) indicating that its anorectic effect was solely due to stimulation of peripheral CCK(1) receptors.
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Affiliation(s)
- I Verbaeys
- Interdisciplinary Research Center, Katholieke Universiteit Leuven Kortrijk, Belgium
| | - F León-Tamariz
- Laboratory of Toxicology and Bromatology, Katholieke Universiteit Leuven Leuven, Belgium
| | - J Buyse
- Laboratory of Physiology and Immunology of Domestic Animals, Katholieke Universiteit Leuven Leuven, Belgium
| | - M De Cuyper
- Interdisciplinary Research Center, Katholieke Universiteit Leuven Kortrijk, Belgium
| | - H Pottel
- Interdisciplinary Research Center, Katholieke Universiteit Leuven Kortrijk, Belgium
| | - M Van Boven
- Laboratory of Toxicology and Bromatology, Katholieke Universiteit Leuven Leuven, Belgium
| | - M Cokelaere
- Interdisciplinary Research Center, Katholieke Universiteit Leuven Kortrijk, Belgium
- Author for correspondence:
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Bi S, Chen J, Behles RR, Hyun J, Kopin AS, Moran TH. Differential body weight and feeding responses to high-fat diets in rats and mice lacking cholecystokinin 1 receptors. Am J Physiol Regul Integr Comp Physiol 2007; 293:R55-63. [PMID: 17409266 PMCID: PMC2084469 DOI: 10.1152/ajpregu.00002.2007] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Prior data demonstrated differential roles for cholecystokinin (CCK)1 receptors in maintaining energy balance in rats and mice. CCK1 receptor deficiency results in hyperphagia and obesity of Otsuka Long-Evans Tokushima Fatty (OLETF) rats but not in mice. To ascertain the role of CCK1 receptors in high-fat-diet (HFD)-induced obesity, we compared alterations in food intake, body weight, fat mass, plasma glucose, and leptin levels, and patterns of hypothalamic gene expression in OLETF rats and mice lacking CCK1 receptors in response to a 10-wk exposure to HFD. Compared with Long-Evans Tokushima Otsuka (LETO) control rats, OLETF rats on HFD had sustained overconsumption over the 10-wk period. High fat feeding resulted in greater increases in body weight and plasma leptin levels in OLETF than in LETO rats. In situ hybridization determinations revealed that, while HFD reduced neuropeptide Y (NPY) mRNA expression in both the arcuate nucleus (Arc) and the dorsomedial hypothalamus (DMH) of LETO rats, HFD resulted in decreased NPY expression in the Arc but not in the DMH of OLETF rats. In contrast to these results in OLETF rats, HFD increased food intake and induced obesity to an equal degree in both wild-type and CCK1 receptor(-/-) mice. NPY gene expression was decreased in the Arc in response to HFD, but was not detectable in the DMH in both wild-type and CCK1 receptor(-/-) mice. Together, these data provide further evidence for differential roles of CCK1 receptors in the controls of food intake and body weight in rats and mice.
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Affiliation(s)
- Sheng Bi
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 720 Rutland Ave., Baltimore, MD 21205, USA.
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20
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Naessén S, Carlström K, Byström B, Pierre Y, Hirschberg AL. Effects of an antiandrogenic oral contraceptive on appetite and eating behavior in bulimic women. Psychoneuroendocrinology 2007; 32:548-54. [PMID: 17475412 DOI: 10.1016/j.psyneuen.2007.03.008] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2006] [Revised: 03/08/2007] [Accepted: 03/17/2007] [Indexed: 11/22/2022]
Abstract
High androgen levels in women with bulimia nervosa may promote bulimic behavior. The aim of the present study was to investigate the effects of an antiandrogenic oral contraceptive (OC) on appetite and eating behavior in women with bulimia nervosa compared to healthy controls. Twenty-one women with bulimia nervosa and 17 healthy controls matched for age and body mass index participated in the study. Basal and meal-related appetite and secretions of the satiety peptide cholecystokinin (CCK) and the appetite-stimulating peptide ghrelin were studied before and after 3 months of treatment with an antiandrogenic OC (30 microg ethinyl estradiol combined with 3 mg drospirenone). Bulimic behavior was evaluated in relation to changes in hormone levels. Before treatment, bulimic women had higher frequency of menstrual disturbances, acne and hirsutism and higher levels of testosterone but lower meal-related CCK secretion than controls. OC treatment reduced meal-related hunger and gastric distention in bulimics. CCK secretion in response to the meal was unchanged in bulimic women but decreased in the controls. Ghrelin secretion was comparable between groups and did not change in response to OC treatment. The treatment improved bulimic behavior in relation to a decline in testosterone levels in the entire group. Our results support the suggestion that androgens play a role in bulimic behavior. Treatment with an antiandrogenic OC may serve as a new strategy for treatment of bulimia nervosa and particularly in those patients with hyperandrogenic symptoms.
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Affiliation(s)
- S Naessén
- Department of Woman and Child Health, Division of Obstetrics and Gynecology, Karolinska Institute, Stockholm, Sweden.
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White CL, Ishihara Y, York DA, Bray GA. Effect of meta-chlorophenylpiperazine and cholecystokinin on food intake of Osborne-Mendel and S5B/P1 rats. Obesity (Silver Spring) 2007; 15:624-31. [PMID: 17372312 DOI: 10.1038/oby.2007.579] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
OBJECTIVE To investigate whether there is a difference in sensitivity to a serotonin agonist, meta-chlorophenylpiperazine (mCPP), or cholecystokinin (CCK-8), an intestinal hormone that inhibits food intake, between the Osborne-Mendel (OM) rat, which becomes obese eating a high-fat diet, and the S5B/Pl (S5B) rat, which is resistant to dietary-induced obesity. RESEARCH METHODS AND PROCEDURES OM and S5B rats were adapted to either a high-saturated-fat diet (56% energy as fat) or a low-fat diet (10% energy as fat) or to both for 14 days and then treated with several doses of mCPP or CCK-8. RESULTS Treatment with mCPP reduced food intake in both strains of rats. The dose-response curve showed that the OM rats had an increased sensitivity to the serotonergic agonist. Animals eating the high-fat diet had less response to mCPP; and in the S5B rats, the response was significantly reduced. After treatment with CCK-8, there was a similar dose-related suppression of food intake in both the OM and S5B rats. DISCUSSION These data are consistent with the hypothesis that the serotonin system in the S5B rat has a greater activity that could act to inhibit fat intake. The response to CCK was not significantly affected by strain or diet.
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Affiliation(s)
- Christy L White
- Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, LA 70808, USA.
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22
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Chikuma T, Shimizu M, Tsuchiya Y, Kato T, Hojo H. Axonal transports of tripeptidyl peptidase II in rat sciatic nerves. Neurochem Int 2006; 50:236-42. [PMID: 17023090 DOI: 10.1016/j.neuint.2006.08.010] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2006] [Accepted: 08/14/2006] [Indexed: 11/22/2022]
Abstract
Axonal transport of tripeptidyl peptidase II, a putative cholecystokinin inactivating serine peptidase, was examined in the proximal, middle, and distal segments of rat sciatic nerves using a double ligation technique. Enzyme activity significantly increased not only in the proximal segment but also in the distal segment 12-72h after ligation, and the maximal enzyme activity was found in the proximal and distal segments at 72h. Western blot analysis of tripeptidyl peptidase II showed that its immunoreactivities in the proximal and distal segments were 3.1- and 1.7-fold higher than that in the middle segment. The immunohistochemical analysis of the segments also showed an increase in immunoreactive tripeptidyl peptidase II level in the proximal and distal segments in comparison with that in the middle segment, indicating that tripeptidyl peptidase II is transported by anterograde and retrograde axonal flow. The results suggest that tripeptidyl peptidase II may be involved in the metabolism of neuropeptides in nerve terminals or synaptic clefts.
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Affiliation(s)
- Toshiyuki Chikuma
- Department of Hygienic Chemistry, Showa Pharmaceutical University, 3-3165 Higashi-tamagawagakuen, Machida-shi, Tokyo 194-8543, Japan.
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Abstract
Functional dyspepsia (FD) is a common disorder of yet uncertain etiology. Dyspeptic symptoms are usually meal related and suggest an association to gastrointestinal (GI) sensorimotor dysfunction. Cholecystokinin (CCK) is an established brain-gut peptide that plays an important regulatory role in gastrointestinal function. It inhibits gastric motility and emptying via a capsaicin sensitive vagal pathway. The effects on emptying are via its action on the proximal stomach and pylorus. CCK is also involved in the regulation of food intake. It is released in the gut in response to a meal and acts via vagal afferents to induce satiety. Furthermore CCK has also been shown to be involved in the pathogenesis of panic disorder, anxiety and pain. Other neurotransmitters such as serotonin and noradrenaline may be implicated with CCK in the coordination of GI activity. In addition, intravenous administration of CCK has been observed to reproduce the symptoms in FD and this effect can be blocked both by atropine and loxiglumide (CCK-A antagonist). It is possible that an altered response to CCK may be responsible for the commonly observed gastric sensorimotor dysfunction, which may then be associated with the genesis of dyspeptic symptoms.
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Affiliation(s)
- A S B Chua
- Ipoh Gastro Centre, 31, Lebuhraya Taman Ipoh, Ipoh Garden South, 31400 Ipoh, Perak, Malaysia.
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24
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Chua ASB, Keeling PWN, Dinan TG. Role of cholecystokinin and central serotonergic receptors in functional dyspepsia. World J Gastroenterol 2006; 12:1329-35. [PMID: 16552797 PMCID: PMC4124306 DOI: 10.3748/wjg.v12.i9.1329] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Symptoms of functional dyspepsia are characterized by upper abdominal discomfort or pain, early satiety, postprandial fullness, bloating, nausea and vomiting. It is a chronic disorder, with symptoms more than 3 mo per year, and no evidence of organic diseases. Dysfunctional motility, altered visceral sensation, and psychosocial factors have all been identified as major pathophysiological mechanisms. It is believed that these pathophysiological mechanisms interact to produce the observed symptoms. Dyspepsia has been categorized into three subgroups based on dominant symptoms. Dysmotility-like dyspepsia describes a subgroup of patients whose symptom complex is usually related to a gastric sensorimotor dysfunction. The brain-gut peptide cholecystokinin (CCK) and serotonin (5-HT) share certain physiological effects. Both have been shown to decrease gastric emptying and affect satiety. Furthermore the CCK induced anorexia depended on serotonergic functions probably acting via central pathways. We believe that abnormalities of central serotonergic receptors functioning together with a hyper responsiveness to CCK or their interactions may be responsible for the genesis of symptoms in functional dyspepsia (FD).
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25
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Ganellin CR, Bishop PB, Bambal RB, Chan SMT, Leblond B, Moore ANJ, Zhao L, Bourgeat P, Rose C, Vargas F, Schwartz JC. Inhibitors of Tripeptidyl Peptidase II. 3. Derivation of Butabindide by Successive Structure Optimizations Leading to a Potential General Approach to Designing Exopeptidase Inhibitors. J Med Chem 2005; 48:7333-42. [PMID: 16279793 DOI: 10.1021/jm0500830] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
The cholecystokinin-8 (CCK-8)-inactivating peptidase is a serine peptidase that has been shown to be a membrane-bound isoform of tripeptidyl peptidase II (EC 3.4.14.10). It cleaves the neurotransmitter CCK-8 sulfate at the Met-Gly bond to give Asp-Tyr(SO3H)-Met-OH + Gly-Trp-Met-Asp-Phe-NH2. Starting from Val-Pro-NHBu, a dipeptide of submicromolar affinity that had previously been generated to serve as a lead, successive optimization at P3, P1, and then P2 gave Abu-Pro-NHBu (18, Ki = 80 nM). Further transformation (by making a benzologue) gave the indoline analogue, butabindide (33) as a reversible inhibitor having nanomolar affinity (Ki = 7 nM). Retrospective analysis suggested the possibility of a general approach to designing exopeptidase inhibitors starting from the structure of the first hydrolysis product. Application of this approach to CCK-8 led to Abu-Phe-NHBu (37), but this only had Ki = 9.4 microM. Molecular modeling, to determine the minimum energy conformations and explain the 1000-fold better affinity of butabindide, indicated that 37 cannot access the likely active conformation of butabindide.
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Affiliation(s)
- C Robin Ganellin
- Department of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ, England.
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26
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Date Y, Toshinai K, Koda S, Miyazato M, Shimbara T, Tsuruta T, Niijima A, Kangawa K, Nakazato M. Peripheral interaction of ghrelin with cholecystokinin on feeding regulation. Endocrinology 2005; 146:3518-25. [PMID: 15890776 DOI: 10.1210/en.2004-1240] [Citation(s) in RCA: 93] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Ghrelin and cholecystokinin (CCK) are gastrointestinal hormones regulating feeding. Both transmitted via the vagal afferent, ghrelin elicits starvation signals, whereas CCK induces satiety signals. We investigated the interaction between ghrelin and CCK functioning in short-term regulation of feeding in Otsuka Long-Evans Tokushima fatty (OLETF) rats, which have a disrupted CCK type A receptor (CCK-AR), and their lean littermates, Long-Evans Tokushima Otsuka (LETO) rats. Intravenous administration of ghrelin increased 2-h food intake in both OLETF and LETO rats. Because OLETF rats are CCK insensitive, iv-administered CCK decreased 2-h food intake in LETO, but not in OLETF, rats. Although preadministration of CCK to LETO rats blocked food intake induced by ghrelin, CCK preadministration to OLETF rats did not affect ghrelin-induced food intake. Conversely, preadministration of ghrelin to LETO rats blocked feeding reductions induced by CCK. In electrophysiological studies, once gastric vagal afferent discharges were altered by ghrelin or CCK administration, they could not be additionally affected by serial administrations of either CCK or ghrelin, respectively. The induction of Fos expression in the hypothalamic arcuate nucleus by ghrelin was also attenuated by CCK preadministration. Using immunohistochemistry, we also demonstrated the colocalization of GH secretagogue receptor (GHS-R), the cellular receptor for ghrelin, with CCK-AR in vagal afferent neurons. These results indicate that the vagus nerve plays a crucial role in determining peripheral energy balance. The efficiency of ghrelin and CCK signal transduction may depend on the balance of their respective plasma concentration and/or on interactions between GHS-R and CCK-AR.
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Affiliation(s)
- Yukari Date
- Third Department of Internal Medicine, Miyazaki Medical College, University of Miyazaki, Kiyotake, Miyazaki 889-1692, Japan.
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27
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Ladenheim EE, Emond M, Moran TH. Leptin enhances feeding suppression and neural activation produced by systemically administered bombesin. Am J Physiol Regul Integr Comp Physiol 2005; 289:R473-R477. [PMID: 15860644 DOI: 10.1152/ajpregu.00835.2004] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Leptin amplifies feeding inhibition and neural activation produced by either cholecystokinin or intragastric preloads, suggesting that leptin may increase the efficacy of gastrointestinal meal-related signals. To determine whether leptin would similarly potentiate the feeding inhibitory actions of another putative satiety peptide, we evaluated the effects of third ventricular leptin administration on food intake and c-Fos activation in response to systemically administered bombesin (BN). Leptin (3.5 microg) was administered 1 h before either 0.9% saline or BN (0.32 and 1.0 nmol/kg) followed by 30-min access to Ensure liquid diet. Although neither leptin nor 0.32 nmol/kg BN alone suppressed Ensure intake, the combination reduced intake by 28%. The higher BN dose (1.0 nmol/kg) produced a significant suppression by itself but was further enhanced in the presence of leptin. Consistent with the behavioral results, c-Fos activation in the nucleus of the solitary tract was increased by combined dosages of leptin and 0.32 nmol/kg BN beyond the individual response to either peptide. In the presence of leptin, BN produced a 3.4- to 5.2-fold increase in the number of c-Fos-positive cells in the nucleus of the solitary tract compared with when BN was given alone. These data provide further support for the hypothesis that the effect of leptin on food intake may be mediated, in part, by modulating meal-related satiety signals.
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Affiliation(s)
- Ellen E Ladenheim
- Dept. of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Ross 618, 720 Rutland Avenue, Baltimore, MD 21205, USA.
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Kraly FS. Eating provides important physiological signals for satiety and drinking. Physiol Behav 2004; 82:49-52. [PMID: 15234589 DOI: 10.1016/j.physbeh.2004.04.026] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2004] [Accepted: 04/02/2004] [Indexed: 10/26/2022]
Abstract
Eating has important physiological consequences. Experiments in which food and components of food are manipulated in ways to activate various food-contingent physiological signals have revealed mechanisms for eating-elicited satiety and thirst. This kind of approach also has revealed that eating can activate physiological signals for drinking to prevent challenges to fluid homeostasis.
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Affiliation(s)
- F Scott Kraly
- Neuroscience Program, Department of Psychology, Colgate University, 13 Oak Drive, Hamilton, NY 13346, USA.
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29
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30
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Bi S, Scott KA, Kopin AS, Moran TH. Differential roles for cholecystokinin a receptors in energy balance in rats and mice. Endocrinology 2004; 145:3873-80. [PMID: 15123537 DOI: 10.1210/en.2004-0284] [Citation(s) in RCA: 79] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Although cholecystokinin A (CCK-A) receptors (CCK-AR) mediate the feeding inhibitory actions of CCK in both rats and mice, the absence of CCK-AR results in species-specific phenotypes. The lack of CCK-AR in Otsuka Long-Evans Tokushima fatty (OLETF) rats results in hyperphagia and obesity. We have suggested that demonstrated increases in meal size and elevated levels of dorsomedial hypothalamic (DMH) neuropeptide Y (NPY) gene expression may contribute to this phenotype. In contrast to OLETF rats, CCK-AR(-/-) mice have normal total daily food intake and do not develop obesity. To assess the basis underlying the different phenotypes in rats and mice lacking CCK-AR, we characterized meal patterns in CCK-AR(-/-) mice and determined whether CCK-AR(-/-) mice exhibited an alteration in DMH NPY gene expression. We demonstrate that although CCK-AR(-/-) mice show a similar dysregulation in meal size as OLETF rats, they do not have an elevation in DMH NPY mRNA expression levels. In fact, intact mice have no CCK-AR in the DMH. Furthermore, in intact rats, NPY and CCK-AR are colocalized in DMH neurons, and parenchymal injection of CCK into the DMH reduces food intake and down-regulates DMH NPY mRNA expression. These results suggest that although CCK-AR plays a role in the mediation of CCK actions in the control of meal size in both rats and mice, CCK-AR seems to contribute to modulating DMH NPY levels only in rats. The deficit in CCK's action in the control of DMH NPY gene expression may play a major role in the obese phenotype in OLETF rats.
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Affiliation(s)
- Sheng Bi
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
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31
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Inui A, Asakawa A, Bowers CY, Mantovani G, Laviano A, Meguid MM, Fujimiya M. Ghrelin, appetite, and gastric motility: the emerging role of the stomach as an endocrine organ. FASEB J 2004; 18:439-56. [PMID: 15003990 DOI: 10.1096/fj.03-0641rev] [Citation(s) in RCA: 264] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Recent progress in the field of energy homeostasis was triggered by the discovery of adipocyte hormone leptin and revealed a complex regulatory neuroendocrine network. A late addition is the novel stomach hormone ghrelin, which is an endogenous agonist at the growth hormone secretagogne receptor and is the motilin-related family of regulatory peptides. In addition to its ability to stimulate GH secretion and gastric motility, ghrelin stimulates appetite and induces a positive energy balance leading to body weight gain. Leptin and ghrelin are complementary, yet antagonistic, signals reflecting acute and chronic changes in energy balance, the effects of which are mediated by hypothalamic neuropeptides such as neuropeptide Y and agouti-related peptide. Endocrine and vagal afferent pathways are involved in these actions of ghrelin and leptin. Ghrelin is a novel neuroendocrine signal possessing a wide spectrum of biological activities that illustrates the importance of the stomach in providing input into the brain. Defective ghrelin signaling from the stomach could contribute to abnormalities in energy balance, growth, and associated gastrointestinal and neuroendocrine functions.
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Affiliation(s)
- Akio Inui
- Division of Diabetes, Digestive and Kidney Diseases, Department of Clinical Molecular Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
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Cigaina V, Hirschberg AL. Gastric pacing for morbid obesity: plasma levels of gastrointestinal peptides and leptin. ACTA ACUST UNITED AC 2004; 11:1456-62. [PMID: 14694209 DOI: 10.1038/oby.2003.195] [Citation(s) in RCA: 63] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
OBJECTIVE A gastric pacemaker has been developed to treat morbid obesity. Patients experience increased satiety, the ability to reduce food intake, and a resultant weight loss. However, the mechanism behind the changed eating behavior in paced patients is still under investigation. RESEARCH METHODS AND PROCEDURES This study was performed on 11 morbidly obese patients (mean BMI, 46.0 kg/m2) treated with gastric pacing. The peripheral blood levels of satiety signals of cholecystokinin (CCK), somatostatin, glucagon-like peptide-1 (GLP-1), and leptin were studied 1 month before gastric pacer implantation, 1 month after implantation, and 6 months after activation of electrical stimulation. Blood samples were drawn 12 hours after fasting and in response to a hypocaloric meal (270 kcal). Patients were followed monthly for vital signs and weight level. RESULTS Gastric pacing resulted in a significant weight loss of a mean of 10.4 kg (4.4 BMI units). No negative side effects or complications were observed during the treatment. After activation of the pacemaker, meal-related response of CCK and somatostatin and basal levels of GLP-1 and leptin were significantly reduced (p < 0.05) compared with the tests before gastric pacing. The weight loss correlated significantly with a decrease of leptin levels (R = 0.79, p < 0.01). DISCUSSION Gastric pacing is a novel and promising therapy for morbid obesity. Activation of the gastric pacer was associated with a decrease in plasma levels of CCK, somatostatin, GLP-1, and leptin. More studies are necessary to elucidate the correlations between satiety, weight loss, and digestive neuro-hormone changes.
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Affiliation(s)
- Valerio Cigaina
- Unit of Digestive Electrophysiology and Obesity, Venice Hospital, Venice, Italy.
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Cain BM, Connolly K, Blum AC, Vishnuvardhan D, Marchand JE, Zhu X, Steiner DF, Beinfeld MC. Genetic inactivation of prohormone convertase (PC1) causes a reduction in cholecystokinin (CCK) levels in the hippocampus, amygdala, pons and medulla in mouse brain that correlates with the degree of colocalization of PC1 and CCK mRNA in these structures. J Neurochem 2004; 89:307-13. [PMID: 15056274 DOI: 10.1046/j.1471-4159.2003.02295.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Prohormone convertase (PC1) is found in endocrine cell lines that express cholecystokinin (CCK) mRNA and process pro CCK to biologically active products. Other studies have demonstrated that PC1 may be a one of the enzymes responsible for the endoproteolytic cleavages that occur in pro CCK during its biosynthesis and processing. Prohormone convertase 1 (PC1) has a distribution that is similar to cholecystokinin (CCK) in rat brain. A moderate to high percentage of CCK mRNA-positive neurons express PC1 mRNA. CCK levels were measured in PC1 knockout and control mice to assess the degree to which loss of PC1 changed CCK content. CCK levels were decreased 62% in hippocampus, 53% in amygdala and 57% in pons-medulla in PC1 knockout mice as compared to controls. These results are highly correlated with the colocalization of CCK and PC1. The majority of CCK mRNA-positive neurons in the pyramidal cell layer of the hippocampus express PC1 mRNA and greater than 50% of CCK mRNA-positive neurons in several nuclei of the amygdala also express PC1. These results demonstrate that PC1 is important for CCK processing. PC2 and PC5 are also widely colocalized with CCK. It may be that PC2, PC5 or another non-PC enzyme are able to substitute for PC1 and sustain production of some amidated CCK. Together these enzymes may represent a redundant system to insure the production of CCK.
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Affiliation(s)
- B M Cain
- Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, Massachusetts 02111, USA
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Cain BM, Connolly K, Blum A, Vishnuvardhan D, Marchand JE, Beinfeld MC, Vishnuvardham D. Distribution and colocalization of cholecystokinin with the prohormone convertase enzymes PC1, PC2, and PC5 in rat brain. J Comp Neurol 2004; 467:307-25. [PMID: 14608596 DOI: 10.1002/cne.10924] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
During posttranslational processing to generate CCK 8, pro-cholecystokinin (CCK) undergoes endoproteolytic cleavage at three sites. Several studies using endocrine and neuronal tumor cells in culture and recombinant enzymes and synthetic substrates in vitro have pointed to the subtilisin/kexin-like enzymes prohormone convertase (PC) 1, PC2, and PC5 as potential candidates for these endoproteolytic cleavages. In these experimental models, they all appear to be able to cleave pro-CCK to make the correct products. One rodent model has provided information about the role of PC2. PC2 knockout mouse brains had less CCK 8 than wild-type, although a substantial amount of CCK was still present. The degree to which CCK levels were reduced in these mice was regionally specific. These data indicated that PC2 is important for normal production of CCK but that it is not the only endoprotease that is involved in CCK processing. To evaluate whether PC1 and PC5 are possible candidates for the other enzymes involved in CCK processing, the distribution of PC1, PC2, and PC5 mRNA was studied in rat brain. Their colocalization with CCK mRNA was examined using double-label in situ hybridization. PC2 was the most abundant of these enzymes in terms of the intensity and number of cells labeled. It was widely colocalized with CCK. PC1 and PC5 mRNA-positive cells were less abundant, but they were also widely distributed and strongly colocalized with CCK in the cerebral cortex, hippocampus, amygdala, ventral tegmental area, and substantia nigra zona compacta. The degree of colocalization of the enzymes with CCK was regionally specific. It is clear that PC1 and PC5 are extensively colocalized with CCK and could be participating in CCK processing in the rat brain and may be able to substitute for PC2 in its absence. These three enzymes may represent a redundant system to ensure production of biologically active CCK.
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Affiliation(s)
- Brian M Cain
- Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, Massachusetts 02111, USA
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Kissileff HR, Carretta JC, Geliebter A, Pi-Sunyer FX. Cholecystokinin and stomach distension combine to reduce food intake in humans. Am J Physiol Regul Integr Comp Physiol 2003; 285:R992-8. [PMID: 12920059 DOI: 10.1152/ajpregu.00272.2003] [Citation(s) in RCA: 112] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The aim of this study was to test the hypothesis that gastric distension can enhance the effect of cholecystokinin (CCK) on reduction of food intake in men and women. Eight normal-weight subjects of each gender were tested four times each with either CCK or saline infusion crossed with gastric distension or no distension. Intravenous infusion of a low dose of CCK octapeptide (CCK-8; 112 ng/min for 23 min) combined with a subthreshold gastric distension induced by a water-filled balloon (300 ml) resulted in a significant (means +/- SED: 191 +/- 61 g in men, 209 +/- 61 g in women, and 200 +/- 43 g combined) reduction in intake of a liquid meal compared with saline infusion and unfilled gastric balloon. This combined effect was the result of a large and significant CCK effect when the stomach was distended (CCK vs. saline with distension: 169 +/- 43 g) and a small and insignificant distension effect (distension vs. no distension without CCK: 31 +/- 43 g). The CCK effect alone on intake (CCK vs. saline) without distension was not significant in men (72 +/- 61 g) but was significant in women (121 +/- 61 g). These results are consistent with the hypothesis that CCK's suppression of food intake is enhanced when the stomach is distended.
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Affiliation(s)
- Harry R Kissileff
- St. Luke's/Roosevelt Hospital, 1111 Amsterdam Ave., New York, NY 10025, USA.
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Abstract
BACKGROUND Because the stomach plays an important role in the development of satiety, gastric function was examined in bulimia nervosa (BN). METHODS Sixteen patients with BN and 16 controls swallowed an inflatable bag, which was positioned in the proximal stomach. Minimal distending pressure (MDP), the pressure needed to overcome intraabdominal pressure, was determined. Gastric volume was recorded after subjects drank a liquid meal. RESULTS MDP was similar in patient and control groups (7.56 +/- 2.13 vs. 7.13 +/- 2.06 mmHg; t =.57, df = 30, p =.58). Average postmeal gastric relaxation was significantly lower in the patient group (29.7 +/- 97.8 vs. 105.1 +/- 103.3 mL; t = 2.13, df = 30, p =.042). CONCLUSIONS Stomach relaxation following food consumption is significantly diminished in patients with BN. Physiologic abnormalities of stomach function in BN may contribute to the perpetuation of disturbances in behavior in this disorder.
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Affiliation(s)
- B Timothy Walsh
- Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, New York, USA
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Nolan LJ, Guss JL, Liddle RA, Pi-Sunyer FX, Kissileff HR. Elevated plasma cholecystokinin and appetitive ratings after consumption of a liquid meal in humans. Nutrition 2003; 19:553-7. [PMID: 12781859 DOI: 10.1016/s0899-9007(03)00039-x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
OBJECTIVE This study had two objectives. The first was to evaluate the possibility that, in a previous study, a soup preload augmented the reduction of food intake in a test meal induced by an exogenous infusion of cholecystokinin (CCK) because the soup also endogenously released CCK. The second was to compare CCK release by soup between men and women to determine whether the increased satiating effectiveness of soup in women as opposed to men could have been partly attributable to differences in CCK release. METHODS By using a bioassay that measures all of its known isoforms, we determined plasma CCK levels at baseline and at several times postprandially in eight healthy, non-obese men and women (four of each sex). Each subject ingested 800 g of tomato soup, which was followed 30 min later by 300 g of a yogurt shake. Appetitive ratings were also collected and related to CCK levels. RESULTS Ingestion of tomato soup significantly increased plasma CCK levels by 3.81 pmol/L (+/- 1.21 standard error, P = 0.016) over baseline within 30 min in all subjects combined. When CCK concentrations at 5 min after soup and 5 min after yogurt were averaged, the women's mean averaged concentration was 5.58 pmol/L (+/- 1.994, t = 2.80, P = 0.0073) higher than the men's. The elevated levels persisted but did not rise further upon consumption of the yogurt shake. Hunger ratings declined and fullness ratings increased after eating, although patterns of ratings did not match exactly patterns of CCK release. CONCLUSIONS A large quantity of tomato soup stimulates significant CCK release; therefore, some of the satiating effects of soup preloads could have been mediated by an elevation in endogenous CCK.
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Affiliation(s)
- Laurence J Nolan
- New York Obesity Research Center, St. Luke's-Roosevelt Hospital Center and Columbia University College of Physicians & Surgeons, 1111 Amsterdam Avenue, New York, NY 10025, USA
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Helm KA, Rada P, Hoebel BG. Cholecystokinin combined with serotonin in the hypothalamus limits accumbens dopamine release while increasing acetylcholine: a possible satiation mechanism. Brain Res 2003; 963:290-7. [PMID: 12560135 DOI: 10.1016/s0006-8993(02)04051-9] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Serotonin (5-HT) or cholecystokinin (CCK) injected in the hypothalamic paraventricular nucleus (PVN) inhibits feeding, but the mechanism is unknown. Prior research suggests that dopamine (DA) input to the nucleus accumbens (NAc) motivates behavior, and a component of that motivation circuit includes hypothalamic feeding systems. Acetylcholine (ACh) in the NAc, on the other hand, may act in part to inhibit feeding and generate satiety. If so, 5-HT and/or CCK in the PVN should lower extracellular DA or release ACh in the NAc. Rats were prepared with microdialysis probes in the NAc and injectors in the PVN. Serotonin (7.75 microg) or CCK-8 (0.12 microg) injected in the PVN significantly decreased ipsilateral accumbens DA (63 and 73% of baseline, respectively, without effect on ACh). However, 5-HT plus CCK injected in combination decreased DA to 72% (P<0.001) and simultaneously increased extracellular ACh to 128% of baseline (P<0.001). In later tests with the same doses and the same animals, unilateral PVN injections of 5-HT, CCK, or both combined, significantly inhibited food intake in the early dark period. The results suggest that 5-HT in the PVN acts as a neural modulator that primes a hypothalamic satiation system to respond to CCK when the gastrointestinal tract contains food to be digested. The synergistic action of 5-HT plus phasic CCK may then activate a circuit that simultaneously limits DA and releases ACh in the accumbens as part of the satiation process.
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Affiliation(s)
- Katherine A Helm
- Department of Psychology, Princeton University, Princeton, NJ 08544-1010, USA
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Ebenezer IS. The effects of a peripherally acting cholecystokinin1 receptor antagonist on food intake in rats: implications for the cholecystokinin-satiety hypothesis. Eur J Pharmacol 2003; 461:113-8. [PMID: 12586206 DOI: 10.1016/s0014-2999(02)02916-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
The observation that systemic administration of the peptide cholecystokinin (CCK) inhibits food intake in mammalian species has led to the hypothesis that endogenous peripheral CCK released from the small intestine during a meal acts as a satiety factor. It was predicted that if CCK does play an important role in satiety, then systemic administration of a specific CCK receptor antagonist should block the effects of the endogenous peptide released during a meal and increase food intake. The present study was undertaken to test the hypothesis by investigating the effects of the cholecystokinin(1) (CCK(1)) receptor antagonist N-alpha-3'-quinolinoyl-D-Glu-N,N-dipentylamide dicyclohexylammonium (A70104), which is unlikely to cross the blood-brain barrier, on food intake in rats. A70104 (20-200 microg/kg, i.p.) had no any significant effect on the intake of a test meal in rats under different experimental conditions. However, pretreatment of rats with A70104 (50 microg/kg, i.p.) abolished the inhibitory effects of exogenous peripheral CCK (5 microg/kg, i.p.) on food intake. The findings that A70104 had no effect on food intake when administered on its own, but abolishes the suppressant effect of exogenous peripheral CCK, suggest that endogenously released peripheral CCK does not play an important role as a satiety factor in rats.
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Affiliation(s)
- Ivor S Ebenezer
- Neuropharmacology Research Group, School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, Hampshire, PO1 2DT, England, UK.
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Abstract
Pro Cholecystokinin (CCK) like other prohormones that pass through the regulated secretory pathway, undergoes a number of post-translational modifications during its biosynthesis including tyrosine sulfation, endoproteolytic cleavages, trimming by carboxypeptidase and c-terminal amidation. This minireview summarizes what is known about this process, what specific enzymes are involved in endocrine and neuronal tumor cells and in mutant and knockout mouse strains. It also points out the major challenges that remain for future research.
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Affiliation(s)
- Margery C Beinfeld
- Department of Pharmacology and Experimental Therapeutics, School of Medicine, Tufts University, 136 Harrison Ave., Boston, MA 02111, USA.
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Campfield LA, Smith FJ. Blood glucose dynamics and control of meal initiation: a pattern detection and recognition theory. Physiol Rev 2003; 83:25-58. [PMID: 12506126 DOI: 10.1152/physrev.00019.2002] [Citation(s) in RCA: 95] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
A new framework for understanding the control of feeding behavior, with special emphasis on the evolution of hunger, the initiation of feeding, and its dependence on patterns of blood glucose, is the subject of this review. A perspective on the current status and future directions of this search for a more complete understanding of the regulation of feeding behavior in laboratory rats and humans is presented including theoretical and experimental components. First, a historical perspective on the role of blood glucose in the control of feeding is presented. Next, the theoretical approaches that have been applied to the control of feeding and had a strong influence on experimental feeding research are summarized. This is followed by a statement and overview of a current theory that has emerged from studies of the role of transient declines in blood glucose in the control of meal initiation. The current working hypothesis that transient declines in blood glucose are endogenous metabolic patterns that are detected and recognized by the central nervous system and are mapped into meal initiation in rats and are correlated with meal requests in humans are then presented. Then, the experimental studies on meal initiation and its dependence on patterns of blood glucose, first in rats and then in humans, are reviewed in detail. Finally, the future directions of the work, limitations, and the implications for the understanding of the control of feeding behavior and the regulation of energy balance are discussed.
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Affiliation(s)
- L Arthur Campfield
- Department of Food Science and Human Nutrition, College of Applied Human Sciences, Colorado State University, Fort Collins, Colorado 80523, USA.
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Abstract
The growing recognition of the health risks of obesity coupled with the difficulties in treating it successfully by lifestyle modification predicates a need for effective drug treatment. The history of drug treatment in the second half of the 20th century is, however, one of disappointment and concern over drug toxicity. However, the advances in our understanding of the mechanism of weight control, together with improved ways of evaluating anti-obesity drugs, has resulted in two effective compounds, sibutramine and orlistat, becoming available for clinical use. Sibutramine has actions on both energy intake and expenditure and had been shown to enhance weight loss and weight maintenance achieved by diet, in simple obesity as well as when accompanied by complications of diabetes or hypertension. About 50-80% of patients can achieve a >5% loss, significantly more than if patients receive the same lifestyle intervention with placebo. Orlistat, which acts peripherally to block the absorption of dietary fat, has had similar results in clinical trials; a recent study (XENDOS) has just reported results which show that the enhanced, albeit modest, weight loss achieved with orlistat delays the development of diabetes over a 4-year period. A number of other compounds are expected to complete or enter clinical trials over the next decade. There is considerable optimism that we will soon have the pharmacological tools needed to make the treatment of obesity feasible.
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Affiliation(s)
- N Finer
- Wellcome Trust Clinical Research Facility, Addenbrooke's Hospital, Cambridge, UK
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Barsh GS, Schwartz MW. Genetic approaches to studying energy balance: perception and integration. Nat Rev Genet 2002; 3:589-600. [PMID: 12154382 DOI: 10.1038/nrg862] [Citation(s) in RCA: 280] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Affiliation(s)
- Gregory S Barsh
- [1] Department of Pediatrics, Stanford University School of Medicine, Stanford, California 94305-5208, USA.
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Burns AA, Livingstone MBE, Welch RW, Dunne A, Rowland IR. Dose-response effects of a novel fat emulsion (Olibra) on energy and macronutrient intakes up to 36 h post-consumption. Eur J Clin Nutr 2002; 56:368-77. [PMID: 11965514 DOI: 10.1038/sj.ejcn.1601326] [Citation(s) in RCA: 43] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2001] [Revised: 08/29/2001] [Accepted: 09/06/2001] [Indexed: 11/09/2022]
Abstract
OBJECTIVE To investigate the dose-response effects of a novel fat emulsion (Olibra) on energy and macronutrient intakes up to 36 h post-consumption in non-overweight subjects. DESIGN A single-blind, placebo-controlled, within-subject cross-over design was used. SETTING Metabolic suite of the University of Ulster, Coleraine. SUBJECTS Fifty subjects (30 female, 20 male) from the student and staff population of the University of Ulster, Coleraine. INTERVENTIONS Subjects were given in random order, 7 days apart, a 200 g portion of yoghurt containing a total of 15 g of fat, which varied in quantity of Olibra fat (0, 2, 4, 6 g) at 09:00 h. At 13:00 h subjects were given ad libitum access to a range of foods. Amounts of food consumed were measured by covert pre- and post-consumption weighing of individual serving dishes. For the remainder of the day and the following 24 h, subjects weighed and recorded all food intakes. RESULTS Relative to the control yoghurt, mean energy (7.42 vs 5.83, 5.60, 5.24 MJ), fat (97.4 vs 74.4, 74.2, 67.5 g; 48.8 vs 46.8, 48.9, 47.6% energy), protein (59.1 vs 50.0, 44.0, 40.8 g; 13.2 vs 13.9, 12.9, 12.8% energy), and carbohydrate (171.5 vs 140.9, 130.2, 126.0 g; 38.0 vs 39.3, 38.2, 39.6% energy), intakes were progressively reduced with increasing doses of Olibra fat in the total group (P<0.001). A similar response was observed in the female group up to 4 g (P<0.001) and in the male group after 2 and 6 g (P<0.05). Energy and macronutrient intakes for the remainder of each study day and over the following 24 h were significantly lower after all dose levels compared to the control (P<0.001). CONCLUSION The results suggest that Olibra fat reduced the effect of overeating during an ad libitum lunch meal and subsequent food intake up to 36 h post-consumption.
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Affiliation(s)
- A A Burns
- The Northern Ireland Centre for Diet and Health, University of Ulster, Coleraine, Co Londonderry, Northern Ireland, UK
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Gärtner K. The forestomach of rats and mice, an effective device supporting digestive metabolism in muridae (review). ACTA ACUST UNITED AC 2002. [DOI: 10.1016/s0939-8600(02)80002-5] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Benson RSP, Sidhu S, Jones MN, Case RM, Thompson DG. Fatty acid signalling in a mouse enteroendocrine cell line involves fatty acid aggregates rather than free fatty acids. J Physiol 2002; 538:121-31. [PMID: 11773321 PMCID: PMC2290028 DOI: 10.1113/jphysiol.2001.012969] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
Fatty acids induce cholecystokinin (CCK) secretion both in humans and from murine enteroendocrine cell lines. In both cases, only fatty acids above a critical acyl chain length (C(10)) are capable of inducing a response. Using the enteroendocrine cell line STC-1, the aim of this study was to determine whether this acyl chain length dependency is related to the fact that longer chain fatty acids are relatively insoluble in aqueous solutions and, if so, whether it is insoluble aggregates of fatty acids rather than free fatty acids which evoke CCK secretion. Solutions of fatty acids (chain length C(8)-C(14)), which were judged by filtration and Zeta sizer measurement to contain no fatty acid aggregates, never evoked CCK secretion from STC-1 cells. Filtering fatty acid solutions (of chain length C(10), C(12) and C(14)) through polytetrafluoroethylene (PTFE) filters (0.45 microm pore size) revealed a narrow concentration range for each acid over which the amount of fatty acid removed from the solution increased sharply due to the formation of fatty acid aggregates. Filtration experiments, in which suspensions of C(10), C(12) and C(14) fatty acids were passed through pore sizes of 0.2, 0.45 or 1.2 microm, suggested that STC-1 cells did not respond to fatty acid aggregates of greater than 1.2 microm, while at least 50 % of the CCK response was mediated by aggregates which were smaller than 0.45 microm. Fatty acids induce CCK secretion from STC-1 cells by elevating intracellular Ca(2+) concentration ([Ca(2+)](i)). We therefore measured the effects on [Ca(2+)](i) of filtered C(10), C(12) and C(14) fatty acids. In all cases, [Ca(2+)](i) responses were closely correlated with CCK secretion. Interestingly, while filtrates of fatty acid solutions evoked CCK secretion and elevated [Ca(2+)](i), freshly prepared solutions of fatty acids at the same concentration as the filtrates did not. This suggested that fatty acid aggregates were not in equilibrium with the solvent after filtration. The observation that the ability of C(10), C(12) and C(14) filtrates to elevate [Ca(2+)](i) decayed with time was consistent with this hypothesis. Furthermore, sonication of the filtrates abolished their ability to elevate [Ca(2+)](i). These data further suggest that it is a physical property of the fatty acid solution (the presence of insoluble fatty aggregates) which is responsible for the observed cellular responses. We conclude that Ca(2+) mobilisation and CCK secretion in STC-1 cells is driven by a signal transduction mechanism that senses insoluble fatty acid aggregates, rather than free fatty acids in solution.
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Affiliation(s)
- R S P Benson
- School of Biological Sciences, The University of Manchester, Manchester, UK.
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Havel PJ. Peripheral signals conveying metabolic information to the brain: short-term and long-term regulation of food intake and energy homeostasis. Exp Biol Med (Maywood) 2001; 226:963-77. [PMID: 11743131 DOI: 10.1177/153537020122601102] [Citation(s) in RCA: 290] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Numerous peripheral signals contribute to the regulation of food intake and energy homeostasis. Mechano- and chemoreceptors signaling the presence and energy density of food in the gastrointestinal (GI) tract contribute to satiety in the immediate postprandial period. Changes in circulating glucose concentrations appear to elicit meal initiation and termination by regulating activity of specific hypothalamic neurons that respond to glucose. Other nutrients (e.g., amino acids and fatty acids) and GI peptide hormones, most notably cholecystokinin, are also involved in short-term regulation of food intake. However, the energy density of food and short-term hormonal signals by themselves are insufficient to produce sustained changes in energy balance and body adiposity. Rather, these signals interact with long-term regulators (i.e., insulin, leptin, and possibly the orexigenic gastric peptide, ghrelin) to maintain energy homeostasis. Insulin and leptin are transported into the brain where they modulate expression of hypothalamic neuropeptides known to regulate feeding behavior and body weight. Circulating insulin and leptin concentrations are proportional to body fat content; however, their secretion and circulating levels are also influenced by recent energy intake and dietary macronutrient content. Insulin and leptin concentrations decrease during fasting and energy-restricted diets, independent of body fat changes, ensuring that feeding is triggered before body energy stores become depleted. Dietary fat and fructose do not stimulate insulin secretion and leptin production. Therefore, attenuated production of insulin and leptin could lead to increased energy intake and contribute to weight gain and obesity during long-term consumption of diets high in fat and/or fructose. Transcription of the leptin gene and leptin secretion are regulated by insulin-mediated increases of glucose utilization and appear to require aerobic metabolism of glucose beyond pyruvate. Other adipocyte-derived hormones and proteins that regulate adipocyte metabolism, including acylation stimulating protein, adiponectin, diacylglycerol acyltransferase, and perilipin, are likely to have significant roles in energy homeostasis.
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Affiliation(s)
- P J Havel
- Department of Nutrition, University of California, Davis, California 95616, USA.
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Cooper GJS. Amylin and Related Proteins: Physiology and Pathophysiology. Compr Physiol 2001. [DOI: 10.1002/cphy.cp070210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Bray GA, York DA. Obesity. Compr Physiol 2001. [DOI: 10.1002/cphy.cp070234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
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Affiliation(s)
- A Inui
- Division of Diabetes, Digestive and Kidney Diseases, Department of Clinical Molecular Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
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