sincalide and Weight-Gain

Bacterially derived factors are implicated in the causation and persistence of obesity. Ingestion of a high fat diet in rodents and obesity in human subjects is associated with chronic elevation of low plasma levels of lipopolysaccharide (LPS), a breakdown product of Gram-negative bacteria. The terminals of vagal afferent neurons are positioned within the gut mucosa to convey information from the gut to the brain to regulate food intake and are responsive to LPS. We hypothesized that chronic elevation of LPS could alter vagal afferent signaling. We surgically implanted osmotic mini-pumps that delivered a constant, low-dose of LPS into the intraperitoneal cavity of rats (12.5 μg/kg/hr for 6 weeks). LPS-treated rats developed hyperphagia and showed marked changes in vagal afferent neuron function. Chronic LPS treatment reduced vagal afferent leptin signaling, characterized by a decrease in leptin-induced STAT3 phosphorylation. In addition, LPS treatment decreased cholecystokinin-induced satiety. There was no alteration in leptin signaling in the hypothalamus. These findings offer a mechanism by which a change in gut microflora can promote hyperphagia, possibly leading to obesity.

Topics: Animals; Blotting, Western; Eating; Hyperphagia; Immunohistochemistry; Leptin; Lipopolysaccharides; Male; Neurons, Afferent; Nodose Ganglion; Peroxidase; Rats, Wistar; Satiation; Sincalide; Weight Gain

Cholecystokinin (CCK) is a hormone that has important physiological effects on energy balance. This study has used a stable CCK(1) receptor agonist, (pGlu-Gln)-CCK-8, to evaluate the metabolic effects of prolonged administration in normal mice. Twice-daily injection of (pGlu-Gln)-CCK-8 for 28 days resulted in significantly lowered body weights (P<0.05) on days 24 and 28, which was associated with decreased accumulated calorie intake (P<0.01) from day 12 onward. Nonfasting plasma glucose was significantly reduced (P<0.05) on day 28, while plasma insulin concentrations were increased (P<0.05). After 28 days, glucose tolerance and glucose-mediated insulin secretion were not significantly different in (pGlu-Gln)-CCK-8-treated mice. However, following a 15-min refeeding period in 18-h fasted mice, glucose levels were significantly (P<0.05) decreased by (pGlu-Gln)-CCK-8 despite similar food intake and nutrient-induced insulin levels. Insulin sensitivity in (pGlu-Gln)-CCK-8-treated mice was significantly (P<0.01) improved compared with controls. Accumulation of triacylglycerol in liver was reduced (P<0.01) but there were no differences in circulating cholesterol and triacylglycerol concentrations, as well as triacylglycerol content of pancreatic, muscle, and adipose tissue in (pGlu-Gln)-CCK-8 mice. These data highlight the beneficial metabolic effects of prolonged (pGlu-Gln)-CCK-8 administration and confirm a lack of detrimental effects.

Topics: Animals; Anti-Obesity Agents; Blood Glucose; Energy Intake; Hyperglycemia; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin-Secreting Cells; Liver; Male; Mice; Postprandial Period; Receptor, Cholecystokinin A; Signal Transduction; Sincalide; Time Factors; Triglycerides; Weight Gain

During digestion, macronutrients are sensed within the small intestine. This sensory process is dependent upon the action of gut mediators, such as cholecystokinin (CCK) or serotonin (5-HT), on vagal afferents that, in turn, convey peripheral information to the brain to influence the control of food intake. Recent studies have suggested that dietary conditions alter vagal sensitivity to CCK and 5-HT. This phenomenon may be of importance to the onset of eating disorders. The aim of the present study was thus to investigate the effects of subjecting mice to 15 days of either an HF diet (30% fat, 54% carbohydrate) or an NF diet (10% fat, 74% carbohydrate) on 1) daily and short-term food intake, 2) vagal sensitivity to peripheral anorectic factors and macronutrient loads, and 3) vagal afferent neuron receptor expression. The results indicated that compared with an NF diet, and while increasing food intake and body weight gain, an HF diet altered the short-term response to CCK-8 and intragastric macronutrient loads, while decreasing vagal activation by CCK-8 and modifying the receptor expression of vagal neurons. These findings, therefore, suggest that dietary intervention effect on food intake could be linked to changes in vagal afferent receptor profiles.

Topics: Animals; Dietary Fats; Eating; Female; Injections, Intraperitoneal; Intestine, Small; Male; Mice; Mice, Inbred BALB C; Neurons, Afferent; Proto-Oncogene Proteins c-fos; Receptors, Neurotransmitter; RNA, Messenger; Satiety Response; Serotonin; Signal Transduction; Sincalide; Solitary Nucleus; Time Factors; Vagus Nerve; Weight Gain

Iron deficiency (ID) is among the most common nutritional diseases, causing deleterious effects that include decreases in cognitive function and weight loss. The ID also induces a reduction in the number and affinity of dopaminergic D2 receptors. The new finding that ID induces an increase in the pancreas cells, leads to the hypothesis that cholecystokinin-8 (CCK-8) is involved in the ID effects. The level of CCK-8 was higher among ID rats, compared with normal rats. The ID rats in our study were anorectic and performed poorly in learning tests (Morris water maze and passive avoidance learning). Essential fatty acids (EFA) mediate dopamine activity and have been found to rehabilitate learning deficits. Treatment with a fatty acid compound blocked both the learning deficits and the anorexia, while a CCK-8 antagonist was successful only against the anorectic effects.

Topics: Animal Feed; Animals; Avoidance Learning; Cholecystokinin; Energy Intake; Hormone Antagonists; Iron Deficiencies; Islets of Langerhans; Linoleic Acid; Male; Motor Activity; Peptide Fragments; Proglumide; Rats; Rats, Long-Evans; Swimming; Weight Gain

Chronic ingestion of diets containing 34% or 54% fat have been reported [Peptides 19 (1998) 1407] to decrease the inhibitory effect on food intake of doses of cholecystokinin-8 (CCK-8) less than 1 microg/kg i.p. We attempted to replicate this phenomenon in three experiments by comparing the effect of high-fat and low-fat diets on the threshold dose of CCK-8 for inhibition and on the dose-response function for doses of CCK-8 that ranged from 0.125 to 2.0 microg/kg. The first experiment tested rats five times per week. Rats on a 34% fat diet had a higher threshold (1.0 microg/kg) than rats on a 5% fat diet (0.25 microg/kg). The dose-response functions, however, were not significantly different. This result replicated the earlier report [Peptides 19 (1998) 1407]. The second experiment tested rats maintained on the same diets every other day as in the original report. It failed, however, to replicate the results of the first experiment or the earlier report because the threshold doses and the dose-response functions of CCK-8 were not significantly different between rats on 34% and 5% fat diets. The third experiment compared the potency of CCK-8 in rats on a 60% fat diet with the potency in rats on a 5% fat diet. CCK-8 was significantly more potent in the rats on the 60% fat diet because the threshold dose of these rats was lower (0.125 microg/kg) than in rats on the 5% fat diet (0.25 microg/kg), and the dose-response function in rats on the 60% fat diet was significantly more potent than in rats on the 5% fat diet. Thus, we observed two effects of the chronic ingestion of high-fat diets on the inhibitory potency of CCK-8: (1). A 34% fat diet increased the threshold dose of CCK-8 without changing the dose-response function in one of two experiments. (2). A 60% fat diet increased the potency of CCK-8 because it decreased the threshold dose and increased the dose-response function significantly.

Topics: Adipose Tissue; Animals; Cholecystokinin; Diet; Dietary Fats; Dose-Response Relationship, Drug; Male; Peptide Fragments; Rats; Rats, Sprague-Dawley; Satiety Response; Weight Gain

CCK octapeptide (CCK-8) is released by the gut in response to a meal and acts via CCK(A) receptors on vagal afferents to induce satiety. However, the central neural pathways by which peripheral CCK-8 affects feeding are poorly understood. In the present study, we tested the hypothesis that norepinephrine (NE) is necessary for satiety induced by peripheral CCK-8 by using mice lacking dopamine beta-hydroxylase (Dbh(-/-)), the enzyme responsible for synthesizing NE and epinephrine from dopamine. We found that Dbh(-/-) mice are as responsive to the satiating effects of CCK-8 as their normal littermates.

Topics: Animals; Cholecystokinin; Dopamine beta-Hydroxylase; Dose-Response Relationship, Drug; Feeding Behavior; Female; Food Deprivation; Gene Deletion; Male; Mice; Mice, Knockout; Norepinephrine; Peptide Fragments; Satiety Response; Weight Gain; Weight Loss

To test the role of gene expression of the classical ER (ER alpha) in the inhibitory effects of E on food intake and body weight, we ovariectomized and administered E2 benzoate (75 pg/d) or vehicle to wild-type (WT) mice and mice with a null mutation of ER alpha (alpha ERKO). Mice were ovariectomized at age 9 wk, at which time there was no significant effect of genotype on food intake or body weight. During an 18-d test after recovery from ovariectomy, vehicle-treated WT mice increased daily food intake and gained more body weight than E2-treated WT mice, whereas food intake and body weight gain were not different in E2- and vehicle-treated alpha ERKO mice. Carcass analysis revealed parallel changes in body lipid content, but not water or protein content. Because an increase in the potency of the peripheral cholecystokinin (CCK) satiation-signaling system mediates part of E2's influence on feeding in rats, the influence of ip injections of 250 microg of the selective CCK(A) receptor antagonist devazepide was then tested. Devazepide increased 3-h food intake in E2-treated WT mice, but was ineffective in both groups of alpha ERKO mice. Furthermore, ip injections of 4 microg/kg CCK-8 increased the number of cells expressing c-Fos immunoreactivity in the nuclei of the solitary tract of E2-treated WT mice more than it did in vehicle-treated WT mice, whereas E2 had no such effect in alpha ERKO mice. Thus, ER alpha is necessary for normal responsivity of food intake, body weight, adiposity, and the peripheral CCK satiation-signaling system to E2 in mice, and ER beta is not sufficient for any of these effects. This is the first demonstration that ER alpha gene expression is involved in the estrogenic control of feeding behavior and weight regulation of female mice.

Topics: Animals; Cholecystokinin; Eating; Estradiol; Estrogen Receptor alpha; Female; Lipids; Mice; Mice, Knockout; Ovariectomy; Proto-Oncogene Proteins c-fos; Receptor, Cholecystokinin A; Receptors, Cholecystokinin; Receptors, Estrogen; Reference Values; Satiety Response; Sincalide; Solitary Nucleus; Weight Gain

The Koletsky ("corpulent) obese rat is homozygous for an autosomal recessive mutation of the leptin receptor (Lepr) that results in hyperphagia, obesity, and hyperlipidemia. Unlike the Lepr mutation that characterizes the fatty Zucker rat (Lepr(fa)), the Koletsky mutation (Lepr(fak)) is null. Because the Lepr(fak) mutation is null, exogenous leptin should have no effect on body weight or food intake in fa(k)/fa(k) rats. We confirmed that prediction: murine leptin, administered into the third ventricle for 5 consecutive days, did not affect daily food intake or body weight in fa(k)/fa(k) rats but produced dose-related inhibitions of food intake and body weight in +/+ and +/fa(k) rats. Although fa(k)/fa(k) rats did not respond to leptin, their response to CCK-8 (4 microg/kg ip) injected before 30-min test meals of 10% sucrose was not different from that of +/+ or +/fa(k) rats. These results demonstrate that the fa(k)/fa(k) rat is a good model in which to analyze the controls of food intake, energy expenditure, and energy storage in the absence of leptin effects.

Topics: Animals; Carrier Proteins; Dietary Sucrose; Disease Models, Animal; Eating; Injections, Intraventricular; Leptin; Obesity; Rats; Rats, Mutant Strains; Receptors, Cell Surface; Receptors, Leptin; Satiation; Sincalide; Weight Gain; Weight Loss

Environmental manipulations during early development can induce permanent alterations in hypothalamic-pituitary-adrenal (HPA) and behavioral responses to stressors. However, little is known about the impact of early life experiences on appetitive responses. The present investigation assessed the effects of brief handling/separation or protracted separation from the dams, on feeding and anxiety responses during development. During the first 3 weeks post-partum, Sprague-Dawley rat pups were exposed daily to either brief (15 min) handling/isolation (H), a more protracted (3 h) period of maternal separation (MS), or were not handled (NH). When tested on the elevated plus-maze (at 5-6 weeks) H groups displayed less anxiety than NH gender-matched controls. Surprisingly, so did the MS females. At weaning (Day 22), the MS rats weighed significantly less than both the H and NH animals; the difference between the H and MS was more robust and persisted throughout the experiment (D 62). The H animals of both genders, and the females of the MS group, consumed more of the palatable 'snack' than their NH counterparts. The feeding suppressant response to the various satiety peptides (bombesin, cholecystokinin, and amylin) was not affected by the early life experience, with exception of cholecystokinin (CCK) effects, which were more pronounced in H and MS males. These results suggest that early life events may contribute to anxiety and/or ingestive disorders such as anorexia nervosa, bulimia and obesity.

Topics: Amyloid; Animals; Animals, Newborn; Anti-Ulcer Agents; Anxiety; Bombesin; Critical Period, Psychological; Dietary Carbohydrates; Dose-Response Relationship, Drug; Feeding Behavior; Female; Hypothalamo-Hypophyseal System; Islet Amyloid Polypeptide; Male; Maternal Deprivation; Pituitary-Adrenal System; Rats; Rats, Sprague-Dawley; Sex Factors; Sincalide; Weight Gain

Plasma cholecystokinin-8 (CCK-8) was studied in pigs with divergent genetic potential for feed intake. Differences in feed intake resulted from selection for either fast (line F) or slow (line S) postweaning gain. The hypothesis was that the relatively lesser feed intake in S versus F may be attributable, in part, to greater circulating concentrations of the putative satiety hormone CCK-8. In Experiment I, barrows from F (n = 23) and S (n = 19) were used to determine changes in CCK-8 associated with ad libitum feed consumption. Blood samples were collected after overnight feed deprivation, then periodically during a 2-hr feeding period. Averaged across sampling times, concentration of CCK-8 tended to be greater (P = 0.07) in S (6.70 pmol/l) than in F (5.06 pmol/l). Concentration of CCK-8 per unit of feed consumed (CCK-8/cumulative feed intake) was greater (P < 0.01) in S than in F during the first 30 min of the feeding period. In Experiment 2, plasma concentrations were determined for nine pairs (F, S) of the same barrows allowed an amount of feed equal to the previous ad libitum intake of the S barrow in the pair. Averaged across times, the difference between CCK-8 concentrations of S (11.65 pmol/l) and F (7.94 pmol/l) barrows was not significant (P = 0.18). A greater concentration of CCK-8 per unit of feed consumed in S than in F supports the hypothesis that satiety effects of CCK-8 may play a role in genetic differences between the lines for feed intake.

Topics: Animals; Eating; Female; Growth; Male; Satiation; Sincalide; Species Specificity; Swine; Weaning; Weight Gain

In this study, we investigated the analogies between the physiological effects of simmondsin, a satiety-inducing glycoside extracted from jojoba seeds, and the gastro-intestinal satiation peptide, cholecystokinin. The effects of intraperitoneal injection of the biological active CCK-octapeptide on the pancreas, interscapular brown adipose tissue, growth performance and energy metabolism in normal-fed, severely food intake-restricted (50 % of normal food intake) or moderately food intake-restricted (65 % of normal food intake) growing rats were compared to the effects of 0.25 % simmondsin mixed in the food, inducing moderate food intake reduction (65 % of normal) in rats. Cholecystokinin induced pancreatic hypertrophy. In normal fed rats, cholecystokinin had no effect on brown adipose tissue or growth, while, in severely food intake-restricted rats, it caused brown adipose tissue hypertrophy and reduced growth. In moderately food intake-restricted rats, both cholecystokinin and simmondsin induced pancreatic hypertrophy, increased brown adipose weight and metabolism and caused a slight decrease in growth. We conclude that cholecystokinin may decrease growth performance in fast growing severely food intake-restricted rats by stimulating brown adipose tissue metabolism, probably because of protein shortage induced by pancreatic hyperstimulation. Simmondsin has similar effects. These results support the hypothesis that endogenous cholecystokinin is involved in the effects of simmondsin in rats.

Topics: Acetonitriles; Adipose Tissue, Brown; Animals; Appetite Depressants; Cyclohexanes; Electron Transport Complex IV; Energy Metabolism; Food Deprivation; Glucosides; Hypertrophy; Male; Organ Size; Pancreas; Rats; Rats, Wistar; Sincalide; Weight Gain

The effects of repeated oral administration of the synthetic trypsin inhibitor camostat on intestinal macromolecular transport and disaccharidase development were investigated in suckling rats. By daily treatment with camostat, bovine immunoglobulin (Ig) G transport in the intestine declined more rapidly in treated than in control rats. The absorption curve shifted to the left in treated rats 3 days before the controls. Morphological inspection of treated pups showed a decline in the number of epithelial cells that absorb bovine IgG and in their vesicle size from basal to upper regions of the villi. Maltase activity precociously increased with camostat treatment. Chronic subcutaneous injection of camostat did not cause any changes in IgG transport and maltase activity. The depression of IgG transport by oral treatment with camostat was not affected by the cholecystokinin (CCK) receptor antagonist L 364718 and was not inhibited by adrenalectomy. The absorptive responses of IgG and maltase activity were not affected by CCK-8 treatment. These data indicate that oral administration of camostat induces precocious maturation of the small intestine and that the effect is not mediated via endogenous CCK released by camostat.

Topics: Administration, Oral; Adrenalectomy; Animals; Animals, Suckling; Biological Transport; Cattle; Esters; Gabexate; Guanidines; Immunoglobulin G; Injections, Subcutaneous; Intestine, Small; Macromolecular Substances; Rats; Rats, Inbred Strains; Sincalide; Time Factors; Trypsin Inhibitors; Weight Gain

This study explored feed intake and carcass responses to active immunization against desulfated cholecystokinin-octapeptide (CCK-8) in ram lambs. Antibody titers 8 wk following primary immunization and booster immunizations given at 4 and 6 wk averaged greater than 1:1,000. Titers increased to greater than 1:10,000 by 16 wk following a final booster immunization at 11 wk. The antibodies developed against desulfated CCK-8 exhibited 29% and 13% cross-reactivities for sulfated CCK-8 and gastrin-17, respectively. Immunization against desulfated CCK-8 had no effect on feed intake, ADG, carcass weight or carcass quality grade. Backfat thickness and carcass yield grade were reduced (P less than .05) by immunization. Organ weights at slaughter, including those of the pancreas and small intestines, were not affected by CCK-8 immunization, with the exception of the lungs, which were 16% lighter (P less than .01) in immunized lambs. In conclusion, active immunization against desulfated CCK-8 resulted in development of high antibody titers against desulfated and sulfated CCK-8. Immunization against CCK-8 decreased fat content of the carcass but failed to affect feed intake, carcass weight or ADG.

Topics: Animals; Antibody Formation; Body Composition; Cross Reactions; Eating; Immunization; Immunization, Secondary; Male; Organ Size; Sheep; Sincalide; Weight Gain