sincalide and Anorexia

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

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

Obesity of middle-aged mammals is followed at old age by anorexia and cachexia leading to sarcopenia. Complex age- and body composition-related alterations in the regulation of energy homeostasis may be assumed in the background. We aimed to test the possible contribution of age- and body composition-related changes of satiety responses to catabolic brain-gut-axis peptide cholecystokinin (CCK) to these alterations in energy balance during aging. Male Wistar rats (6-8 animals/group) aged 2 months (juvenile), 3 months (young adult), 6 or 12 months (early or late middle-aged), and 24 months (old) were injected intraperitoneally with 5 μg CCK-8 prior to re-feeding after 48-h food-deprivation. CCK suppressed re-feeding in young adult (26.8%), early middle-aged (35.5%), and old (31.4%) animals, but not in juvenile or late middle-aged rats (one-way ANOVA). CCK-resistance of 12 months old rats was prevented by life-long calorie-restriction: CCK suppressed their re-feeding by 46.8%. Conversely, in highfat diet-induced obese 6 months old rats CCK failed to suppress re-feeding. In conclusion, age-related changes in satiety responsiveness to CCK may contribute to the age-related obesity of middle-aged as well as to the anorexia of old animals. CCK-responsiveness is also influenced by body composition: calorie-restriction prevents the resistance to CCK, pre-existing obesity enhances it.

Topics: Adiposity; Age Factors; Aging; Animals; Anorexia; Body Composition; Caloric Restriction; Diet, High-Fat; Energy Metabolism; Feeding Behavior; Homeostasis; Injections, Intraperitoneal; Male; Obesity; Rats; Rats, Wistar; Satiety Response; Sincalide

Cannabinoid CB1 receptor and cholecystokinin-1 (CCK(1)) receptors are located in peripheral nerve terminals of the gut, where they mediate satiety signals. Here we describe a detailed analysis of the interaction of both receptors in the control of feeding of food-deprived rats. Male Wistar rats were deprived for food 24h before testing. Rats were pre-treated with SR141716A (Rimonabant) or WIN 55,212-2 before CCK-8 sulphated administration and tested for food intake 60, 120 and 240 min after last drug injection. In parallel, the effect of Lorglumide--a CCK(1) receptor antagonist--pre-treatment was evaluated on feeding behaviour after SR141716A administration. Results show that SR141716A activates c-Fos expression in brainstem areas receiving vagal inputs. Blockade of CB1 receptors with SR141716A (1 mg/kg) reduces feeding and display additive satiety induction with the CCK(1) receptor agonist CCK-8 sulphated (5, 10, 25 μg/kg). The effect of SR141716A is not blocked by Lorglumide (10 mg/kg), indicating independent sites of action. Conversely, the administration of the CB1 agonist WIN 55,212-2 (2 mg/kg) reduced satiety induced by CCK-8. In conclusion, these results report additive anorectic actions for CCK1 activation and peripheral CB1 receptor blockade providing a framework for combined therapies in the treatment of eating disorders.

Topics: Animals; Anorexia; Benzoxazines; Brain; Drug Synergism; Feeding Behavior; Gene Expression; Genes, fos; Male; Morpholines; Naphthalenes; Piperidines; Proglumide; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Receptor, Cholecystokinin B; Rimonabant; Sincalide

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

Oleoylethanolamide (OEA) is a structural analog of the endogenous cannabinoid anandamide, which does not activate cannabinoid receptors. The biosynthesis of OEA in rat small intestine is increased by feeding and reduced by fasting. Moreover, OEA decreases food intake in food-deprived rats via a mechanism that requires intact sensory fibers (Rodríguez de Fonseca, 2001). These results suggest that OEA may contribute to the peripheral regulation of feeding. In the present study, we have investigated the effects of systemic OEA administration (1-20 mg/kg, intraperitoneal) on meal pattern in free-feeding and food-deprived rats. In free-feeding animals, OEA delayed feeding onset in a dose-dependent manner, but had no effect on meal size or postmeal interval. In food-deprived animals, OEA both delayed feeding onset and reduced meal size. The selective effects of OEA in free-feeding rats are strikingly different from those of the serotonergic anorexiant d-fenfluramine (which delayed feeding and reduced meal size) and the intestinal peptide cholecystokinin (which reduced meal size). These results suggest that OEA may participate in the regulation of satiety and may provide a chemical scaffold for the design of novel appetite-suppressing medications.

Topics: Animals; Anorexia; Appetite Depressants; Behavior, Animal; Dose-Response Relationship, Drug; Eating; Feeding Behavior; Fenfluramine; Food Deprivation; Male; Oleic Acid; Oleic Acids; Periodicity; Rats; Rats, Wistar; Reaction Time; Selective Serotonin Reuptake Inhibitors; Sincalide; Time Factors

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

To study the role of cholecystokinin octapeptide (CCK-8),beta endorphin (beta EP), and gastrin in an anorexic infantile rat model and no subsequent regulation of nose peptides by the Yunpi complex prescription ErBao Granule.. We fed infantile rats with special prepared forage. A liquid extract of ErBao Granule was administered to the rats daily for 3 weeks, CCK-8, beta-EP, and gastrin concentrations in hypothalamus, gastric antrum, and plasma of the rats were measured by radioimmunoassay, and were compared with controls.. Treatment of rats with ErBao Granule inhibited CCK-8 secretion and increased beta-EP and gastrin secretion. CCK-8 concentration in hypothalamus and plasma of model control group increased significantly and correlated negatively with food intake of models, respectively. beta-EP concentration in gastric antrum and plasma of model control group decreased significantly and showed a positive correlation with food intake of models, respectively. Hypothalamus concentration of beta-EP was similar in models and controls. Gastrin concentration in gastric antrum of models was lower than in the blank control group, and correlated positively to food intake of models. Finally, CCK-8 concentrations in plasma of rats showed a positive correlation with plasma beta-EP (r=-0.68, P<0.05).. The increased plasma and hypothalamus concentration of CCK-8, decreased gastric antrum and plasma level of beta-EP, and decreased gastric antrum concentration of gastrin are associated significantly with the anorexia of infantile anorexic rat models produced by special for-age. ErBao Granule can reverse these changes, which may be the major mechanisms of ErBao Granule simulating feeding.

Topics: Animals; Anorexia; beta-Endorphin; Diet; Female; Gastrins; Hypothalamus; Male; Models, Animal; Pyloric Antrum; Rats; Rats, Sprague-Dawley; Sincalide

Simmondsin, 2-(cyanomethylene)-3 hydroxy 4,5 dimethoxy cyclohexyl beta-D-glucoside, from jojoba meal reduces food intake in rats. We investigated the mechanism of action simmondsin, by studying the effects of fasting or of vagotomy on the food intake reduction. The food intake reduction was significantly less in fasted rats than in non-fasted rats. The reduction of food intake was also significantly diminished after vagotomy. The results of the present experiments suggest that simmondsin reduces intake of food in rats through the augmentation of satiety, in part vagally mediated.

Topics: Acetonitriles; Analysis of Variance; Animals; Anorexia; Appetite Depressants; Body Weight; Cyclohexanes; Eating; Fasting; Glucosides; Male; Nootropic Agents; Rats; Rats, Wistar; Sincalide; Vagotomy; Vagus Nerve

To study the regulatory effect of Erbao granules (EBG) on central and peripheral brain-gut peptide in juvenile animal model of anorexia.. Juvenile rat model of anorexia was established by imitating the major cause of infantile anorexia and treated with EBG. The cholocystokinin-octapeptide (CCK-8) and beta-endorphin (beta-EP) concentration in hypothalamus, antrum pyloricum and peripheral blood were examined by radioimmunoassay.. CCK-8 concentration in hypothalamus and plasma in the model rats increased (P < 0.05), while blood beta-EP concentration decreased (P < 0.05). After EBG treatment, the CCK-8 concentration normalized and beta-EP increased significantly.. EBG could reduce the central and peripheral CCK-8 and increase beta-EP secretion significantly in the juvenile anorexia model.

Topics: Animals; Anorexia; beta-Endorphin; Disease Models, Animal; Drugs, Chinese Herbal; Female; Gastric Mucosa; Hypothalamus; Male; Rats; Rats, Sprague-Dawley; Sincalide

The effects of the neurotransmitter serotonin (5-HT) and the neuropeptide cholecystokinin (CCK) on food intake are well established. Based on pharmacological studies, an interactive model for 5-HT and CCK was proposed. The present microdialysis study was aimed to provide neurochemical evidence for a facilitatory effect of CCK-8S on 5-HT release in the lateral hypothalamus under in vivo conditions. The results indicate an increase of extracellular hypothalamic 5-HT both during food intake in previously food-deprived rats and also after systemic administration of 8 microg/kg and 40 microg/kg CCK-8s in food-deprived rats. The results show that peripherally administered CCK-8s induces central serotonergic effects, possibly related to feeding.

Topics: Animals; Anorexia; Feeding Behavior; Hypothalamic Area, Lateral; Male; Rats; Rats, Wistar; Serotonin; Serotonin Agents; Sincalide

An anorectic substance similar to satietin was purified from ethanolic-acid precipitate of rat urine by gel filtration and ion exchange chromatography. The obtained glycoprotein (molecular mass 67 kDa) reduced food intake after intraperitoneal and intracisternal administration in mice in a dose-dependent manner (in the range of 5-80 mg/kg). The anorectic effect was specific. In the presence of sodium dodecylsulphate the substance dissociated into small proteins with a molecular mass of 9-11 kDa. Its anorectic effect was long lasting and differed from that of the anorectic peptide cholecystokinin octapeptide. Our finding supports the idea that anorectic protein isolated from plasma, membranes, and urine may be related substances.

Topics: Animals; Anorexia; Appetite Depressants; Eating; Glycopeptides; Glycoproteins; Guinea Pigs; Male; Mice; Rats; Rats, Wistar; Sincalide

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

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 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

Cholecystokinin octapeptide (CCK-8, 5 micrograms/kg) was injected i.p. into male Sprague-Dawley rats bearing the Walker 256-carcinosarcoma, or into non-tumour bearing controls, on a 20-h food deprivation schedule. Food and water intake and body weight maintenance were monitored for 15 days after tumour implantation and compared to that of tumour-bearing animals not injected with CCK-8. Food intake was significantly reduced for the duration of the two 4-day periods of CCK-8 injection, indicating that behavioural tolerance to this peptide did not occur. The severity of anorexia and body weight loss in tumour-bearing animals was significantly greater than that observed in non-tumour bearing controls, for the first 13 days of observation. These results indicate that endogenous peptides, such as CCK, may function in tumour-bearing animals to enhance the anorexia and wasting which typifies the anorexia cachexia syndrome.

Topics: Animals; Anorexia; Body Weight; Cachexia; Carcinoma 256, Walker; Drinking; Eating; Feeding and Eating Disorders; Male; Rats; Rats, Inbred Strains; Satiation; Sincalide