cholecystokinin and Anorexia

 Various neuropeptides play an essential role in the nutrient sensing mechanism and related homeostasis. Nesfatin-1 is a newly identified neuropeptide having anorectic activity, and nesfatin-1-containing neurons are widely distributed in the brain, including the hypothalamus and brain stem. Our previous study showed that dehydration-induced anorectic effects are mediated via the central nesfatin-1 pathway in rats. Our recent studies have also shown that peripheral anorectic peptides (cholecystokinin-8, glucagon-like peptide-1, and leptin) and an antineoplastic agent (cisplatin) caused inhibition of feeding via the central nesfatin-1 pathway in rats. Nesfatin-1-containing neurons in the central nervous system, in particular the hypothalamus and the brain stem, may mediate peripheral nutrient signals and regulate feeding behavior.

Topics: Animals; Anorexia; Antineoplastic Agents; Brain Stem; Calcium-Binding Proteins; Cholecystokinin; Cisplatin; DNA-Binding Proteins; Eating; Food; Glucagon-Like Peptide 1; Hypothalamus; Leptin; Male; Nerve Tissue Proteins; Nucleobindins; Nutritional Physiological Phenomena; Rats, Wistar; Signal Transduction

Topics: Animals; Anorexia; Appetite; Cholecystokinin; Digestion; Glucagon-Like Peptide 1; Humans; Hypothalamus; Insulin; Norepinephrine

Appetite and food intake decrease with normal ageing, predisposing to the development of under-nutrition. Under-nutrition is common in older people and has been implicated in the development and progression of chronic diseases commonly affecting the elderly, as well as in increasing mortality. An understanding of the factors that contribute to the physiological and pathological declines in food intake in older people is likely to aid in the development of effective forms of prevention and treatment. Ageing affects many of the endocrine factors involved in the control of appetite and feeding but few studies have been performed in humans to clarify these changes. Possible hormonal causes of the anorexia of ageing include increased activity of cholecystokinin, leptin and various cytokines and reduced activity of ghrelin and testosterone.

Topics: Aged; Aging; Androgens; Animals; Anorexia; Appetite Regulation; Cholecystokinin; Cytokines; Ghrelin; Hormones; Humans; Leptin; Neurotransmitter Agents; Peptide Hormones; Protein-Energy Malnutrition

Ageing is associated with a reduction in appetite and food intake, which has been termed the 'anorexia of ageing'. After age 70-75 years average body weight decreases, even in healthy people, disproportionately due to loss of lean tissue. The 'physiological' anorexia and weight loss of ageing predispose to pathological weight loss and malnutrition. Marked weight loss is common in the elderly and a major cause of morbidity and increased mortality. The cause(s) of the anorexia of ageing are largely unknown. We have identified several possibilities. Animal and preliminary human studies indicate that ageing is associated with increased satiety factors and a reduced feeding drive. Endogenous opioids stimulate eating. We administered i.v. infusions of the opioid antagonist naloxone to young and older adults. Overall, the suppression of food intake was not different in the two age groups, but was increased in older women, suggesting reduced stimulation of feeding by endogenous opioids in this group. Plasma concentrations of the satiety hormone cholecystokinin (CCK) increase with ageing. Intravenous CCK-8 infusion produced greater suppression of food intake in older than young subjects (33.5 vs 15.5% P = 0.026), indicating that sensitivity to the satiating effects of CCK is at least maintained and may increase with age. This raises the possibility of using CCK antagonists as stimulants of appetite and food intake in malnourished older people.

Topics: Aged; Aging; Animals; Anorexia; Cholecystokinin; Female; Humans; Male

Anorexia during infection is thought to be mediated by immunoregulatory cytokines such as interleukins 1 and 6 and tumor necrosis factor. This article reviews the potential mechanisms of action by which these cytokines are thought to suppress food intake during infection and examines the proposition that blocking of cytokine activity might be one approach to improving food intake of the infected host.

Topics: Acute-Phase Reaction; Animals; Anorexia; Cholecystokinin; Cytokines; Dinoprostone; Disease Models, Animal; Eating; Fever; Gastroparesis; Humans; Infections; Inflammation Mediators; Leptin; Vagus Nerve

Immune-induced cachetic response is an example of a biological opportunity to develop technologies that ensure improved performance in animal agriculture. We have estimated that reduced performance of immune stimulated animals, whether by exposure to conventional environments or through vaccination, results in more than U.S. $500 million in reduced productivity. Nontraditional methods to alleviate the adverse effects of the immune response provide an opportunity for those skilled in the art of vaccinology and immunology to develop new technologies and feeding practices. Too often, biologists are blinded by the limits of their disciplines and rarely venture to the fringe of their field to engage in collaborations that at first glance do not seem logical. The examples of CLA and antigastrointestinal peptides suggest that new opportunities await in ensuring that the cost of the immune response is minimized and that new approaches to animal agriculture await discovery.

Topics: Animal Nutritional Physiological Phenomena; Animals; Anorexia; Cholecystokinin; Drug Design; Linoleic Acid; Vaccination

This article explores the mechanisms by which peripheral gastrointestinal hormones produce central nervous system effects on memory and feeding. Cholecystokinin produces its satiety effects and memory-enhancing effects by stimulating ascending vagal fibers. Hyperglycemia has been demonstrated to be a cause of memory dysfunction in persons with diabetes mellitus. A number of other hormones, such as amylin and bombesin, modulate both memory processing and feeding. The causes of the anorexia of aging are briefly reviewed.

Topics: Aging; Animals; Anorexia; Appetite; Blood Glucose; Brain; Cholecystokinin; Eating; Gastrointestinal Hormones; Hormones; Humans; Insulin; Memory; Neuropeptides

Healthy aging is associated with reductions in appetite and food intake--the so-called anorexia of aging, which may predispose to protein-energy malnutrition. One possible cause of the anorexia of aging is an increased satiating effect of cholecystokinin (CCK). To investigate the impact of aging on the satiating effects of CCK, 12 young and 12 older healthy subjects received 25-min iv infusions of saline (control) and CCK-8, 1 ng/kg per min or 3 ng/k per min, on 3 separate days before a test meal. Older subjects ate less than young subjects, and food intake was suppressed 21.6% by CCK-8, compared with the control day (P < 0.05). The suppression of energy intake by CCK-8 in older subjects was twice that in young subjects (32 +/- 6% vs. 16 +/- 6% SEM, P < 0.05) and was related to plasma CCK-8 concentrations, which were higher at baseline (P < 0.05) and increased more during CCK-8 infusions in older than young subjects (P < 0.01). The extent of suppression of food intake per given rise in plasma CCK-8 concentrations did not differ between the two age groups (P = 0.35). Endogenous CCK concentrations were higher at baseline in older subjects (P < 0.001) and decreased during the CCK-8 but not control infusions (P < 0.01), suggesting that CCK suppresses its own release. Plasma leptin concentrations were not affected by CCK infusion, whereas postprandial insulin concentrations were lowered and the peak postprandial glucose concentration was delayed but not affected by CCK-8 infusion. Because older people retain their sensitivity to the satiating effects of exogenous CCK and plasma endogenous CCK concentrations are higher in older people, increased CCK activity may contribute to the anorexia of aging.

Topics: Adult; Aged; Aged, 80 and over; Aging; Anorexia; Blood Glucose; Cholecystokinin; Eating; Fasting; Female; Humans; Hunger; Injections, Intravenous; Insulin; Leptin; Male; Nausea; Osmolar Concentration; Satiety Response; Sincalide

Anorexia of aging, defined as a decrease in appetite and a preponderant loss of body weight occurring in late life, is one of the most common diseases affecting older people. The peptide hormone cholecystokinin (Cck) is known to play a key role in regulating food intake and satiety in higher vertebrates. In humans as well as in rats, an increased concentration of Cck was described as the basis of appetite loss in elderly. However, the role of increased plasma Cck concentrations in mediating the age-related decrease in appetite remains to be established. Although in vitro studies are an excellent resource for investigating aging, the use of a model organism that shares and imitates the human physiological processes guarantees a better understanding of the in vivo mechanisms. African annual fishes from the genus Nothobranchius are emerging as a prominent model organism in biogerontology and developmental biology due to their short captive lifespan. Therefore, in the current study, we aimed to investigate the possibility of using the genus Nothobranchius to model the anorexia of aging and their potential contribution to better understanding the pathway by which Cck induce appetite loss in older people providing a comparative/evolutionary localization of the current study model among the aging canonicals models, the morphology of its gastrointestinal tract and its Cck expression pattern.. The comparative/evolutionary investigation was conducted using the NCBI blastp (protein-protein BLAST) and NCBI Tree Viewer. The macroscopic morphology, histological features, ultrastructural organization of Nothobranchius rachovii gastrointestinal tract were investigated using stereomicroscope, Masson's trichrome and alcian blue-PAS staining, and transmission electron microscopy, respectively. The cck expression pattern was studied through immunofluorescence labeling, western blotting, and quantitative RT-PCR.. The intestine was folded into different segments divided into an anterior intestine made of a rostral intestinal bulb and an intestinal annex of lower diameter, mid and posterior intestine. The gradual transition from the rostral intestinal bulb to the posterior intestine sections's epithelium is characterized by a gradual reduction in the striated muscular bundles, villi height, and goblet mucous cells count. The lining epithelium of the intestinal villi was characterized by a typical brush border enterocytes full of mitochondria. Moreover, Cck expression was detected in scattered intraepithelial cells concentrated in the anterior tract of the intestine.. Our study introduces Nothobranchius rachovii as a model for anorexia of aging, giving the first bases on the gastrointestinal tract morphology and cck expression pattern. Future studies on young and elderly Notobranchius can divulge the contribution of cck in the mechanisms of anorexia associated with aging.

Topics: Aged; Aging; Animals; Anorexia; Appetite; Cholecystokinin; Geroscience; Humans; Rats

To evaluate whether the potent hypophagic and weight-suppressive effects of growth differentiation factor-15 (GDF15) and semaglutide combined would be a more efficacious antiobesity treatment than either treatment alone by examining whether the neural and behavioural mechanisms contributing to their anorectic effects were common or disparate.. Three mechanisms were investigated to determine how GDF15 and semaglutide induce anorexia: the potentiation of the intake suppression by gastrointestinal satiation signals; the reduction in motivation to feed; and the induction of visceral malaise. We then compared the effects of short-term, combined GDF15 and semaglutide treatment on weight loss to the individual treatments. Rat pharmaco-behavioural experiments assessed whether GDF15 or semaglutide added to the satiating effects of orally gavaged food and exogenous cholecystokinin (CCK). A progressive ratio operant paradigm was used to examine whether GDF15 or semaglutide reduced feeding motivation. Pica behaviour (ie, kaolin intake) and conditioned affective food aversion testing were used to evaluate visceral malaise. Additionally, fibre photometry studies were conducted in agouti-related protein (AgRP)-Cre mice to examine whether GDF15 or semaglutide, alone or in combination with CCK, modulate calcium signalling in hypothalamic AgRP neurons.. Semaglutide reduced food intake by amplifying the feeding-inhibitory effect of CCK or ingested food, inhibited the activity of AgRP neurons when combined with CCK, reduced feeding motivation and induced malaise. GDF15 induced visceral malaise but, strikingly, did not affect feeding motivation, the satiating effect of ingested food or CCK signal processing. Combined GDF15 and semaglutide treatment produced greater food intake and body weight suppression than did either treatment alone, without enhancing malaise.. GDF15 and semaglutide reduce food intake and body weight through largely distinct processes that produce greater weight loss and feeding suppression when combined.

Topics: Agouti-Related Protein; Animals; Anorexia; Body Weight; Cholecystokinin; Eating; Glucagon-Like Peptides; Growth Differentiation Factor 15; Mice; Rats; Weight Loss

The cytokine, GDF15, is produced in pathological states which cause cellular stress, including cancer. When over expressed, it causes dramatic weight reduction, suggesting a role in disease-related anorexia. Here, we demonstrate that the GDF15 receptor, GFRAL, is located in a subset of cholecystokinin neurons which span the area postrema and the nucleus of the tractus solitarius of the mouse. GDF15 activates GFRAL

Topics: Animals; Anorexia; Brain Stem; Cholecystokinin; Growth Differentiation Factor 15; Male; Mice; Mice, Inbred C57BL; Neurons; Pica; Random Allocation; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Signal Transduction

Anorexia is a hallmark of animal and human exposed to T-2 toxin, a most poisonous trichothecene mycotoxins contaminating various cereal grains including wheat, corn and barley. Although this adverse effect has been well characterized in several animal species, the underlying mechanisms are unclear. The goal for this study was to elucidate the roles of two gut satiety hormones, glucagon-like peptide-1

Topics: Animals; Anorexia; Cholecystokinin; Dose-Response Relationship, Drug; Eating; Female; Glucagon-Like Peptide 1; Mice; Mice, Inbred Strains; Peptide Fragments; T-2 Toxin

Ghrelin is an important gut-derived hormone with an appetite stimulatory role, while most of the intestinal hormones, including cholecystokinin (CCK), peptide YY (PYY) and glucagon-like peptide-1 (GLP-1), are appetite-inhibitors. Whether these important peptides with opposing roles on food intake interact to regulate energy balance in fish is currently unknown. The aim of this study was to characterize the putative crosstalk between ghrelin and CCK, PYY and GLP-1 in goldfish (Carassius auratus). We first determined the localization of CCK, PYY and GLP-1 in relation to ghrelin and its main receptor GHS-R1a (growth hormone secretagogue 1a) in the goldfish intestine by immunohistochemistry. Colocalization of ghrelin/GHS-R1a and CCK/PYY/GLP-1 was found primarily in the luminal border of the intestinal mucosa. In an intestinal explant culture, a significant decrease in prepro-cck, prepro-pyy and proglucagon transcript levels was observed after 60min of incubation with ghrelin, which was abolished by preincubation with the GHS-R1a ghrelin receptor antagonist [D-Lys3]-GHRP-6 (except for proglucagon). The protein expression of PYY and GLP-1 was also downregulated by ghrelin. Finally, intraperitoneal co-administration of CCK, PYY or GLP-1 with ghrelin results in no modification of food intake in goldfish. Overall, results of the present study show for the first time in fish that ghrelin exerts repressive effects on enteric anorexigens. It is likely that these interactions mediate the stimulatory effects of ghrelin on feeding and metabolism in fish.

Topics: Animals; Anorexia; Appetite; Appetite Depressants; Cholecystokinin; Eating; Female; Ghrelin; Glucagon-Like Peptide 1; Goldfish; Intestinal Mucosa; Intestines; Male; Oligopeptides; Peptide YY; Protein Precursors; Receptors, Ghrelin

Topics: Animals; Anorexia; Appetite Regulation; Behavior, Animal; Cholecystokinin; Disease Models, Animal; Feeding Behavior; Female; Glucagon-Like Peptide 1; Mice; Peptide Fragments; Satiety Response; Signal Transduction; T-2 Toxin; Time Factors; Trichothecenes; Up-Regulation

Food contamination by the trichothecene mycotoxin deoxynivalenol (DON, vomitoxin) has the potential to adversely affect animal and human health by suppressing food intake and impairing growth. In mice, the DON-induced anorectic response results from aberrant satiety hormone secretion by enteroendocrine cells (EECs) of the gastrointestinal tract. Recent in vitro studies in the murine STC-1 EEC model have linked DON-induced satiety hormone secretion to activation of calcium-sensing receptor (CaSR), a G-coupled protein receptor, and transient receptor potential ankyrin-1 (TRPA1), a TRP channel. However, it is unknown whether similar mechanisms mediate DON's anorectic effects in vivo. Here, we tested the hypothesis that DON-induced food refusal and satiety hormone release in the mouse are linked to activation of CaSR and TRPA1. Oral treatment with selective agonists for CaSR (R-568) or TRPA1 (allyl isothiocyanate (AITC)) suppressed food intake in mice, and the agonist's effects were suppressed by pretreatment with corresponding antagonists NPS-2143 or ruthenium red (RR), respectively. Importantly, NPS-2143 or RR inhibited both DON-induced food refusal and plasma elevations of the satiety hormones cholecystokinin (CCK) and peptide YY

Topics: Animals; Anorexia; Appetite Depressants; Appetite Stimulants; Behavior, Animal; Cholecystokinin; Drug Therapy, Combination; Energy Intake; Environmental Pollutants; Female; Models, Biological; Peptide Fragments; Peptide YY; Random Allocation; Receptors, Calcium-Sensing; Receptors, G-Protein-Coupled; Satiety Response; Transient Receptor Potential Channels; Trichothecenes; TRPA1 Cation Channel

The lateral parabrachial nucleus is a conduit for visceral signals that cause anorexia. We previously identified a subset of neurons located in the external lateral parabrachial nucleus (PBel) that express calcitonin gene-related peptide (CGRP) and inhibit feeding when activated by illness mimetics. We report here that in otherwise normal mice, functional inactivation of CGRP neurons markedly increases meal size, with meal frequency being reduced in a compensatory manner, and renders mice insensitive to the anorexic effects of meal-related satiety peptides. Furthermore, CGRP neurons are directly innervated by orexigenic hypothalamic AgRP neurons, and photostimulation of AgRP fibers supplying the PBel delays satiation by inhibiting CGRP neurons, thereby contributing to AgRP-driven hyperphagia. By establishing a role for CGRP neurons in the control of meal termination and as a downstream mediator of feeding elicited by AgRP neurons, these findings identify a node in which hunger and satiety circuits interact to control feeding behavior.

Topics: Agouti-Related Protein; Animals; Anorexia; Calcitonin Gene-Related Peptide; Central Amygdaloid Nucleus; Cholecystokinin; Feeding Behavior; Glucagon-Like Peptide-1 Receptor; Hyperphagia; Leptin; Mice, Inbred C57BL; Neurons; Parabrachial Nucleus; Satiety Response

The central nervous system controls food consumption to maintain metabolic homoeostasis. In response to a meal, visceral signals from the gut activate neurons in the nucleus of the solitary tract (NTS) via the vagus nerve. These NTS neurons then excite brain regions known to mediate feeding behaviour, such as the lateral parabrachial nucleus (PBN). We previously described a neural circuit for appetite suppression involving calcitonin gene-related protein (CGRP)-expressing PBN (CGRP(PBN)) neurons; however, the molecular identity of the inputs to these neurons was not established. Here we identify cholecystokinin (CCK) and noradrenergic, dopamine β-hydroxylase (DBH)-expressing NTS neurons as two separate populations that directly excite CGRP(PBN) neurons. When these NTS neurons are activated using optogenetic or chemogenetic methods, food intake decreases and with chronic stimulation mice lose body weight. Our optogenetic results reveal that CCK and DBH neurons in the NTS directly engage CGRP(PBN) neurons to promote anorexia.

Topics: Action Potentials; Animals; Anorexia; Anxiety; Calcitonin Gene-Related Peptide; Cholecystokinin; Dopamine beta-Hydroxylase; Eating; Mice, Inbred C57BL; Neural Pathways; Neurons; Parabrachial Nucleus; Proto-Oncogene Proteins c-fos; Solitary Nucleus

A high-altitude environment causes appetite loss in unacclimatised humans, leading to weight reduction. Ghrelin, cholecystokinin (CCK), and glucagon like peptide-1 (GLP-1), are gut hormones involved in the regulation of food intake and energy metabolism. The liver is an important site of metabolic regulation, and together with the gut it plays a role in food intake regulation. This study intends to study the time-dependent changes occurring in plasma gut hormones, PPARα, PPARδ, and PGC1α, in the stomach and liver during hypoxia.. Male Sprague Dawley rats were exposed to hypobaric hypoxia in a decompression chamber at 7620 m for different durations up to seven days.. Hypoxia increased circulating ghrelin from the third day onwards while CCK and GLP-1 decreased immediately. An increase in ghrelin, ghrelin receptor protein levels, and GOAT mRNA levels in the stomach was observed. Stomach cholecystokinin receptor (CCKAR), PPARα, and PPARδ decreased. Liver CCKAR decreased during the first day of hypoxia and returned to normal levels from the third day onwards. PPARα and PGC1α expression increased while PPARδ protein levels reduced in the liver on third day.. Hypoxia alters the expression of ghrelin and ghrelin receptor in the stomach, CCKAR in the liver, and PPAR and its cofactors, which might be possible role players in the contribution of gut and liver to anorexia at high altitude.

Topics: Animals; Anorexia; Cholecystokinin; Disease Models, Animal; Gastric Mucosa; Gene Expression Regulation; Ghrelin; Glucagon-Like Peptide 1; Hypoxia; Liver; Male; Peroxisome Proliferator-Activated Receptors; Rats; Rats, Sprague-Dawley

Deoxynivalenol (DON), a trichothecene mycotoxin that commonly contaminates cereal grains, is a public health concern because of its adverse effects on the gastrointestinal and immune systems. The objective of this study was to compare effects of DON on anorectic responses in aged (22 mos) and adult (3 mos) mice. Aged mice showed increased feed refusal with both acute i.p. (1 mg/kg and 5 mg/kg) and dietary (1, 2.5, 10 ppm) DON exposure in comparison to adult mice. In addition to greater suppression of food intake from dietary DON exposure, aged mice also exhibited greater but transient body weight suppression. When aged mice were acutely exposed to 1 mg/kg bw DON i.p., aged mice displayed elevated DON and DON3GlcA tissue levels and delayed clearance in comparison with adult mice. Acute DON exposure also elicited higher proinflammatory cytokine and satiety hormone responses in the plasma of the aged group compared with the adult group. Increased susceptibility to DON-induced anorexia in aged mice relative to adult mice suggests that advanced life stage could be a critical component in accurate human risk assessments for DON and other trichothecenes.

Topics: Aging; Animals; Anorexia; Body Weight; Cholecystokinin; Cytokines; Eating; Male; Mice, Inbred C57BL; Peptide YY; Satiety Response; Tissue Distribution; Trichothecenes

Cereal grain contamination by trichothecene mycotoxins is known to negatively impact human and animal health with adverse effects on food intake and growth being of particular concern. The head blight fungus Fusarium graminearum elaborates five closely related 8-ketotrichothecene congeners: (1) deoxynivalenol (DON), (2) 3-acetyldeoxynivalenol (3-ADON), (3) 15-acetyldeoxynivalenol (15-ADON), (4) fusarenon X (FX), and (5) nivalenol (NIV). While anorexia induction in mice exposed intraperitoneally to DON has been linked to plasma elevation of the satiety hormones cholecystokinin (CCK) and peptide YY₃₋₃₆ (PYY₃₋₃₆), the effects of oral gavage of DON or of other 8-keotrichothecenes on release of these gut peptides have not been established. The purpose of this study was to (1) compare the anorectic responses to the aforementioned 8-ketotrichothecenes following oral gavage at a common dose (2.5 mg/kg bw) and (2) relate these effects to changes plasma CCK and PYY₃₋₃₆ concentrations. Elevation of plasma CCK markedly corresponded to anorexia induction by DON and all other 8-ketotrichothecenes tested. Furthermore, the CCK1 receptor antagonist SR 27897 and the CCK2 receptor antagonist L-365,260 dose-dependently attenuated both CCK- and DON-induced anorexia, which was consistent with this gut satiety hormone being an important mediator of 8-ketotrichothecene-induced food refusal. In contrast to CCK, PYY₃₋₃₆ was moderately elevated by oral gavage with DON and NIV but not by 3-ADON, 15-ADON, or FX. Taken together, the results suggest that CCK plays a major role in anorexia induction following oral exposure to 8-ketotrichothecenes, whereas PYY₃₋₃₆ might play a lesser, congener-dependent role in this response.

Topics: Administration, Oral; Animals; Anorexia; Chemokines, CC; Cholecystokinin; Female; Mice; Mycotoxins; Peptide Fragments; Peptide YY; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; Trichothecenes

Chronic acalculous gallbladder disease (CAGD) falls within the spectrum of diseases associated with gallbladder dysmotility. Cholecystokinin-cholescintigraphy (CCK-CS) has been used to evaluate for CAGD, with a gallbladder ejection fraction (GBEF) of <35 % being indicative of gallbladder dysfunction. The reproduction of biliary colic upon administration of CCK has been cited as indicative of CAGD. Our purpose was to determine whether low GBEF or reproduction of pain during CCK-CS was predictor of surgical outcomes related to resolution of symptoms or as a correlate to gallbladder pathology.. A retrospective review of patients was performed to evaluate adults with a diagnosis of CAGD who underwent CCK-CS prior to surgical intervention. CPT and ICD-9 coding queries were used to identify the patient population. Patients with cholelithiasis were excluded.. Sixty-four patients met inclusion criteria. Two patients were lost to follow-up and were excluded. During CCK-CS, 41 patients (66 %) reported symptoms similar to their presenting complaint. Twenty-one patients reported no symptoms with CCK-CS. There was no significant relationship between gallbladder pathology and either GBEF or reproduction of symptoms with CCK-CS (p = 0.14). About 81 % of patients (n = 50) had relief of symptoms following cholecystectomy. Sixty-six percentage of patients (n = 33) with long-term symptom relief after cholecystectomy had reproduction of symptoms with CCK-CS. Nineteen percentage of all patients (n = 12) had long-term symptom recurrence despite surgery. Eight of these patients (66 %) had symptom reproduction with CCK-CS. There was no significant correlation with either the GBEF or symptoms reproduction with CCK-CS as a predictor of postoperative outcome (p = 0.12).. Provocation of pain by CCK-CS and low GBEF are unreliable predictors of postoperative relief of symptoms following cholecystectomy for biliary dyskinesia or chronic acalculous gallbladder disease.

Topics: Abdominal Pain; Anorexia; Cholecystectomy; Cholecystokinin; Gallbladder; Gallbladder Diseases; Humans; Nausea; Pain Measurement; Radionuclide Imaging; Vomiting

Cholecystokinin (CCK)-induced suppression of feeding is mediated by vagal sensory neurons that are destroyed by the neurotoxin capsaicin (CAP). Here we determined whether CAP-sensitive neurons mediate anorexic responses to intravenous infusions of gut hormones peptide YY-(3-36) [PYY-(3-36)] and glucagon-like peptide-1 (GLP-1). Rats received three intraperitoneal injections of CAP or vehicle (VEH) in 24 h. After recovery, non-food-deprived rats received at dark onset a 3-h intravenous infusion of CCK-8 (5, 17 pmol·kg⁻¹·min⁻¹), PYY-(3-36) (5, 17, 50 pmol·kg⁻¹·min⁻¹), or GLP-1 (17, 50 pmol·kg⁻¹·min⁻¹). CCK-8 was much less effective in reducing food intake in CAP vs. VEH rats. CCK-8 at 5 and 17 pmol·kg⁻¹·min⁻¹ reduced food intake during the 3-h infusion period by 39 and 71% in VEH rats and 7 and 18% in CAP rats. In contrast, PYY-(3-36) and GLP-1 were similarly effective in reducing food intake in VEH and CAP rats. PYY-(3-36) at 5, 17, and 50 pmol·kg⁻¹·min⁻¹ reduced food intake during the 3-h infusion period by 15, 33, and 70% in VEH rats and 13, 30, and 33% in CAP rats. GLP-1 at 17 and 50 pmol·kg⁻¹·min⁻¹ reduced food intake during the 3-h infusion period by 48 and 60% in VEH rats and 30 and 52% in CAP rats. These results suggest that anorexic responses to PYY-(3-36) and GLP-1 are not primarily mediated by the CAP-sensitive peripheral sensory neurons (presumably vagal) that mediate CCK-8-induced anorexia.

Topics: Animals; Anorexia; Behavior, Animal; Capsaicin; Cholecystokinin; Disease Models, Animal; Energy Intake; Feeding Behavior; Glucagon-Like Peptide 1; Infusions, Intravenous; Injections, Intraperitoneal; Intestinal Mucosa; Intestine, Small; Male; Neuritis; Neurons, Afferent; Peptide Fragments; Peptide YY; Rats; Vagus Nerve; Vagus Nerve Diseases

The mycotoxin deoxynivalenol (DON) elicits robust anorectic and emetic effects in several animal species. However, less is known about the potential for naturally occurring and synthetic congeners of this trichothecene to cause analogous responses. Here we tested the hypothesis that alterations in DON structure found in the plant metabolite deoxynivalenol-3-glucoside (D3G) and two pharmacologically active synthetic DON derivatives, EN139528 and EN139544, differentially impact their potential to evoke food refusal and emesis. In a nocturnal mouse food consumption model, oral administration with DON, D3G, EN139528, or EN139544 at doses from 2.5 to 10 mg/kg BW induced anorectic responses that lasted up to 16, 6, 6, and 3 h, respectively. Anorectic potency rank orders were EN139544>DON>EN139528>D3G from 0 to 0.5 h but DON>D3G>EN139528>EN139544 from 0 to 3 h. Oral exposure to each of the four compounds at a common dose (2.5 mg/kg BW) stimulated plasma elevations of the gut satiety peptides cholecystokinin and to a lesser extent, peptide YY3-36 that corresponded to reduced food consumption. In a mink emesis model, oral administration of increasing doses of the congeners differentially induced emesis, causing marked decreases in latency to emesis with corresponding increases in both the duration and number of emetic events. The minimum emetic doses for DON, EN139528, D3G, and EN139544 were 0.05, 0.5, 2, and 5 mg/kg BW, respectively. Taken together, the results suggest that although all three DON congeners elicited anorectic responses that mimicked DON over a narrow dose range, they were markedly less potent than the parent mycotoxin at inducing emesis.

Topics: Animals; Anorexia; Cholecystokinin; Dose-Response Relationship, Drug; Eating; Female; Glucosides; Intestinal Mucosa; Intestines; Mice, Inbred Strains; Mink; Molecular Structure; No-Observed-Adverse-Effect Level; Peptide Fragments; Peptide YY; Trichothecenes; Vomiting

Peptide YY(3-36) [PYY(3-36)] is postulated to act as a hormonal signal from gut to brain to inhibit food intake. PYY(3-36) potently reduces food intake when administered systemically or into the brain. If action of endogenous PYY(3-36) is necessary for normal satiation to occur, then pharmacological blockade of its receptors should increase food intake. Here, we determined the effects of iv infusion of Y1, Y2, and Y5 receptor antagonists (BIBP 3226, BIIE 0246, CGP 71683) during the first 3 h of the dark period on food intake in non-food-deprived rats. Our results showed that 1) Y2 receptor blockade reversed the anorexic response to iv infusion of PYY(3-36) but did not increase food intake when administered alone; 2) Y1 and Y5 receptor antagonists neither attenuated PYY(3-36)-induced anorexia nor altered food intake when given alone; and 3) Y2 receptor blockade attenuated anorexic responses to gastric infusions of casein hydrolysate and long-chain triglycerides, but not maltodextrin. Previous work showed that Y2 antagonist BIIE 0246 does not penetrate the blood-brain barrier. Together, these results support the hypothesis that gut PYY(3-36) action at Y2 receptors peripheral to the blood brain barrier plays an essential role in mediating satiety responses to gastric delivery of protein and long-chain triglycerides, but not polysaccharide.

Topics: Animals; Anorexia; Cholecystokinin; Eating; Hunger; Intubation, Gastrointestinal; Islet Amyloid Polypeptide; Male; Peptide Fragments; Peptide YY; Polysaccharides; Protein Hydrolysates; Rats; Rats, Sprague-Dawley; Receptors, Gastrointestinal Hormone; Satiety Response; Triglycerides

Cholecystokinin (CCK) is anorexic, irrespective whether it is applied intraperitoneally (IP) or intracerebroventricularly (ICV) in male Wistar rats. The metabolic effects depend on the route of administration: by the IP route it elicits hypothermia (presumably by type-1 receptors, CCK1R-s), while ICV administration is followed by fever-like hypermetabolism and hyperthermia via activation of CCK2R-s, which latter response seems to be most important in the postprandial (compensatory) hypermetabolism. The efficacy of the IP injected CCK varies with age: it causes strong anorexia in young adult 4 and 6-months old and again in old rats (aged 18-24 months), but the middle-aged (12-month old) ones seem to be resistant to this effect. Such pattern of effects may contribute to the explanation of age-related obesity observed in middle-aged animals as well as to the aging anorexia and loss of body weight in old ones. Diet-induced obesity accelerates the appearance of CCK-resistance as well as the return of high sensitivity to CCK in further aging, while chronic calorie-restriction prevents the development of resistance, as if the speed of the age-related regulatory changes was altered by the nutritional state. The effects of ICV applied CCK also change with age: the characteristic anorexic and hypermetabolic/hyperthermic effects can be observed in young adult rats, but the effects gradually and monotonically decline with age and disappear by the old age of 24 months. These disparate age-related patterns of CCK efficacy upon peripheral or central administration routes may indicate that although both peripheral and central CCKR-s exert anorexic effects, they may have dissimilar roles in the regulation of overall energy balance.

Topics: Aging; Animals; Anorexia; Body Temperature Regulation; Body Weight; Caloric Restriction; Cholecystokinin; Diet, High-Fat; Eating; Energy Metabolism; Injections, Intraperitoneal; Injections, Intraventricular; Male; Nutritional Status; Obesity; Rats; Rats, Wistar

Consumption of deoxynivalenol (DON), a trichothecene mycotoxin known to commonly contaminate grain-based foods, suppresses growth of experimental animals, thus raising concerns over its potential to adversely affect young children. Although this growth impairment is believed to result from anorexia, the initiating mechanisms for appetite suppression remain unknown. Here, we tested the hypothesis that DON induces the release of satiety hormones and that this response corresponds to the toxin's anorectic action. Acute ip exposure to DON had no effect on plasma glucagon-like peptide-1, leptin, amylin, pancreatic polypeptide, gastric inhibitory peptide, or ghrelin; however, the toxin was found to robustly elevate peptide YY (PYY) and cholecystokinin (CCK). Specifically, ip exposure to DON at 1 and 5mg/kg bw induced PYY by up to 2.5-fold and CCK by up to 4.1-fold. These responses peaked within 15-120 min and lasted up to 120 min (CCK) and 240 min (PPY), corresponding with depressed rates of food intake. Direct administration of exogenous PYY or CCK similarly caused reduced food intake. Food intake experiments using the NPY2 receptor antagonist BIIE0246 and the CCK1A receptor antagonist devazepide, individually, suggested that PYY mediated DON-induced anorexia but CCK did not. Orolingual exposure to DON induced plasma PYY and CCK elevation and anorexia comparable with that observed for ip exposure. Taken together, these findings suggest that PYY might be one critical mediator of DON-induced anorexia and, ultimately, growth suppression.

Topics: Administration, Oral; Animals; Anorexia; Appetite Depressants; Appetite Regulation; Arginine; Behavior, Animal; Benzazepines; Chemokines, CC; Cholecystokinin; Devazepide; Dose-Response Relationship, Drug; Eating; Female; Food Contamination; Injections, Intraperitoneal; Mice; Mycotoxins; Peptide YY; Receptors, Cholecystokinin; Receptors, Neuropeptide Y; Satiation; Time Factors; Trichothecenes

Leptin is thought to reduce food intake, in part, by increasing sensitivity to satiation signals, including CCK. Leptin action in both forebrain and hindbrain reduces food intake, and forebrain leptin action augments both the anorexic and neuronal activation responses to CCK. Here, we asked whether leptin signaling in hindbrain also enhances these responses to CCK. We found that food intake was strongly inhibited at 30 min after a combination of 4th-intracerebroventricular (4th-icv) leptin injection and intraperitoneal CCK administration, whereas neither hormone affected intake during this period when given alone. Leptin injections targeted directly at the dorsal vagal complex (DVC) similarly enhanced the anorexic response to intraperitoneal CCK. Intra-DVC leptin injection also robustly increased the number of neurons positive for phospho-STAT3 staining in the area surrounding the site of injection, confirming local leptin receptor activation. Conversely, the anorexic response to 4th-icv leptin was completely blocked by IP devazepide, a CCKA-R antagonist, suggesting that hindbrain leptin reduces intake via a mechanism requiring endogenous CCK signaling. We then asked whether hindbrain leptin treatment enhances the dorsomedial hindbrain, hypothalamus, or amygdala c-Fos responses to IP CCK. We found that, in contrast to the effects of forebrain leptin administration, 4th-icv leptin injection had no effect on CCK-induced c-Fos in any structures examined. We conclude that leptin signaling in either forebrain or hindbrain areas can enhance the response to satiation signals and that multiple distinct neural circuits likely contribute to this interaction.

Topics: Animals; Anorexia; Cholecystokinin; Devazepide; Disease Models, Animal; Eating; Hormone Antagonists; Injections, Intraventricular; Leptin; Male; Proto-Oncogene Proteins c-fos; Rats; Rats, Wistar; Receptors, Leptin; Rhombencephalon; Satiety Response; STAT3 Transcription Factor; Vagus Nerve

The physiological involvement of endogenous cholecystokinin (CCK) in the termination of feeding has been challenged by evidence of aversive effects of exogenous CCK8. We previously prolonged the anorectic effect of CCK by conjugation to polyethylene glycol (PEGylation) to produce PEG-CCK9. In this study, we investigated the ability of different doses of PEG-CCK9 to induce conditioned taste aversion (CTA) and satiety and identified the receptors involved in CTA induction.. Induction of CTA, measured by the saccharin preference ratio determined in a two-bottle CTA procedure, and of satiety in adult male Wistar rats after intraperitoneal (i.p.) injection of different doses of PEG-CCK9 (1, 2, 4, 8, 16 or 32 microg kg(-1)) was compared. Devazepide (100 microg kg(-1)) and 2-NAP (3 mg kg(-1)), two selective CCK1-receptor antagonists, were co-administered i.p. with PEG-CCK9 (8 microg kg(-1)) and the CTA effects monitored.. PEG-CCK9 dose-dependently induced CTA, with a minimal effective dose of 8 microg kg(-1), whereas the minimal effective dose to induce satiety was 1 microg kg(-1). The CTA effects of PEG-CCK9 were completely abolished by i.p. administration of devazepide prior to PEG-CCK9 treatment and only partially abolished by administration of 2-NAP.. Although PEG-CCK9-induced satiety and PEG-CCK9-induced CTA both increased with dose, the conjugate was more potent in inducing satiety, suggesting that the anorexia could not be completely attributed to the aversiveness of the drug. As observed with induction of satiety, PEG-CCK9-induced CTA was mediated by CCK1-receptors.

Topics: Animals; Anorexia; Aspartic Acid; Avoidance Learning; Cholecystokinin; Devazepide; Dose-Response Relationship, Drug; Injections, Intraperitoneal; Male; Naphthalenesulfonates; Peptide Fragments; Polyethylene Glycols; Rats; Rats, Wistar; Receptor, Cholecystokinin A; Saccharin; Satiety Response; Taste

We have previously reported that pancreatic polypeptide (PP) overexpressing mice display thin phenotype with delayed gastric emptying and decreased food intake. In the present study, we further examined if CCK contributes to anorexia and anxiety behavior in PP overexpressing mice. Plasma CCK levels in PP overexpressing mice and their littermates were determined by radioimmunoassay using antisera specific to sulfated CCK-8 and CCK-33. To elucidate the role of CCK in PP overexpressing mice, CCK-1 receptor antagonist (L-364,718) or saline was administered intraperitoneally and food intake was measured for 2 h. CCK-2 antagonist (L-365,260) or saline was injected intraperitoneally and the elevated plus-maze test was performed to assess anxiety. Plasma CCK levels were significantly increased in PP overexpressing mice. Administration of L-364,718 increased food intake in PP overexpressing mice compared to the saline-injected PP overexpressing group, while L-364,718 did not increase food intake in non-transgenic littermates. PP overexpressing mice exhibited anxiety in the plus-maze test. Administration of CCK-2 receptor antagonist (L-365,260) reversed the decreased percentage of entry into the open arms in PP overexpressing mice. These results indicated that elevated CCK may contribute to anorexic and anxious phenotype of PP overexpressing mice.

Topics: Animals; Anorexia; Anxiety; Cholecystokinin; Devazepide; Eating; Hormone Antagonists; Male; Mice; Mice, Transgenic; Pancreatic Polypeptide; Radioimmunoassay; Receptors, Cholecystokinin; Sincalide

The anorectic compound CCK-9 was coupled to polyethylene glycol 5 kDa, 10 kDa, 20 kDa and 30 kDa, under different reaction conditions. Conjugates were purified by HPLC and characterized by MALDI-TOF MS. A 96% PEGylation yield was obtained in buffer pH 7.5 after 6h reaction at 20 degrees C. The anorectic activity was tested in vivo in rats. A single bolus intra-peritoneal injection of non-modified CCK-9 resulted in a significant initial food intake reduction 30 min after food presentation (87% compared to paired control group). When PEG-CCK-9 conjugates modified with polymers of molecular weight up to 20 kDa were injected, lower but statistically significant initial food intake reductions were obtained (76% for PEG 10 kDa-CCK-9 conjugate compared to control group). The cumulative food intake reduction of non-modified CCK-9 is normalized within 1-2h, whereas the PEG-CCK-9 molecules showed a prolonged anorectic activity lasting for 6h for PEG 5 kDa-CCK-9; 23 h for PEG 10 kDa-CCK-9 and between 8h and 23 h for PEG 20 kDa-CCK-9. For PEG 30 kDa-CCK-9 conjugate, neither an initial nor a cumulative FI reduction was observed. PEG-CCK-9 conjugates show a significantly prolonged anorectic activity in comparison to the non-modified peptide. This effect is most evident for the PEG 10 kDa-CCK-9 conjugate.

Topics: Animals; Anorexia; Cholecystokinin; Chromatography, High Pressure Liquid; Chromatography, Thin Layer; Drug Stability; Eating; Injections, Intraperitoneal; Male; Molecular Structure; Molecular Weight; Peptide Fragments; Polyethylene Glycols; Rats; Rats, Wistar; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Structure-Activity Relationship; Time Factors

Amylin and CCK activate the area postrema (AP)/nucleus of the solitary tract (NTS) - lateral parabrachial nucleus (LPBN) - central amygdala (CeA) pathway. However, except for the brainstem structures the role of these nuclei for the anorectic effect of these peptides is not yet well characterized. The current study investigated the role of the LPBN in mediating the inhibitory effect of peripheral amylin and CCK on feeding behavior. Rats with electrolytic lesions in the LPBN (LPBN-X) were used in behavioral as well as in immunohistological c-Fos studies. LPBN-X significantly reduced the anorectic effect of amylin (5 microg/kg, i.p.). The effect of a higher amylin dose (10 microg/kg, i.p.) was only slightly attenuated in the LPBN-X rats. In agreement with previous studies, LPBN lesions also reduced the inhibitory effect of CCK on food intake. In the immunohistological experiments, amylin and CCK induced c-Fos expression in the AP, NTS, LPBN and CeA in the SHAM rats. Both the amylin- and CCK-induced activation of the CeA was completely abolished in the animals with a LPBN lesion. These results clearly suggest that the signal transduction pathway between the AP/NTS and CeA has been disrupted by the LPBN ablation. We conclude that the LPBN is a crucial brain site mediating the anorectic effect of amylin and CCK. Furthermore, an intact LPBN seems to be essential for the c-Fos response in the CeA induced by these peptides.

Topics: Amyloid; Analysis of Variance; Animals; Anorexia; Behavior, Animal; Brain Stem; Cell Count; Cholecystokinin; Eating; Gene Expression Regulation; Islet Amyloid Polypeptide; Male; Proto-Oncogene Proteins c-fos; Rats; Rats, Wistar

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.. 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.. 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).. 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.

Topics: Animals; Anorexia; Appetite Depressants; Aspartic Acid; Blood-Brain Barrier; Cholecystokinin; Delayed-Action Preparations; Devazepide; Dose-Response Relationship, Drug; Eating; Injections, Intraperitoneal; Male; Naphthalenesulfonates; Peptide Fragments; Polyethylene Glycols; Rats; Rats, Wistar; Receptor, Cholecystokinin A; Satiation

We have shown previously that prolactin-releasing peptide (PrRP) plays a role in the regulation of feeding and energy expenditure in rats. We hypothesize that PrRP may have a physiological action through its putative receptor, GPR10, to mediate the central anorexigenic effects of peripheral satiety factors. Here we examine the effects of PrRP and cholecystokinin (CCK) on feeding in mice, including PrRP receptor gene knockout animals (GPR10(-/-)). Intracerebroventricular administration of PrRP (1-4 nmol) inhibited feeding in C57B6/J mice under both fast-induced and nocturnal feeding conditions. In contrast to the observations made in wild-type mice, neither PrRP nor CCK reduced food intake in GRP10(-/-) mice. The reduction in feeding and the release of corticosterone induced by systemic injection of the stressor lipopolysaccharide was similar in both GPR10(+/+) and GPR10(-/-) mice. These findings suggest that PrRP, acting through GPR10, is involved in regulating food intake and may be a key intermediary in the central satiating actions of CCK.

Topics: Animals; Anorexia; Cholecystokinin; Corticotropin-Releasing Hormone; Eating; Genes, fos; Hypothalamic Hormones; Injections, Intraventricular; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neuropeptides; Oligopeptides; Oxytocin; Prolactin-Releasing Hormone; Satiety Response; Signal Transduction

Brain-derived neurotrophic factor (BDNF) has recently been implicated as an anorexigenic factor in the central control of food intake. Previous studies focused on the hypothalamus as a probable site of action for this neurotrophin. It was demonstrated that BDNF is an important downstream effector of melanocortin signaling in the ventromedial hypothalamus. In this study, we addressed whether BDNF can modulate food intake in the hindbrain autonomic integrator of food intake regulation, i.e. the dorsal vagal complex (DVC). To this end, we used two complementary methodological approaches in adult rats. First, we measured the effects of intraparenchymal infusions of exogenous BDNF within the DVC on food intake and body weight. Second, we measured the endogenous BDNF protein content in the DVC and hypothalamus after food deprivation, refeeding, or peripheral treatments by the anorexigenic hormones leptin and cholecystokinin (CCK). BDNF infusion within the DVC induced anorexia and weight loss. In the DVC, BDNF protein content decreased after 48 h food deprivation and increased after refeeding. Acute and repetitive peripheral leptin injections induced an increase of the BDNF protein content within the DVC. Moreover, peripheral CCK treatment induced a transient increase of BDNF protein content first in the DVC (30 min after CCK) and later on in the hypothalamus (2 h after CCK). Taken together, these results strongly support the view that BDNF plays a role as an anorexigenic factor in the DVC. Our data also suggest that BDNF may constitute a common downstream effector of leptin and CCK, possibly involved in their synergistic action.

Topics: Animal Feed; Animals; Anorexia; Body Weight; Brain Stem; Brain-Derived Neurotrophic Factor; Cholecystokinin; Drinking; Drug Synergism; Eating; Food Deprivation; Humans; Hypothalamus; Injections; Leptin; Male; Rats; Rats, Wistar; Recombinant Proteins; Time Factors; Vagus Nerve

Anorexia-associated malnutrition is a severe complication that increases mortality in peritoneal dialysis (PD) patients. Ghrelin is a recently-discovered orexigenic hormone with actions in brain and stomach. We analyzed, in 42 PD patients, the possible relationship between ghrelin and appetite regulation with regard to other orexigens [neuropeptide Y (NPY), NO3] and anorexigens [cholecystokinin (CCK), leptin, glucose-dependent insulinotropic peptide (GIP), tumor necrosis factor alpha (TNFalpha)]. All orexigens and anorexigens were determined in plasma. Eating motivation was evaluated using a visual analog scale (VAS). The patients were divided into three groups: those with anorexia (n = 12), those with obesity associated with high intake (n = 12), and those with no eating behavior disorders (n = 18). A control group of 10 healthy volunteers was also evaluated. Mean plasma levels of ghrelin were high (3618.6 +/- 1533 mg/mL), with 36 patients showing values above the normal range (< 2600 mg/mL). Patients with anorexia had lower ghrelin and NPY levels and higher peptide-C, CCK, interleukin-1 (IL-1), TNFalpha, and GIP levels than did the other patients. Patients with anorexia also had an early satiety score and low desire and pleasure in eating on the VAS and diet survey. We observed significant positive linear correlations between ghrelin and albumin (r = 0.43, p < 0.05), prealbumin (r = 0.51, p < 0.05), transferrin (r = 0.4, p < 0.05), growth hormone (r = 0.66, p < 0.01), NO3 (r = 0.36, p < 0.05), and eating motivation (VAS). At the same time, negative relationships were observed between blood ghrelin and GIP (r = -0.42, p < 0.05), insulin (r = -0.4, p < 0.05), leptin (r = -0.45, p < 0.05), and creatinine clearance [r = -0.33, p = 0.08 (nonsignificant)]. Ghrelin levels were not related to Kt/V or to levels of CCK and cytokines. Ghrelin plasma levels are elevated in PD patients. Uremic patients with anorexia show relatively lower ghrelin plasma levels than the levels seen in obese patients or in patients with normal appetite. The role of ghrelin in appetite modulation is altered in uremic PD patients, and that alteration is possibly associated with disorders in insulin and growth hormone metabolism.

Topics: Adult; Aged; Anorexia; Appetite Regulation; Blood Proteins; Cholecystokinin; Cytokines; Eating; Female; Gastric Inhibitory Polypeptide; Ghrelin; Humans; Leptin; Male; Middle Aged; Neuropeptide Y; Nitric Oxide; Nutritional Status; Obesity; Peptide Hormones; Peritoneal Dialysis

Previous studies indicated that amylin contributes to the anorectic effects of cholecystokinin (CCK) and bombesin (BBS), possibly by enhancing the release of pancreatic amylin or by modulating their anorectic actions within the central nervous system (CNS). To elucidate the interaction between amylin and CCK or BBS, respectively, we investigated the influence of an IP injection of CCK or BBS on feeding in amylin-deficient mice (IAPP(-/-)). The anorectic effects of CCK and BBS were nearly abolished in IAPP(-/-) mice compared to wildtype (WT) mice (e.g. 20 microg/kg CCK, 1-h food intake: WT/NaCl 0.53 +/- 0.03 g; WT/CCK 0.16 +/- 0.03 g (P < 0.001); IAPP(-/-)/NaCl 0.49 +/- 0.05 g; IAPP(-/-)/CCK 0.39 +/- 0.04 g). Acute amylin replacement restored the anorectic effect of CCK in IAPP(-/-) mice. To find out whether CCK or BBS enhance the feeding-induced release of pancreatic amylin, we injected rats with CCK-8 (0.5-50 microg/kg) or BBS (5 microg/kg) and measured plasma amylin levels after injections. Neither CCK nor BBS increased the plasma amylin level in rats. We suggest that the mediation of the anorectic effects of CCK and BBS by amylin is not dependent on a CCK- or BBS-induced release of pancreatic amylin, but may rather be due to a modulation of their effects by amylin within the CNS.

Topics: Amyloid; Animals; Anorexia; Bombesin; Cholecystokinin; Islet Amyloid Polypeptide; Mice; Mice, Inbred C57BL

We examined the effect of lateral (visceral) and medial (gustatory) parabrachial nucleus (PBN) lesions on the suppression of milk intake induced with cholecystokinin (CCK) in 24 h food-deprived rats. Irrespective of CCK dose, each type of PBN lesion significantly elevated the consumption of milk. Neither medial nor lateral PBN lesions had any discernible influence on the anorectic action of CCK, however. In combination with the results from a previous study using the same rats (Brain Res. 894 (2001) 288), the present results support the view that the role of the lateral PBN in CCK-induced anorexia depends on the nature of the food used at test.

Topics: Animals; Anorexia; Appetite Depressants; Appetite Regulation; Cholecystokinin; Denervation; Feeding Behavior; Food Deprivation; Male; Milk; Neurotoxins; Pons; Rats; Rats, Sprague-Dawley; Visceral Afferents

Behavioral, autonomic, and endocrine outputs of the CNS are subject to important feedback modulation by viscerosensory signals that are conveyed initially to the hindbrain nucleus of the solitary tract (NST). In the present study, noradrenergic (NA) neurons [i.e., those that express the NA synthetic enzyme dopamine beta hydroxylase (DbH)] in the caudal NST were lesioned to determine their role in mediating anorexic responses to gastric stimulation and in conveying gastric sensory signals to the hypothalamus and amygdala. For this purpose, saporin toxin conjugated to an antibody against DbH was microinjected bilaterally into the caudal NST in adult rats. Control rats received similar microinjections of vehicle. Several weeks later, rats were tested for the ability of systemic cholecystokinin octapeptide (CCK) (0 or 10 microg/kg) to inhibit food intake. CCK-induced anorexia was significantly attenuated in toxin-treated rats. Rats subsequently were used in a terminal cFos study to determine central neural activation patterns after systemic CCK or vehicle and to evaluate lesion extent. Toxin-induced loss of DbH-positive NST neurons was positively correlated with loss of CCK-induced anorexia. Hypothalamic cFos expression was markedly attenuated in lesioned rats after CCK treatment, whereas CCK-induced neural activation in the parabrachial nucleus and amygdala appeared normal. These findings suggest that hindbrain NA neurons are an integral component of brainstem circuits that mediate CCK-induced anorexia and also are necessary for hypothalamic but not parabrachial or amygdala responses to gastric sensory stimulation.

Topics: Amygdala; Animals; Anorexia; Central Nervous System; Cholecystokinin; Dopamine beta-Hydroxylase; Eating; Hypothalamus; Immunotoxins; Male; Microinjections; Neurons; Norepinephrine; Pons; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Rhombencephalon; Solitary Nucleus; Visceral Afferents

This study was designed to investigate the effect of orexin on anorexia induced by cholecystokinin (CCK),a peripheral satiety signal.. We administered orexin A (0.01-1 nmol/mouse) and CCK-8 (3 nmol/mouse) to mice. Food intake was measured at different time-points: 20 min, 1, 2 and 4 h post-intracerebroventricular (i.c.v.) or intraperitoneal (i.p.) administrations.. Intracerebroventricular-administered orexin significantly increased food intake in a dose-dependent manner. The inhibitory effect of i.p.-administered CCK-8 on food intake was significantly negated by the simultaneous i.c.v. injection of orexin in a dose-dependent manner.. Orexin reversed the CCK-induced loss of appetite. Our results indicate that orexin might be a promising target for pharmacological intervention in the treatment of anorexia and cachexia induced by various diseases.

Topics: Analysis of Variance; Animals; Anorexia; Carrier Proteins; Cholecystokinin; Dose-Response Relationship, Drug; Eating; Intracellular Signaling Peptides and Proteins; Mice; Neuropeptides; Orexins; Weight Loss

The two major components of the pontine parabrachial nucleus (PBN), the medial (gustatory) and lateral (visceral) subdivisions, have been implicated in a variety of ingestive behaviors. The present study examined the influence of bilateral ibotenic acid lesions of the medial or lateral PBN on the anorectic effects of two systemically administered drug treatments. In Experiment 1, 24-h food-deprived rats where injected with sulfated cholecystokinin (26-33) (CCK; 0, 4.0, or 8.0 microg/kg) and then given 60 min access to food. In Experiment 2, the influence of D-fenfluramine (DFEN; 0, 0.5, 1.0, or 2.0 mg/kg) on deprivation-induced feeding was examined in the same rats using the same behavioral procedure as in Experiment 1. Lesions of the lateral PBN abolished CCK-, but not DFEN-induced anorexia whereas lesions of the medial PBN augmented DFEN-, but had no influence on CCK-induced anorexia. The results suggest that the satiating effects of CCK and DFEN are mediated through different mechanisms involving, respectively, visceral and orosensory processing.

Topics: Animals; Anorexia; Cholecystokinin; Eating; Excitatory Amino Acid Agonists; Feedback; Fenfluramine; Food Deprivation; Ibotenic Acid; Male; Pons; Rats; Rats, Sprague-Dawley; Serotonin Agents; Taste

Anorexia is a frequent finding in patients with biliary obstruction (BO). This study investigates the role of biochemical and hormonal factors in the pathogenesis of reduced food intake in BO and the effects of internal biliary drainage.. Sixty-two patients with BO were prospectively investigated. Transaminases, amylase, cholecystokinin, secretin, bile acids, tumor necrosis factor-alpha, and endotoxin were determined at admission. Caloric intake was quantified by a controlled diet. In a subset of 27 patients, studies were repeated after internal biliary drainage.. Sixty-six percent of patients had spontaneous food intakes below the estimated caloric requirements. Serum bilirubin, alkaline phosphatase, and cholecystokinin plasma levels were independent predictor factors for calorie intake (p = 0.0001). After internal biliary drainage, cholestasis parameters and cholecystokinin concentrations decreased significantly; this was associated with an improvement of spontaneous food intake in both benign and malignant biliary obstruction (p < 0.01 and p < 0.05, respectively).. Decreased food intake in BO was associated with the degree of obstruction and with increased cholecystokinin plasma levels. Biliary drainage improved biochemical and food intake derangements.

Topics: Adult; Aged; Aged, 80 and over; Amylases; Analysis of Variance; Anorexia; Bile Acids and Salts; Bilirubin; Case-Control Studies; Cholecystokinin; Cholestasis; Drainage; Endotoxins; Energy Intake; Female; Humans; Linear Models; Male; Middle Aged; Nutritional Requirements; Prospective Studies; Secretin; Time Factors; Transaminases; Tumor Necrosis Factor-alpha

A common complaint among pain patients is that they lose their appetite. These accounts are anecdotal, however, and the neural mechanism underlying pain-induced loss of appetite remains unknown. In this study, we documented the occurrence of appetite loss in patients under migraine attack and investigated the neuronal substrate of pain-induced anorexia in our animal model of intracranial pain. We found that loss of appetite during the migraine attack in humans coincided strongly with the onset and duration of the head pain in 32/39 cases, and that brief noxious stimulation of the dura in conscious rats produced a transient suppression of food intake. Mapping of neuronal activation in the rat showed that noxious dural stimulation induced a 3- to 4-fold increase in the number of Fos-positive neurons in medullary dorsal horn areas that process nociceptive signals (laminae I, V) and in parabrachial and hypothalamic neurons positioned to suppress feeding behavior. In the parabrachial area, activated neurons were localized in the superior-lateral subnucleus, and 40% of them expressed the mRNA encoding the anorectic neuropeptide cholecystokinin. In the hypothalamus, activated Fos-positive neurons were found in the dorsomedial area of the ventromedial nucleus, and 76% of them expressed the mRNA for cholecystokinin type-B receptor. Based on these findings, we suggest that at least one of several groups of hypothalamic neurons that normally inhibit appetite in response to metabolic cues is positioned to mediate the suppression of food intake by pain signals.

Topics: Animals; Anorexia; Brain Stem; Cholecystokinin; Dura Mater; Eating; Electric Stimulation; Humans; In Situ Hybridization; Male; Migraine Disorders; Nerve Tissue Proteins; Neurons; Nociceptors; Pain; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Receptors, Cholecystokinin; RNA, Messenger; Trigeminal Nuclei; Ventromedial Hypothalamic Nucleus

Anorexia is a noxious symptom, and over half of patients with advanced cancer experience it. Neuropeptide Y (NPY), leptin, and cholecystokinin 8 (CCK8) have been implicated.. This exploratory study 1) compared circulating concentrations of NPY and leptin between anorectic cancer patients and historic controls and 2) explored whether NPY, leptin, or CCK8 may serve as correlates of anorexia severity. Cancer patients met predefined eligibility criteria: 1) weight loss > or = 2.3 kg over the preceding 2 months and/or a physician-estimated caloric intake of < 20 calories per kilogram of body weight per day and 2) patient acknowledgment that appetite or weight loss was an ongoing problem.. Seventy-three cancer patients were studied, and > 90% reported a > or = 50% decline in appetite from baseline in the preceding 2 months. NPY levels were lower than control values: mean +/- standard deviation, 466 pg/mL +/- 161 pg/mL versus 560 pg/mL +/- 151 pg/mL, respectively (P = 0.004). Because a few (but not all) earlier studies suggested an age-related decline in NPY levels, a subgroup analysis was performed and found no age-adjusted difference in NPY levels between groups. Similarly, leptin concentrations were not different between groups. Significant correlations were not observed between anorexia severity and NPY, leptin, or CCK8 levels.. There were no differences in leptin and CCK8 levels between anorectic cancer patients and historic controls. Circulating concentrations of NPY, leptin, and CCK8 did not correlate with anorexia severity. However, the current results suggest a need for further examination of NPY in cancer-associated anorexia.

Topics: Adult; Aged; Aged, 80 and over; Anorexia; Cholecystokinin; Female; Humans; Leptin; Male; Middle Aged; Neoplasms; Neuropeptide Y; Peptide Fragments

We investigated the role of histamine H1 receptors in mediating the anorectic effect of intraperitoneally injected amylin (5 and 20 microg/kg), the amylin agonist salmon calcitonin (sCT; 10 microg/kg), leptin (1.3 mg/kg), and cholecystokinin (CCK; 20 microg/kg). The experiments were performed with mice lacking functional H1 receptors (H1Rko) and wild-type (WT) controls. The mice were also injected with the H3 antagonist thioperamide (20 mg/kg), which reduces feeding by enhancing the release of endogenous histamine through presynaptic H3 receptors. The feeding-suppressive effect of thioperamide was abolished in H1Rko mice. The anorectic effects of amylin and sCT were significantly reduced in 12-h food-deprived H1Rko mice compared with WT mice [1-h food intake: WT-NaCl 0.51 +/- 0.05 g vs. WT-amylin (5 microg/kg) 0.30 +/- 0.06 g (P < 0.01); H1Rko-NaCl 0.45 +/- 0.05 g vs. H1Rko-amylin 0.40 +/- 0.04 g; WT-NaCl 0.40 +/- 0.09 g vs. WT-sCT (10 microg/kg) 0.14 +/- 0.10 g (P < 0.05); H1Rko-NaCl 0.44 +/- 0.08 g vs. H1Rko-sCT 0.50 +/- 0.06 g]. The anorectic effect of leptin was absent in ad libitum-fed H1Rko mice, whereas CCK equally reduced feeding in WT and H1Rko animals. This suggests that the histaminergic system is involved in mediating the anorectic effects of peripheral amylin and sCT via histamine H1 receptors. The same applies to leptin but not to CCK. H1Rko mice showed significantly increased body weight gain compared with WT mice, supporting the role of endogenous histamine in the regulation of feeding and body weight.

Topics: Amyloid; Animals; Anorexia; Body Weight; Calcitonin; Cholecystokinin; Eating; Histamine Antagonists; Islet Amyloid Polypeptide; Leptin; Male; Mice; Mice, Knockout; Pancreas; Piperidines; Receptors, Histamine H1

Previous studies provided evidence for an interaction between the satiety effects of cholecystokinin (CCK), bombesin (BBS), and amylin. Amylin released in response to CCK (or BBS) was supposed to mediate part of CCK's (or BBS's) anorectic effect since the amylin and calcitonin gene-related peptide (CGRP) antagonist CGRP 8-37 attenuated their anorectic action. Due to the low specificity of CGRP 8-37 for amylin vs. CGRP binding sites, the aim of the present study was to test whether the specific amylin antagonist AC 253 also influenced the anorectic effects of CCK and BBS. Injections took place at dark onset in 24-h food-deprived rats. At a dose that attenuated the anorectic effect of amylin (5 microg/kg), the amylin antagonist AC 253 (500 microg/kg) significantly attenuated the anorectic effects of CCK and BBS (0.5 microg/kg). It can therefore be concluded that amylin, rather than CGRP, mediates part of the anorectic effects of CCK and BBS.

Topics: Amyloid; Animals; Anorexia; Appetite Stimulants; Bombesin; Cholecystokinin; Eating; Food Deprivation; Injections, Intraperitoneal; Islet Amyloid Polypeptide; Male; Peptide Fragments; Peptides; Rats; Rats, Sprague-Dawley

Islet amyloid polypeptide (IAPP or amylin) potently reduces food intake in rats at or near physiological concentrations. Although the mechanisms of action of IAPP are not understood, the brain is a suggested site. Changes in hypothalamic and striatal neurotransmission have been reported following acute systemic administration of a pharmacological concentration of IAPP. In the current study, we evaluated the effects of chronic administration of low doses of IAPP on satiety-related neurotransmitters and neuropeptides in the hypothalamus, hippocampus, striatum, left cortex, and right cortex of the rat. Doses of 0, 5 and 25 pmol IAPP/kg-min were administered subcutaneously for 2 or 5 days. Food intake was reduced by 27 and 44% (both P<0.001) for the 5 and 25 pmol/kg-min groups, respectively, in the 2-day experiment and was decreased by 14% (P<0.01) and 24% (P<0.001), respectively, in the 5-day experiment. Body weight was significantly decreased in a dose-dependent fashion. In the 2-day experiment, norepinephrine increased in the hypothalamus in the 5 pmol IAPP/kg-min group, and neurotensin increased in the hippocampus in the 25 pmol/kg-min rats (both P<0.05). In the 5-day, 5 pmol/kg-min rats, 5-hydroxyindoleacetic acid (5-HIAA) increased in the hypothalmus and cholecystokinin (CCK) increased in the striatum (both P<0.05). In the 5-day, 25 pmol/kg-min group, neuropeptide Y (NPY) increased in the hypothalamus (P<0.01) and CCK increased in the hypothalmus and striatum (both P<0.05). The present study confirms that IAPP is a potent anorectic peptide at low doses and suggests that IAPP not only affects classical neurotransmitters in the brain but also alters concentrations of neuropeptides known to be involved in food intake.

Topics: 3,4-Dihydroxyphenylacetic Acid; Amyloid; Animals; Anorexia; Biogenic Monoamines; Blood Glucose; Brain; Cholecystokinin; Chromatography, High Pressure Liquid; Dopamine; Dose-Response Relationship, Drug; Homovanillic Acid; Hydroxyindoleacetic Acid; Infusions, Parenteral; Insulin; Islet Amyloid Polypeptide; Male; Methoxyhydroxyphenylglycol; Neuropeptide Y; Neuropeptides; Neurotensin; Norepinephrine; Rats; Rats, Wistar; Serotonin

The present study was aimed to test the hypothesis that increased endogenous CCK may interact with the anorectic serotonergic agent dl-fenfluramine to reduce food intake in rats. Previous studies, using selective CCK receptor antagonists, could demonstrate CCK-dependent 5-HT-induced anorexia. In the present approach, we used protease inhibitors to increase levels of endogenous CCK instead of blocking CCK receptors by antagonists. The protease inhibitors we used were soybean trypsin inhibitor (STI) and camostate. We hypothesized that combining the anorectic serotonergic drug dl-fenfluramine with either STI or camostate should result in an enhanced hypophagic effect when compared to single drug treatment. All feeding experiments were performed in non-deprived rats during night time feeding. Given alone, STI (500 mg/kg, po), camostate (200 mg/kg po) and also fenfluramine (1-9 mg/kg ip) reduced significantly food intake, with a more pronounced effect following fenfluramine. However, the experiments do not provide evidence for any additive or synergistic action between camostate or STI and the anorectic serotonergic drug dl-fenfluramine on food intake.

Topics: Animals; Anorexia; Body Weight; Cholecystokinin; Dose-Response Relationship, Drug; Drug Interactions; Eating; Esters; Fenfluramine; Gabexate; Guanidines; Male; Protease Inhibitors; Rats; Rats, Wistar; Selective Serotonin Reuptake Inhibitors; Serotonin; Time Factors; Trypsin Inhibitors

The aims of the present study were to measure the satiety neuropeptide cholecystokinin (CCK) in humans at terrestrial high altitude to investigate its possible role in the pathophysiology of anorexia, cachexia, and acute mountain sickness (AMS). Nineteen male mountaineers aged 38 +/- 12 years participated in a 20 +/- 5 day trek to Mt. Kanchenjunga basecamp (BC) located at 5,100 m, where they remained for 7 +/- 5 days. Subjects were examined at rest and during a maximal exercise test at sea-level before/after the expedition (SL1/SL2) and during the BC sojourn. There was a mild increase in Lake Louise AMS score from 1.1 +/- 1.2 points at SL1 to 2.3 +/- 2.3 points by the end of the first day at BC (P < 0.05). A marked increase in resting plasma CCK was observed on the morning of the second day at BC relative to sea-level control values (62.9 +/- 42.2 pmol/L(-1) vs. SL1: 4.3 +/- 8.3 pmol/L(-1), P < 0.05 vs. SL2: 26.5 +/- 25.2 pmol/L(-1), P < 0.05). Maximal exercise increased CCK by 78.5 +/- 24.8 pmol/L(-1), (P < 0.05 vs. resting value) during the SL1 test and increased the plasma concentration of non-esterified fatty acids and glycerol at BC (P < 0.05 vs. SL1/SL2). The CCK response was not different in five subjects who presented with anorexia on Day 2 compared with those with a normal appetite. While there was no relationship between the increase in CCK and AMS score at BC, a more pronounced increase in resting CCK was observed in subjects with AMS (> or =3 points at the end of Day 1 at BC) compared with those without (+98.9 +/- 1.4 pmol/L(-1) vs. +67.6 +/- 37.2 pmol/L(-1), P < 0.05). Caloric intake remained remarkably low during the stay at BC (8.9 +/- 1.4 MJ.d(-1)) despite a progressive decrease in total body mass (-4.5 +/- 2.1 kg after 31 +/- 13 h at BC, P < 0.05 vs. SL1/SL2), which appeared to be due to a selective loss of torso adipose tissue. These findings suggest that the satiogenic effects of CCK may have contributed to the observed caloric deficit and subsequent cachexia at high altitude despite adequate availability of palatable foods. The metabolic implications of elevated CCK in AMS remain to be elucidated.

Topics: Adult; Altitude Sickness; Analysis of Variance; Anorexia; Anthropometry; Appetite; Blood Glucose; Cachexia; Cholecystokinin; Energy Intake; Exercise; Fatty Acids, Nonesterified; Glycerol; Hand Strength; Humans; Male; Mountaineering

We used the cholecystokinin receptor antagonist devazepide to assess the importance of CCK in mediating the anorexia produced by 2-h duodenal infusions of peptone, a protein digest, at dark onset in nonfasted rats. Peptone alone (0.14-2.24 g/h) suppressed food intake dose dependently by 18-96%, with an approximate half-maximal dose of 1 g/h. Peptone-induced reductions in caloric ingestion were comparable to the caloric loads infused. Devazepide alone (30-1,000 microgram/kg) stimulated food intake dose dependently by 30-73%, with a minimal effective dose of 100 micrograms/kg. Devazepide appeared to reverse the anorexic response to peptone (1.1 g/h) dose dependently by 29-65%, with a minimal effective dose of 30 micrograms/kg. The magnitudes of these devazepide-induced effects were similar to, and in some cases were larger than, those produced when the same doses of devazepide were administered alone. Coadministration of devazepide (1,000 micrograms/kg) and a lower peptone dose (0.8 g/h) produced similar results. These results suggest that an essential CCK mechanism plays a significant role in mediating the satiety response to duodenal delivery of protein.

Topics: Animals; Anorexia; Cholecystokinin; Devazepide; Dose-Response Relationship, Drug; Duodenum; Eating; Hormone Antagonists; Injections; Male; Peptones; Rats; Rats, Sprague-Dawley; Receptors, Cholecystokinin

Several analogs of Boc-protected C-terminal heptapeptide of cholecystokinin (Boc-CCK-7) with modified C-end Phe were pharmacologically characterized. The influence of the number of methyl groups on aromatic side chain of Phe was investigated in following tests: binding to pancreatic and brain membrane receptors, gall bladder contraction, amylase secretion, anorexia, sedation and analgesia. Two analogs seem to be promising selective anorectic agents with strongly protracted effect: Boc-[Phe(triMe)7]CCK-7 and Boc-[Phe(pentaMe)7]CCK-7. The first analog exhibits the same spectrum of activities as CCK-8, however partially decreased central effects, the second one shows partially decreased peripheral activities and totally suppressed central ones. Our study supports the idea that C-terminal residue of CCK is more important for biological potency than for binding to CCK receptors.

Topics: Amylases; Analgesics, Non-Narcotic; Animals; Anorexia; Central Nervous System; Cholecystokinin; Eating; Gallbladder; Guinea Pigs; Hypnotics and Sedatives; Male; Mice; Pain Threshold; Rats; Rats, Wistar; Receptor, Cholecystokinin A; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; Sleep

Malnutrition has definitely been related to mortality among dialysis patients. Persistent loss of appetite is one of the major symptoms found in these patients. It is also well recognized that several substances produce anorexia or disorders of the hunger-satiety cycle in several diseases. The aim of this study was to identify the role of anorexigen substances (TNF-alpha and cholecystokinin or CCK) and an orexigen substance (neuropeptide Y or NPY) in anorexia and malnutrition among 55 clinically stable peritoneal dialysis (PD) patients.. High TNF-alpha plasma levels were found in 41 of 42 patients (97.6%) with a mean of 70.5+/-32.3 pg/ml. Patients with anorexia (n=11) or anorexia with nausea or vomiting (n=5) had higher TNF-alpha values than patients without these symptoms (75.9+/-34 vs 52.1 +/-24.5 pg/ml, P<0.05). Eight patients with a prior diagnosis of acid pylori disease showed higher TNF-alpha values (87.2+/-24.3) than 30 unaffected patients (63.6+/-30.5, P<0.05). TNF-alpha showed a significant negative linear correlation with retinol binding protein (RBP) (r=-0.37, n=34, P<0.05), and venous pH (r=-0.4, n=42, P<0.01); also, TNF-alpha values higher than 65 pg/ml were inversely associated with transferrin, cholesterol, blood urea nitrogen (BUN) and CCK. Patients with prealbumin levels lower than 30 mg/dl, a BMI lower than 30 kg/m2, nPCR lower than 1.1 g/kg/day and urea KT/V lower than 2.2 showed higher serum TNF-alpha levels. Patients who had been on CAPD treatment for longer periods showed higher TNF-alpha values. High plasma CCK levels were found in 38 of 45 patients (84%), mean 45.9+/-32.3 pg/ml. Patients with anorexia had no difference in CCK values compared with those without. A direct association was found between CCK levels and some nutritional markers (albumin, fibronectin, triglycerides, folic acid and nPCR in non diabetic patients). Although CCK has a recognized anorectic effect, this direct association might be because of an abnormal stimulation of CCK glucose feedback (trypsin) due to continuous peritoneal glucose absorption. This suggests that CCK could be an immediate food intake marker in PD patients. The NPY plasma levels were normal in 33 patients, high in 6 and low in 11. Patients with anorexia showed lower NPY levels than those without. NPY values greater than 50 pg/ml were directly associated with higher transferrin, prealbumin, RBP, nPCR and urea KT/V values. Importantly, a negative linear correlation between NPY and TNF-alpha was found (r=-0.42, n= 41, P<0.01). There was no significant relationship between residual renal clearance and the serum levels of the three peptides.. In conclusion, our data suggest that high TNF-alpha and low NPY serum levels are associated with anorexia. High TNF-alpha, low CCK and low NPY serum levels are also related to a poor nutritional status. Further research on these circulating substances is required.

Topics: Adult; Aged; Aged, 80 and over; Anorexia; Biomarkers; Cholecystokinin; Cross-Sectional Studies; Female; Humans; Male; Middle Aged; Neuropeptide Y; Nutrition Disorders; Nutritional Status; Peritoneal Dialysis; Protein-Energy Malnutrition; Tumor Necrosis Factor-alpha

We investigated the extrinsic gut neural mediation of the suppression of food intake in male Sprague-Dawley rats induced by peripheral intraperitoneal administration of 2 microg/kg interleukin-1beta (IL-1beta), 100 microg/kg bacterial lipopolysaccharide (LPS), and 2 mg/kg muramyl dipeptide (MDP). Food intake during the first 3 and 6 h of the dark cycle was measured in rats with subdiaphragmatic vagal deafferentation (n = 9), celiac superior mesenteric ganglionectomy (n = 9), combined vagotomy and ganglionectomy (n = 9), and sham deafferentation (n = 9). IL-1beta, LPS, and MDP suppressed food intake at 3 and 6 h in all surgical groups. The results demonstrate that neither vagal nor nonvagal afferent nerves from the upper gut are necessary for the feeding-suppressive effects of intraperitoneal IL-1beta, LPS, or MDP in the rat and suggest that peripheral administration of immunomodulators produces anorexia via a humoral pathway.

Topics: Acetylmuramyl-Alanyl-Isoglutamine; Afferent Pathways; Analysis of Variance; Animals; Anorexia; Cholecystokinin; Energy Intake; Feeding Behavior; Ganglionectomy; Injections, Intraperitoneal; Interleukin-1; Lipopolysaccharides; Male; Rats; Rats, Sprague-Dawley; Splanchnic Nerves; Vagotomy; Vagus Nerve

1. The pyridopyrimidine derivative IQM-95,333 ((4aS,5R)-2-benzyl-5-[N alpha-tert-butoxicarbonyl)L-tryptophyl] amino-1,3dioxoperhydropyrido[1,2-c]pyrimidine), a new non-peptide antagonist of cholecystokinin type A (CCKA) receptors, has been evaluated in vitro and in vivo in comparison with typical CCKA and CCKB receptor antagonists, such as devazepide, lorglumide, L-365,260 and PD-135,158. 2. IQM-95,333 displaced [3H]-CCK-8S binding to CCKA receptors from rat pancreas with a high potency in the nanomolar range. Conversely, the affinity of this new compound at brain CCKB receptors was negligible (IC50 > 10 microM). IQM-95,333 was a more selective CCKA receptor ligand than devazepide and other CCKA receptor antagonists. 3. Like devazepide, IQM-95,333 was a more potent antagonist of CCK-8S- than of CCK-4-induced contraction of the longitudinal muscle from guinea-pig ileum, suggesting selective antagonism at CCKA receptors. 4. IQM-95,333 and devazepide were also potent inhibitors of CCK-8S-stimulated amylase release from isolated pancreatic acini, a CCKA receptor-mediated effect. The drug concentrations required (IC50s around 20 nM) were higher than in binding studies to pancreas homogenates. 5. Low doses (50-100 micrograms kg-1, i.p.) of IQM-95,333 and devazepide, without any intrinsic effect on food intake or locomotion, blocked the hypophagia and the hypolocomotion induced by systemic administration of CCK-8S, two effects associated with stimulation of peripheral CCKA receptors. 6. IQM-95,333 showed an anxiolytic-like profile in the light/dark exploration test in mice over a wide dose range (10-5,000 micrograms kg-1). Typical CCKA and CCKB antagonists, devazepide and L-365,260 respectively, were only effective within a more limited dose range. 7. In a classical conflict paradigm for the study of anxiolytic drugs, the punished-drinking test, IQM-95,333, devazepide and L-365,260 were effective within a narrow dose range. The dose-response curve for the three drugs was biphasic, suggesting that other mechanisms are operative at higher doses. 8. In conclusion, IQM-95,333 is a potent and selective CCKA receptor antagonist both in vitro and in vivo with an anxiolytic-like activity in two different animal models, which can only be attributed to blockade of this CCK receptor subtype.

Topics: Amylases; Animals; Anorexia; Anti-Anxiety Agents; Benzodiazepinones; Carbamates; Cholecystokinin; Devazepide; Diazepam; Disease Models, Animal; Fenfluramine; Guinea Pigs; Hormone Antagonists; Locomotion; Male; Mice; Phenylurea Compounds; Pyrimidinones; Rats; Rats, Wistar; Receptors, Cholecystokinin; Selective Serotonin Reuptake Inhibitors

Because previous studies had suggested that the anorectic effects of cholecystokinin (CCK) and bombesin (BBS) depend partly on the release of amylin or calcitonin gene-related peptide (CGRP), we investigated the influence of the amylin and CGRP receptor antagonist CGRP (8-37) on the anorectic effects of CCK and BBS in streptozotocin (STZ)-diabetic and nondiabetic rats. STZ-diabetic rats had significantly lower plasma amylin and insulin concentrations than nondiabetic control rats. Amylin (5 micrograms/kg or 2.5 micrograms/rat) injected IP at dark onset after 24-h food deprivation elicited an anorectic effect of similar extent in STZ-diabetic and control rats. Under similar conditions, CCK (0.25 and 2 micrograms/kg) and BBS (5 micrograms/kg) reduced food intake in both STZ-diabetic and nondiabetic rats. These effects were markedly attenuated by CGRP (8-37) (10 micrograms/kg) in non-diabetics but not in STZ-diabetic rats. It is concluded that part of the anorectic effects of CCK and BBS depend on the release of amylin from pancreatic B-cells.

Topics: Amyloid; Animals; Anorexia; Bombesin; Calcitonin Gene-Related Peptide; Cholecystokinin; Diabetes Mellitus, Experimental; Drug Combinations; Eating; Injections, Intraperitoneal; Islet Amyloid Polypeptide; Male; Peptide Fragments; Rats; Streptozocin

Neuropeptide Y is one of the most powerful neurochemical stimulants of food intake known. The neuronal substrate for this action is believed to be the neuropeptide Y-expressing cell population in the hypothalamic arcuate nucleus. In this study, mice homozygous for the anorexia mutation (anx) were investigated histochemically; anx is a recessive mutation that causes decreased food intake and starvation, leading to death 22 days after birth. We were interested to see whether any hypothalamic neurochemical abnormalities could be detected in this genetic model of starvation. By using immunohistochemistry and in situ hybridization, the hypothalamic distributions of neuropeptide Y, cholecystokinin, galanin, and serotonin, all messenger molecules postulated to be involved in the regulation of food intake and energy metabolism, were investigated. Immunoreactivities for somatostatin, the excitatory amino acid aspartate, and acetylcholinesterase were also studied. Neuropeptide Y-like immunoreactivity was increased markedly in arcuate cell bodies and decreased in terminals in the arcuate nucleus and other hypothalamic regions of anx/anx mice compared with normal litter mates. In situ hybridization for neuropeptide Y mRNA, however, showed no significant difference in gene expression in the arcuate nucleus. In addition, immunoreactivities for aspartate, acetylcholinesterase, and somatostatin in the arcuate nucleus were decreased in anx/anx mice. For cholecystokinin, galanin, and serotonin, no certain differences in hypothalamic immunoreactivity could be seen. These data suggest that a defect in neuropeptide Y-ergic signalling in the arcuate neurons may contribute to the failure to thrive in anx/anx mice.

Topics: Animals; Anorexia; Arcuate Nucleus of Hypothalamus; Cholecystokinin; Energy Metabolism; Food Deprivation; Galanin; Hypothalamus; Immunohistochemistry; Mice; Models, Genetic; Mutation; Neural Pathways; Neuropeptide Y; Phenotype; Serotonin

The anorectic effect of IP injection of amylin (1 microgram/kg) was abolished by simultaneous IP injection of the amylin receptor antagonist calcitonin gene-related peptide-(8-37) [CGRP(8-37), 10 micrograms/kg]. The IP injection of pancreatic glucagon (400 micrograms/kg) at dark onset also reduced food intake in 24-h food-deprived rats, and this effect was also totally blocked by coadministration of CGRP(8-37) (10 micrograms/kg). In another feeding paradigm with glucagon (540 micrograms/kg IP 3 h into the light phase in 3 h-prefed rats), however, the anorectic effect of glucagon was not significantly antagonized by CGRP(8-37). The anorectic effect of cholecystokinin (CCK) (0.25 microgram/kg) and bombesin (BBS) (2 micrograms/kg) was partly neutralized by CGRP(8-37). In contrast, the anorectic effect of vasopressin (VP) (2.5 micrograms/kg) was not influenced by CGRP(8-37). As glucagon has been shown previously to increase the secretion of amylin, we conclude that the anorectic effect of peripherally administered glucagon is mediated by the release of amylin, at least under certain conditions. This may also be true for CCK and BBS, as these peptides are insulinotropic and may therefore be presumed to increase amylin release.

Topics: Amyloid; Animals; Anorexia; Bombesin; Calcitonin Gene-Related Peptide; Cholecystokinin; Glucagon; Humans; Islet Amyloid Polypeptide; Male; Peptide Fragments; Rats; Receptors, Islet Amyloid Polypeptide; Receptors, Peptide; Vasopressins

We used the type A cholecystokinin receptor (CCK-AR) antagonist devazepide to assess the importance of CCK in mediating the anorexia produced by 2-h duodenal infusions of glucose (9.2, 11.0, and 18.3 mmol.kg-1.h-1) and the glucose dimer maltose (4.5, 6.7, and 8.5 mmol.kg-1.h-1) at the start of the dark period in nonfasted rats with free access to food. Glucose and maltose appeared to inhibit 2- to 3-h food intakes dose dependently from 19 to 91%. The highest doses of glucose and maltose administered suppressed feeding similarly by increasing first meal latency and decreasing meal frequency; lower doses produced less reliable effects on meal patterns. Devazepide appeared to completely reverse the cumulative intake responses and some of the meal pattern responses to the 9.2-mmol.kg-1.h-1 dose of glucose and to partially attenuate responses to the two higher glucose doses and to the minimal effective dose of maltose (6.7 mmol.kg-1.h-1). The magnitudes of these devazepide effects were not statistically different from those produced by devazepide when vehicle was infused duodenally. These results suggest that CCK may play a significant necessary role in mediating the satiety response to duodenal delivery of small but not large loads of glucose.

Topics: Animals; Anorexia; Benzodiazepinones; Cholecystokinin; Devazepide; Dose-Response Relationship, Drug; Duodenum; Eating; Glucose; Hormone Antagonists; Male; Maltose; Rats; Rats, Sprague-Dawley; Receptor, Cholecystokinin A; Receptors, Cholecystokinin

To assess the importance of triglyceride digestion products in producing satiety, we determined the effects of duodenal infusions of triolein, oleic acid, and oleic acid plus monoolein on meal patterns in ad libitum-feeding rats. Oleic acid and oleic acid plus monoolein inhibited feeding similarly; triolein's effect was delayed and fourfold less potent. We then used the type A cholecystokinin (CCK-A)-receptor antagonist devazepide to assess the importance of CCK in mediating the anorexia produced by oleic acid. Oleic acid (at 320, 440, and 640 mumol/h) inhibited 3-h intake dose dependently by 32, 56, and 75%, respectively. Devazepide (1 or 2 mg/kg) blocked the responses to the 320 mumol/h dose, but had little if any effect on responses to the larger doses. Devazepide (1 mg/kg) did block anorexic responses to 3-h cholecystokinin octapeptide infusions (3 and 10 nmol.kg-1.h-1 iv) that inhibited 3-h intake by 25 and 65%, respectively. Our results suggest that the satiety response to triolein is produced by the products of triolein digestion and that CCK plays a significant, indispensable role in mediating the satiety response to duodenal delivery of small but not large loads of oleic acid.

Topics: Animals; Anorexia; Benzodiazepinones; Catheterization; Cholecystokinin; Devazepide; Digestion; Duodenum; Eating; Feeding Behavior; Male; Oleic Acid; Oleic Acids; Rats; Rats, Sprague-Dawley; Receptor, Cholecystokinin A; Receptors, Cholecystokinin; Satiety Response; Sincalide; Triolein

It has been proposed that there might be a link between the anorectic actions of cholecystokinin (CCK) and serotonin (5HT). The present study compared the patterns of c-fos protein-like immunoreactivity (FLI) induced in rat brain by CCK and the indirect 5HT agonist dexfenfluramine (DFEN), as well as the ability for devazepide, a CCK-A receptor antagonist, to antagonize both anorexia and FLI induced by these agents. Devazepide reversed the anorectic effect of CCK but not that of DFEN in food deprived rats. The FLI induced by CCK and DFEN occurred in similar brain regions, but in different subdivisions. Such regions included the bed nucleus of the stria terminalis (BST), the lateral central nucleus of the amygdala (CeL), and the lateral parabrachial nucleus (LPB). Devazepide abolished the FLI induced by CCK in most of these brain regions, but had no effect on FLI induced by DFEN. These results suggest that the LPB-CeL/BST pathway might be responsible for the anorectic effects of both CCK and DFEN, but different parts or neuronal populations in these structures might be differentially engaged by CCK and DFEN. The putative interaction between CCK and 5HT might happen along this pathway, rather than in the periphery.

Topics: Animals; Anorexia; Benzodiazepinones; Brain; Cholecystokinin; Devazepide; Feeding Behavior; Fenfluramine; Gene Expression; Genes, fos; Immunohistochemistry; Male; Organ Specificity; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Receptors, Cholecystokinin

Plasma and cerebrospinal fluid (CSF) concentrations of three well-known satiety neuropeptides, cholecystokinin (CCK), somatostatin and calcitonin gene-related peptide (CGRP), along with two powerful orexigenic neuropeptides, neuropeptide Y (NPY) and beta-endorphin have been measured in elderly persons with idiopathic anorexia and normal weight healthy subjects in a similar age range. Plasma and CSF immunoreactivity levels of the two main fractions of CCK (CCK8s and CCK33) after being separated by HPLC were measured by a radioimmunoassay (RIA) developed in our laboratory, whereas the other neuropeptides were assayed by commercially available RIA kits. Elderly underweight anorectic patients had significantly lower levels of beta-endorphin but increased concentrations of NPY in both plasma and CSF when compared to controls. In addition to significantly higher levels of CCK8s but not CCK33 in plasma, we found a trend to higher CSF concentrations of CCK8s and a positive correlation between the body mass index and either beta-endorphin (r = 0.58, P < 0.05) or CCK8s (r = 0.69, P < 0.01) concentrations in CSF in the anorectic group. CSF somatostatin concentrations were decreased significantly, but plasma somatostatin levels and plasma and CSF concentrations of CGRP were similar in senile anorectics and controls. Treatment of five anorectic patients with megestrol acetate, 480 mg daily for 6 months, reversed only the decrease in CSF beta-endorphin levels but did not normalize the body weight or the fat body mass. On the basis of our findings, we hypothesize that a decrease in CSF beta-endorphin concentration along with a rise in plasma levels of CCK8s might be accounted for the primary anorexia of aging.

Topics: Aged; Aged, 80 and over; Aging; Anorexia; beta-Endorphin; Calcitonin Gene-Related Peptide; Cholecystokinin; Female; Humans; Male; Middle Aged; Neuropeptide Y; Neuropeptides; Somatostatin

These studies compared the effects of total abdominal vagotomy (VGX) on ingestive actions produced by peripheral serotonergic and cholecystokinergic (CCKergic) stimulation in rats. Subcutaneous injection of 0.01-0.16 mumol/kg of the serotonin (5-HT) analogue 5-carboxamidotryptamine (5-CT) dose-dependently reduced mash intake equally in VGX rats and their laparotomized (LAP) controls but concurrently stimulated drinking only in the controls. The sulfated octapeptide of cholecystokinin (CCK-8, 4.0 nmol/kg ip) also reduced food intake only in the controls. In a second set of rats, vagotomy did not alter anorexia after intraperitoneal administration of either 2.0 or 8.0 mumol/kg of 5-HT or of 0.03 mumol/kg of 5-CT but abolished anorexia after a large dose of CCK-8 (8.0 nmol/kg). The completeness of vagotomy was verified histologically by immunohistochemical staining of the vagal bundles for the high molecular weight form of neurofilament-H protein. We report for the first time that 5-CT produces anorexia by a vagally independent mechanism. In contrast, 5-CT stimulates drinking by a pathway that does involve vagal function. Finally, we confirm the prediction that vagotomy dissociates the neural mechanisms for the anorectic action of peripheral 5-HTergic and CCKergic stimulation.

Topics: Abdomen; Animals; Anorexia; Cholecystokinin; Dose-Response Relationship, Drug; Eating; Male; Rats; Rats, Sprague-Dawley; Serotonin; Serotonin Receptor Agonists; Sincalide; Thirst; Vagotomy

In this study we examined the ability of intraperitoneal cholecystokinin COOH-terminal octapeptide (CCK-8; 0.2, 0.6, and 2.0 micrograms/kg) to suppress food intake in rats that had consumed a control diet, 6-8 g.kg-1.day-1 of ethanol (EtOH) in sucrose, or sucrose alone for 6 mo. Both the EtOH- and sucrose-fed rats developed significant dietary obesity. After 3 mo, the EtOH group was significantly more sensitive to CCK-8 than the sucrose and control groups, while the responses of the sucrose and control groups were comparable. In contrast, after 6 mo the EtOH and sucrose groups' response to CCK-8 was no longer significantly different. After 6 mo there were no significant differences in basal or postprandial plasma CCK-8 levels. The sucrose group had significantly higher basal insulin levels than the control and EtOH groups, and postprandial insulin levels, relative to basal, were significantly elevated in the EtOH group. Basal glucose levels did not differ among groups. Postprandial glucose levels (relative to baseline) were significantly lower in the EtOH group compared with the other groups and in fact never rose above baseline levels. These results are consistent with the hypothesis that EtOH, when taken on a chronic basis, increases the sensitivity to CCK-8.

Topics: Alcoholism; Animals; Anorexia; Blood Glucose; Cholecystokinin; Eating; Insulin; Male; Rats; Rats, Inbred Strains; Sincalide; Time Factors

We previously established pluripotent transformed rat islet cell lines, MSL-cells, of which certain clones have been used to study processes of islet beta-cell maturation, including the transcriptional activation of the insulin gene induced by in vivo passage. Thus, successive sc transplantation in NEDH rats resulted in stable hypoglycemic insulinoma tumor lines, such as MSL-G2-IN. Occasionally, hypoglycemia as well as severe weight loss were observed in the early tumor passages of MSL-G and the subclone, NHI-5B, which carry the transfected neomycin and human insulin genes as unique clonal markers. By selective transplantation, it was possible to segregate stable anorectic normoglycemic tumor lines, MSL-G-AN and NHI-5B-AN, from both clones. These tumors cause an abrupt onset of anorexia when they reach a size of 400-500 mg (< 0.3% of total body weight), and the observed weight loss parallels that of starved rats until death results from cachexia. After tumor resection, animals immediately resume normal feeding behavior. Comparative studies of hormone release and mRNA content in anorectic lines, MSL-G-AN and NHI-5B-AN, vs. those in the insulinoma line, MSL-G2-IN, revealed selective glucagon gene expression in both of the anorectic tumors, whereas insulin and islet amyloid polypeptide gene expression were confined to the insulinoma. Both tumor phenotypes produced cholecystokinin and gastrin in variable small amounts, making it unlikely that these hormones contribute to the anorectic phenotype. Tumor necrosis factor (cachectin) was not produced by any of the tumors. Proglucagon was processed as in the fetal islet to products representative of both pancreatic alpha-cell and intestinal L-cell phenotypes, with glucagon and Glp-1 (7-36)amide as the major extractable products. In contrast to the administration of cholecystokinin, neither glucagon, Glp-1 (7-36)amide, nor their combination, affected feeding behavior in fasted mice, suggesting the presence of a hitherto unidentified anorectic substance released from the glucagonoma. We conclude 1) that glucagonomas and insulinomas can be derived from a common clonal origin of pluripotent MSL cells, thus supporting the existence of a cell lineage relationship between islet alpha- and beta-cell during ontogeny; and 2) that our glucagonomas release an anorexigenic substance(s) of unknown nature that causes a severe weight loss comparable to that reported in animals carrying tumor necrosis factor-producing experimental

Topics: Adenoma, Islet Cell; Animals; Anorexia; Base Sequence; Blotting, Northern; Cholecystokinin; Eating; Gastrins; Gene Expression; Glucagon; Hormones; Hypoglycemia; Molecular Sequence Data; Neoplasm Transplantation; Pancreatic Neoplasms; Protein Precursors; Rats; Tumor Cells, Cultured; Weight Loss

New analogues of cholecystokinin-7 (CCK-7) modified at amino acid residues 5 and 7 were assayed for their effect on gall bladder, pancreatic secretion, food intake (anorectic activity), amount of rearing (sedative activity) and analgesia, as well as their ability to inhibit 125I-CCK-8 binding to pancreatic cell membrane receptors and brain membrane receptors. The results were compared to the activities of standard compounds, CCK-8, cerulein, BOC-CCK-7 (BOC = tertbutyloxycarbonyl) and BOC-[Nle2,Nle5]CCK-7. All analogues exhibited agonistic effects. Their anorectic activity was significantly prolonged.

Topics: Amylases; Analgesia; Animals; Anorexia; Cholecystokinin; Dose-Response Relationship, Drug; Gallbladder; Guinea Pigs; Male; Mice; Muscle Contraction; Pancreas; Rats; Rats, Wistar; Receptors, Cholecystokinin

We studied the behavioral effects of a novel cholecystokinin tetrapeptide (CCK-4) analogue, A71623, with full agonist activity and high affinity and selectivity for the CCK-A receptor subtype relative to the CCK-B receptor. In tests for anorectic activity, A71623 was found to suppress 60-min intakes of a liquid diet in both deprived and sated rats, and the effects were blocked by a selective CCK-A antagonist, A70104. Compared with CCK-8, A71623 was found to have improved potency and duration of action; the most potent route of administration was intraperitoneal. A71623 also suppressed the intake of a liquid diet and a 0.2 M sucrose solution in lean and obese Zucker rats. In daily injection studies, the anorectic activity of CCK-8 diminished rapidly, whereas the suppressant effects of A71623 on food intakes and body weight gains persisted throughout the 11-day treatment period. Finally, A71623 reduced the spontaneous locomotor activity of rats at doses above those required to suppress intakes. These studies are the first to describe the behavioral effects of a potent and highly selective CCK-A receptor agonist.

Topics: Animals; Anorexia; Behavior, Animal; Body Weight; Cholecystokinin; Circadian Rhythm; Eating; Food Deprivation; Male; Motor Activity; Peptides; Rats; Rats, Inbred Strains; Sincalide; Tetragastrin; Time Factors

Although a number of studies have characterized the anorectic state induced by phenylpropanolamine (PPA), the mechanism by which this drug suppresses appetite remains elusive. PPA inhibits gastric emptying at doses that also suppress appetite as does the gut hormone cholecystokinin (CCK). To evaluate whether PPA anorexia results via an action on gut CCK activity, rats in the present study were treated (IP) with either 0.9% saline or 150 mg/kg proglumide, a CCK receptor antagonist, 30 minutes before a 15 min feeding trial and then injected (IP) 5 min prior to the trial with either 0.9% saline, 5 mg/kg PPA, 10 mg/kg PPA, 8 ug/kg CCK or 16 ug/kg CCK. Although 150 mg/kg proglumide antagonized CCK anorexia, this dose of proglumide significantly enhanced the anorectic action of PPA. These results suggest that PPA does not act via an endogenous CCK system to suppress feeding.

Topics: Analysis of Variance; Animals; Anorexia; Appetite; Cholecystokinin; Drinking; Drug Synergism; Eating; Male; Phenylpropanolamine; Proglumide; Random Allocation; Rats

In these experiments we examined the effects on gastric motility of cholecystokinin, LiCl, hypertonic NaCl solution, gastric distension, and intraduodenal glucose loads, five dissimilar treatments known to reduce food intake in rats. In addition, we investigated whether any observed effects were dependent on the afferent vagus nerve by pretreating subjects with the neurotoxin capsaicin. Each of the five treatments virtually eliminated the gastric contractions seen after rats had consumed a large meal of chow; these effects were rapid in onset and continued for up to 30 min. The inhibitory effects of cholecystokinin and gastric distension were eliminated by pretreatment with capsaicin, whereas the effects of the other treatments were attenuated only slightly or not at all. Because most of these treatments have been shown to stimulate pituitary oxytocin secretion in rats as well as to inhibit food intake and gastric motility, these results are consistent with the hypothesis that the hypothalamic paraventricular nucleus is a site at which information is integrated in the coordinated control of food intake, gastric function, and neuroendocrine secretion.

Topics: Animals; Anorexia; Capsaicin; Chlorides; Cholecystokinin; Eating; Feeding and Eating Disorders; Gastrointestinal Motility; Glucose; Lithium; Lithium Chloride; Male; Oxytocin; Paraventricular Hypothalamic Nucleus; Rats; Rats, Inbred Strains; Saline Solution, Hypertonic

The existence of a relationship between cholecystokinin (CCK)-induced satiety and the serotoninergic system was evaluated. The food intake of 3-h-fasted male rats was studied after treatment with the COOH-terminal octapeptide of CCK (CCK-8) alone or in combination with one of two blockers of serotonin (5-HT) receptors, metergoline (MET; 1.0 or 0.06 mg/kg), active in both the periphery and brain, or xylamidine tosylate (XYL; 1.5 mg/kg), active only in the periphery. CCK-8 reduced food intake in the 30 min after food presentation by 37% at 2 micrograms/kg, 68% at 4 micrograms/kg, and 80% at 8 micrograms/kg compared with controls. Both doses of MET attenuated CCK-8-induced satiety, increasing food intake of rats treated with all doses of CCK-8 to control values. Food intake was significantly increased over base line by the 1.0-mg/kg dose of MET alone but unaffected by the 0.06-mg/kg dose of MET alone. XYL had no effect either given alone or in combination with CCK-8. These results indicate that the inhibitory action of CCK-8 on food intake is dependent on intact functioning of the serotoninergic system, probably at central sites.

Topics: Amidines; Animals; Anorexia; Cholecystokinin; Dose-Response Relationship, Drug; Eating; Feeding and Eating Disorders; Fenfluramine; Male; Metergoline; Rats; Serotonin

The syndrome of cancer anorexia includes early satiety in man and a reduction in the duration of feeding in experimental animals. These aberrations suggest dysfunction of peripheral and/or central nervous system satiety mechanisms in tumor-bearing individuals. Since the gut peptide, cholecystokinin (CCK), has been implicated as a potent satiety cue in man and animals, plasma and brain concentrations of CCK were measured by radioimmunoassay in anorectic tumor-bearing rats. Plasma concentrations of immunoreactive CCK were not significantly altered in either an acute Walker 256 carcinosarcoma or more chronic methylcholanthrene-induced sarcoma animal model of cancer anorexia. However, levels of immunoreactive CCK were significantly reduced in the hypothalamus and cerebral cortex of animals bearing the methylcholanthrene sarcoma during both mild and severe anorexia. These data demonstrate that elevations in immunoreactive CCK are not a major factor in the etiology of cancer anorexia. If brain CCK is involved in satiety, tumor-bearing rats may be attempting to compensate for their anorexia by down-regulating CCK production.

Topics: Animals; Anorexia; Brain; Carcinoma 256, Walker; Cerebral Cortex; Cholecystokinin; Eating; Feeding and Eating Disorders; Female; Humans; Hypothalamus; Rats; Rats, Inbred F344; Rats, Inbred Strains; Sarcoma, Experimental

Topics: Animals; Anorexia; Cholecystokinin; Feeding and Eating Disorders; Female; Humans; Intestinal Diseases, Parasitic; Intestine, Small; Sheep; Sheep Diseases; Trichostrongyloidiasis; Trichostrongylosis