Gastrin releasing peptide-29 evokes feeding responses in the rat

In mammals, gastrin releasing peptide (GRP) 10 and 27 reduce food intake. In the current work, we test the hypothesis that GRP-29, the large molecular form of GRP in the rat, also evokes feeding responses consistent with a possible role in satiety. Here, we measured three feeding responses, size of first meal, intermeal interval (IMI, time between first and second meal) and satiety ratio (SR, satiation period for every unit of food consumed in the first meal), in overnight food deprived rats following GRP-10, 27 or 29 (0, 0.3, 1.0, 2.1, 4.1, 10.3, 17.2 nmol/kg) intraperitoneally and presentation of a 10% sucrose test diet. GRP-29 and GRP-27 reduced the size of the first meal, prolonged IMI and increased SR, but GRP-10 failed to exhibit similar feeding responses. The order of potency was GRP-29 = GRP-27 > GRP-10. The current data support a role for GRP-29 in the short-term regulation of food intake.     

Measuring meals: structure of prandial food and water intake of rats

Attempts to understand ingestion have sought to understand the control of meals. The present study evaluated a meal definition that included prandial drinking (drinking-explicit meals). The spontaneous nocturnal intake of male Wistar rats was studied. The meal breakpoint was defined as the interval between feeding or drinking events providing the most stable estimate of meal structure. Alternative breakpoints derived from prevailing methodology, log-survivorship, or frequency histogram analysis of interfeeding intervals without respect to drinking were compared (drinking-naive meals). Threshold interfeeding intervals that accounted for drinking indirectly were evaluated as surrogate breakpoints (drinking-implicit meals). Definitions were compared by determining which criterion better conformed to predictions of satiety. Microstructural differences resulting from the definitions were also studied. Under the drinking-explicit definition, rats averaged nine or ten 13-min meals/night, during which they consumed food and water equally in duration (5-6 min) and quantity (2.3 g). Individual differences were observed in microstructure measures. Meals defined by drinking-informed, but not drinking-naive, methods were followed by the behavioral satiety sequence and by an initially low likelihood of resuming feeding that monotonically increased with time. The drinking-explicit definition uniquely revealed preprandial and postprandial correlations of similar magnitude. Under drinking-informed definitions, food restriction increased meal size, whereas drinking-naive definitions increased meal frequency. Drinking-implicit definitions provided workable approximations of meal frequency and size but inferior estimates of feeding duration, eating rate, and the preprandial correlation. Thus log-survivorship analysis is not appropriate for identifying meal breakpoints, and the consideration of drinking in meal definitions can provide a better estimate of meal structure.     

Cholecystokinin-33 inhibits meal size and prolongs the subsequent intermeal interval

There are various forms of the satiety gut-brain peptide cholecystokinin (CCK), a short, widely utilized form or CCK-8, and a long, putatively more effective form or CCK-33. The issue of which of these forms is a more effective satiety peptide is not resolved. Here, we compared the satiety responses, including the sizes of the first three meals (MS) and intermeal intervals (IMI) as well as their calculated satiety ratios (SR), evoked by both peptides. CCK-8 and 33 (1, 3 and 5 nmol/kg, i.p) reduced the size of the first meal similarly, only CCK-33 prolonged the first IMI and increased SR and both peptides failed to affect second and third MS and IMI. As such, CCK-33 is a more effective satiety peptide than CCK-8. The current results confirm previous findings which showed that both peptides reduce food intake by inhibiting meal size, whereas only CCK-33 reduces food intake by prolonging the intermeal interval.     

Celiac and the cranial mesenteric arteries supply gastrointestinal sites that regulate meal size and intermeal interval length via cholecystokinin-58 in male rats

The site(s) of action that control meal size and intermeal interval (IMI) length by cholecystokinin-58 (CCK-58), the only detectable endocrine form of CCK in the rat, are not known. To test the hypothesis that the gastrointestinal tract may contain such sites, we infused low doses of CCK-58 (0.01, 0.05, 0.15 and 0.25 nmol/kg) into the celiac artery (CA, supplying stomach and upper duodenum), the cranial mesenteric artery (CMA, supplying small and most of the large intestines), the femoral artery (FA, control) and the portal vein (PV, draining the gastrointestinal tract) prior to the onset of the dark cycle in freely fed male rats. We measured the first meal size (chow), second meal size, IMI and satiety ratio (SR, IMI/meal size). We found that (1) all doses of CCK-58 given in the CA and the highest dose given in the CMA reduced the first meal size, (2) all doses of CCK-58 given in the CA reduced the second meal size, (3) a CCK-58 dose of 0.15 nmol/kg given in the CA and 0.15 and 0.25 nmol/kg given in the CMA prolonged the IMI, (4) CCK-58 (0.05, 0.15, 0.25 nmol/kg) given in the CA and 0.25 nmol/kg given in the CMA increased the SR, and (5) CCK-58 given in the FA and PV had no effect on the meal size or intermeal interval. These results support our hypothesis that the gastrointestinal tract contains sites of action that regulate meal size and IMI length via CCK-58. The stomach and upper duodenum may contain sites regulating meal size, whereas the small intestine and part of the large intestine may contain sites regulating the IMI.     

Reduced feeding during water deprivation depends on hydration of the gut

Removal of drinking water at the start of the dark period reduced food intake in freely feeding rats within 45 min. Both first and later meals were smaller during 7.5 h of water deprivation, but meal frequency did not change. Ingestion of a normal-sized meal (3 g) rapidly increased plasma tonicity when drinking water was withheld, but intravenous infusions of hypertonic NaCl causing similar increases in plasma tonicity did not reduce feeding. Feeding during 6 h of water deprivation was restored by slowly infusing the volume of water normally drunk into the stomach, jejunum, or cecum, but not in the vena cava or hepatic portal vein. The infusions did not alter water or electrolyte excretion or affect food intake in rats allowed to drink. We conclude that the inhibition of feeding seen during water deprivation is mediated by a sensor that is located in the gastrointestinal tract or perhaps in the mesenteric veins draining the gut, but not the hepatic portal vein or the liver. In the absence of drinking water, signals from this sensor provoke the early termination of a meal.     

5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside renders glucose output by the liver of the dog insensitive to a pharmacological increment in insulin

This study aimed to test whether stimulation of net hepatic glucose output (NHGO) by increased concentrations of the AMP analog, 5-aminoimidazole-4-carboxamide-1-beta-d-ribosyl-5-monophosphate, can be suppressed by pharmacological insulin levels. Dogs had sampling (artery, portal vein, hepatic vein) and infusion (vena cava, portal vein) catheters and flow probes (hepatic artery, portal vein) implanted >16 days before study. Protocols consisted of equilibration (-130 to -30 min), basal (-30 to 0 min), and hyperinsulinemic-euglycemic (0-150 min) periods. At time (t) = 0 min, somatostatin was infused, and basal glucagon was replaced via the portal vein. Insulin was infused in the portal vein at either 2 (INS2) or 5 (INS5) mU.kg(-1).min(-1). At t = 60 min, 1 mg.kg(-1).min(-1) portal venous 5-aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside (AICAR) infusion was initiated. Arterial insulin rose approximately 9- and approximately 27-fold in INS2 and INS5, respectively. Glucagon, catecholamines, and cortisol did not change throughout the study. NHGO was completely suppressed before t = 60 min. Intraportal AICAR stimulated NHGO by 1.9 +/- 0.5 and 2.0 +/- 0.5 mg.kg(-1).min(-1) in INS2 and INS5, respectively. AICAR stimulated tracer-determined endogenous glucose production similarly in both groups. Intraportal AICAR infusion significantly increased hepatic acetyl-CoA carboxylase (ACC, Ser(79)) phosphorylation in INS2. Hepatic ACC (Ser(79)) phosphorylation, however, was not increased in INS5. Thus intraportal AICAR infusion renders hepatic glucose output insensitive to pharmacological insulin. The effectiveness of AICAR in countering the suppressive effect of pharmacological insulin on NHGO occurs even though AICAR-stimulated ACC phosphorylation is completely blocked.     

The short term satiety peptide cholecystokinin reduces meal size and prolongs intermeal interval

Camostat mesilate (or mesylate) releases endogenous cholecystokinin (CCK) or CCK-58, the only detectable endocrine form of CCK in the rat, and reduces cumulative food intake by activating CCK₁ receptor. However, the literature lacks meal pattern analysis and an appropriate dose-response curve for this peptide. Therefore, the current study determines meal size (MS), intermeal interval (IMI) and satiety ratio (SR) by orogastric gavage of camostat (0, 12.5, 25, 50, 100, 200, 300, 400, 800 mg/kg) and compares them to those previously reported by a single dose of CCK-8 (1 nmol/kg, i.p), the most utilized form of CCK. We found that camostat (200, 300, 400 and 800 mg/kg) and CCK-8 reduced cumulative food intake and the size of the first meal, but only camostat prolonged IMI and increased SR. There was no change in the duration of the first two meals or in rated behaviors such as feeding, grooming, standing and resting in response to camostat and CCK-8, but there was more resting during the IMI in response to camostat. This study provides meal pattern analysis and an appropriate dose-response curve for camostat and CCK-8. Camostat reduces food intake by decreasing MS and prolonging IMI, whereas CCK-8 reduces food intake by reducing only meal size.     

Validation of ⁹⁹mTechnetium-labeled mebrofenin hepatic extraction method to quantify meal-induced splanchnic blood flow responses using a porcine model

The aim of this study was to evaluate the measurement of the total splanchnic blood flow (SBF) using a clinical diagnostic method based on Fick's principle and hepatic extraction of 99mTc-mebrofenin (99mTc-MBF) compared with a paraaminohippuric acid (pAH) dilution method in a porcine model. Another aim was to investigate whether enterohepatic cycling of 99mTc-MBF affected the SBF measurement. Five indwelling catheters were placed in each pig (n = 15) in the portal, mesenteric, and hepatic veins, as well as in the aorta and the vena cava. The SBF was measured using both methods. The portal blood flow; the intestinal and hepatic oxygen uptake; the net fluxes of oxygen, lactate, and glucose; and the extraction fraction (EF) of 99mTc-MBF were measured before and for 70 min after feeding. The mean baseline SBF was 2,961 ml/min vs. 2,762 ml/min measured by pAH and 99mTc-MBF, respectively, and increased significantly to 3,977 ml/min and 3,981 ml/min postprandially. The hepatic EF of 99mTc-MBF decreased from 40% at the start of the investigation to 16% 70 min after feeding. The arterial-portal difference in 99mTc-MBF concentration was 0.21% (P = 0.48), indicating no intestinal extraction or metabolism. The clinical method for measuring the SBF based on hepatic 99mTc-MBF extraction is robust compared with the indicator dilution method, despite the decrease seen in hepatic extraction of 99mTc-MBF. Because there was no difference in the content of 99mTc-MBF between the arterial and portal vein plasma, the SBF can be calculated from an arterial and a hepatic vein sample.     

Estradiol increases glucagon's satiating potency in ovariectomized rats

Estradiol decreases meal size, food intake, and body weight in female rats. To investigate whether these effects of estradiol involve a change in the sensitivity of the signaling pathway through which pancreatic glucagon released during meals contributes to meal termination (satiation), glucagon or glucagon antibodies were infused via the hepatic portal vein in ovariectomized rats that were chronically treated with estradiol benzoate (2 microg/day sc) or vehicle alone (100 microl sesame oil). Infusions began at 1 h after dark onset, as rats were refed after 7 h of food deprivation. Glucagon (3 microg/min for 30 min) decreased feeding during the initial 45 min of food access in both groups of rats, but the inhibition was significantly greater in estradiol- than in oil-treated rats. Similarly, antagonism of endogenous glucagon by infusion of glucagon antibodies (a dose neutralizing 3 ng of glucagon in vitro during the first 3 min of refeeding) increased feeding significantly more in estradiol- than in oil-treated rats. These data indicate that an increase in the activity of the endogenous glucagon satiation-signaling pathway may be part of the mechanism for estradiol's inhibitory effect on feeding.     

Effects of meal intake on materno-foetal exchanges of energetic substrates in the pig.

Catheters were implanted in 18 gilts at 99 days of pregnancy to study the effects of meal intake on uterine and umbilical uptake of energetic substrates in the conscious pig. Blood samples were withdrawn at 105 days of pregnancy from 10 min before and up to 90 min after feeding of a 2.5-kg meal. Plasma glucose was 2.2 to 2.5 times lower and blood lactate 2 to 3 times higher in the foetus than in the sow. Glucose and lactate increased after the meal. Their umbilical uptake amounted to 0.32 and 0.26 mmol x L(-1), respectively. Fructose was found in large amounts in foetal plasma (4.3 mmol x L(-1)), but it did not seem to be metabolised by the foetus. Meal intake decreased plasma levels of FFA and glycerol in the sows, whereas they increased in the foetuses. A small FFA and glycerol umbilical uptake was recorded (14 and 6 micromol L(-1), respectively). Most features of the materno-foetal exchanges in the porcine species resemble those of other species, especially ruminants.     

Cholecystokinin-33, but not cholecystokinin-8 shows gastrointestinal site specificity in regulating feeding behaviors in male rats

Two separate experiments were performed to localize the gastrointestinal sites of action regulating meal size (MS), intermeal interval (IMI) length and satiety ratio (SR, IMI/MS) by cholecystokinin (CCK) 8 and 33. Experiment 1: CCK-8 (0, 0.05, 0.15, 0.25 nmol/kg) was infused in the celiac artery (CA, supplies stomach and upper duodenum) or the cranial mesenteric artery (CMA, supplies small and part of the large intestine) prior to the onset of the dark cycle in free feeding, male Sprague Dawley rats and MS (normal rat chow), IMI and SR were recorded. Experiment 2: CCK-33 (0, 0.05, 0.15, 0.25 nmol/kg) were infused in the CA or the CMA, under the same experimental conditions above, and MS, IMI and SR were recorded. Experiment 1 found that CCK-8 reduces MS, prolongs the IMI and increases the SR at sites supplied by both arteries. Experiment 2 found that CCK-33 reduces MS and increases the SR at sites supplied by the CMA. We conclude that in male rats the feeding behaviors evoked by CCK-33, but not CCK-8, are regulated at specific gastrointestinal sites of action.     

Tracer mixing: sites of tracer infusion and sampling

Controversy exists in the literature concerning the correct infusion and sampling sites in studies measuring substrate turnover rates. To investigate this problem, we examined the results obtained with various infusion and sampling sites in 7 anesthetized dogs. [1-14C]lactate was infused by a primed continuous infusion method in three different sites (the left ventricle, ascending aorta, and the aortic arch) in a sequential fashion; samples were obtained simultaneously from five sites (femoral artery, carotid artery, pulmonary artery, superior vena cava and inferior vena cava) for each of the three different infusion sites. [U-13C]lactate was also infused in a femoral vein and simultaneous samples were obtained in the carotid artery and femoral artery for analysis of the stable isotope. [14C]lactate analysis demonstrated that infusion of the tracer into the left ventricular chamber resulted in a uniform distribution in the systemic circulation. Infusion into the ascending aorta near the aortic valve resulted in uniform distribution of tracer in four out of five experiments. Tracer infusion into the aortic arch resulted in nonuniform systemic distribution of tracer. The [U-13C]lactate results showed that infusion into the femoral vein gives uniform systemic distribution, similar to that observed with left ventricular infusion. The pulmonary artery lactate specific activities varied from those in the superior vena cava. Thus, this study shows that the tracer must be infused in the left ventricle or upstream from this chamber to obtain optimal systemic distribution. Vena caval sampling, especially superior vena caval sampling, will not give a consistent mixed venous concentration of the lactate tracer. Therefore, aortic tracer infusion with vena caval sampling may lead to errors in determining substrate turnover values.     

Lactate uptake by the fetal sheep liver

Lactate is produced by the sheep placenta and is an important metabolic substrate for fetal sheep. However, lactate uptake and release by the fetal liver have not been assessed directly. We measured lactate flux across the liver in 16 fetal sheep at 129 (120-138) days gestation that had catheters chronically maintained in the fetal descending aorta, inferior vena cava, right or left hepatic vein, and umbilical vein. Lactate and hemoglobin concentrations and oxygen saturation were measured in blood drawn from all vessels. Umbilical venous, portal venous, and hepatic blood flow were measured by injecting radionuclide-labeled microspheres into the umbilical vein while obtaining a reference sample from the descending aorta. We found net hepatic uptake of lactate (5.0 +/- 4.4 mg/min per 100 g liver). A large quantity of lactate was delivered to the liver (94.2 +/- 78.1 mg/min per 100 g), so that the hepatic extraction of lactate was only 7.7 +/- 6.5%. Hepatic oxygen consumption was 3.18 +/- 3.3 ml/min per 100 g, and the hepatic lactate/oxygen quotient was 2.07 +/- 1.54. There was no significant correlation between hepatic lactate uptake and hepatic lactate or glucose delivery, hepatic oxygen consumption, hepatic blood flow, hepatic glucose flux, total body oxygen consumption, arterial pH, oxygen content, or oxygen saturation. There was, however, a significant correlation between hepatic lactate uptake and umbilical lactate uptake (r = 0.74, P less than 0.005) such that net hepatic lactate uptake was nearly equivalent to that produced across the umbilical-placental circulation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Sequence analysis and feeding responses evoked by the large molecular form of gastrin releasing peptide (GRP) in the rat GRP-29

Microisolation techniques utilizing several reverse phase high performance liquid chromatography (HPLC) steps have resulted in the purification of two rat gastrin releasing peptide (GRP) forms suitable for microsequence and mass spectral analysis. The sequence of the larger form is APVSTGAGGGTVLAKMYPRGSHWAVGHLM-amide and the smaller form is GSHWAVGHLM-amide which is the carboxyl terminal decapeptide of the larger peptide. The peptides were synthesized and their feeding patterns e.g. first meal size (MS), intermeal interval (IMI) and satiety ratio (SR, IMI/MS) were determined in overnight food-, but not water deprived, male Sprague Dawley rats. The peptides were administered in the femoral vein (0, 0.21, 0.41 and 1.03 nmol/kg) immediately before presenting the rats with a 10% sucrose solution. We found that (1) GRP-10 (all doses) and GRP-29 (0.41 nmol/kg) reduced first MS, (2) both peptides prolonged IMI length and (3) both peptides increased the SR to similar extents. In conclusion, GRP-10 and GRP-29 are the two endogenous forms of GRP in the rat intestine and they reduce short term feeding to similar extents when administered intravenously.     

Effects of muscarinic blockade on the thermic effect of oral or intravenous carbohydrate.

Muscarinic blockade by atropine has been shown to decrease the thermic effect of a mixed meal, but not of intravenous glucose. To further delineate the mechanisms involved in the atropine-induced inhibition of thermogenesis after a meal, plasma substrate and hormone concentrations, energy expenditure (EE) and substrate oxidation rates were measured before and during a continuous glucose infusion (44.4 mumol.kg-1.min-1) with or without atropine. After 2 h of glucose infusion, a 20-g oral fructose load was administered while the glucose infusion was continued. Plasma insulin concentrations attained a plateau at 596 (SEM 100) pmol.l-1 after 120 min of glucose infusion and were not affected by muscarinic blockade; plasma glucose concentrations peaked at 13.3 (SEM 0.5) mmol.l-1 at 90 min and decreased progressively thereafter; no difference was observed with or without atropine. Plasma free fatty acid and glucagon concentrations, with or without atropine, were both decreased to 201 (SEM 18) mumol.l-1 and 74 (SEM 4) ng.l-1, respectively, after 2 h of glucose infusion, and were not further suppressed after oral fructose. Carbohydrate oxidation rates (CHO(ox)) increased to 20.8 (SEM 1.4) mumol.kg-1.min-1 and lipid oxidation rates (Lox) decreased to 1.5 (SEM 0.3) mumol.kg-1.min-1 between 90 and 120 min after the beginning of glucose infusion and were not affected by atropine. Glucose-induced thermogenesis was similar with [6.5% (SEM 1.4%) of basal EE] or without [6.0% (SEM 1.0%), NS) muscarinic blockade during the 30 min preceding fructose ingestion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cortisol induces perinatal hepatic gluconeogenesis in the lamb.

To examine the influence of a prenatal increase in plasma cortisol concentration on perinatal initiation of hepatic gluconeogenesis, we infused cortisol into seven fetal sheep at 137-140 days gestation. 14C-Lactate provided tracer substrate for estimation of gluconeogenesis. We measured hepatic blood flow using radionuclide-labeled microspheres. After delivery, fetal arterial blood glucose concentration (1.33 +/- 0.4 mmol/l) increased transiently, but returned to fetal levels within 1 h after delivery. Substantial hepatic gluconeogenesis was induced in the fetus after cortisol infusion, averaging 23.4 +/- 12.2 mumol/min/100 g liver (7.8 +/- 4.4 mumol/min/kg fetal weight). Fetal hepatic glucose output was 44.4 +/- 17.7 mumol/min/100 g liver. Hepatic glucose output did not change after delivery; estimated gluconeogenesis decreased immediately, then increased by 6 h after delivery. Lactate supply to the liver fell substantially, from 1.1 +/- 0.4 mmol/min/100 g in the fetus to 0.24 +/- 0.09 at 1 h after delivery. Lactate flux across the liver decreased from 75.3 +/- 23 mumol/min/100 g in the fetus to 20.2 +/- 15.7 at 1 h after delivery. Hepatic lactate flux was significantly related to gluconeogenesis (r = 0.734, P = 0.0001). We conclude that cortisol induces substantial hepatic gluconeogenesis in fetal sheep near term. After delivery, there appears to be a transient decline in gluconeogenesis from lactate, which may be secondary to limited hepatic oxygen and substrate supply. Onset of gluconeogenesis in the fetus fails to sustain increases in either fetal or postnatal blood glucose concentrations.     

Gastrin releasing peptide-29 requires vagal and splanchnic neurons to evoke satiation and satiety

We have shown that gastrin-releasing peptide-29 (GRP-29), the large molecular form of GRP in rats, reduces meal size (MS, intake of 10% sucrose solution) and prolongs the intermeal interval (IMI). In these studies, we first investigated possible pathways for these responses in rats undergoing total subdiaphragmatic vagotomy (VGX, removal of vagal afferent and efferent innervation of the gut), celiaco-mesenteric ganglionectomy (CMGX, removal of splanchnic afferent and efferent innervation of the gut) and combined VGX and CMGX. Second, we examined if the duodenum communicates the feeding signals (MS and IMI) of GRP-29 (0, 0.3, 1.0, 2.1, 4.1, 10.3 and 17.2 nmol/kg) with the feeding control areas of the hindbrain by performing duodenal myotomy (MYO), a procedure that severs some layers of the duodenal wall including the vagal, splanchnic and enteric neurons. We found that GRP-29 (2.1, 4.1, 10.3, 17.2 nmol/kg) reduced the size of the first meal (10% sucrose) and (1, 4.1, 10.3 nmol/kg) prolongs the first IMI but did not affect the subsequent meals or IMIs. In addition, CMGX and combined VGX/CMGX attenuated reduction of MS by GRP-29 and all surgeries attenuated the prolongation of the IMI. Therefore, reduction of MS and prolongation of IMI by GRP-29 require vagal and splanchnic nerves, and the duodenum is the major conduit that communicates prolongation of IMI by GRP-29 with the brain.     

Effects of fourth ventricle bombesin injection on meal-related parameters and grooming behavior.

Injections of bombesin (BN) into the vicinity of the caudal brainstem suppress food intake in rats. In the present study, the food intake parameters [meal size (MS), intermeal interval (IMI), satiety ratio (SR)] affected by 4th ventricle BN injections were determined. Following a 15-h food deprivation, rats were administered 4th ventricle injections of saline (0.15 M) and BN in doses of 1, 5, 10, and 20 ng BN, and were then given access to sweetened milk. The animals' behaviors (feeding, resting, grooming, exploring) were scored every one min and milk intake every five min for 60 min following the injections. Fourth ventricle injections of 5 ng BN and greater reliably suppressed milk. intake. This reduction was reflected in a significant reduction in the MS. The IMI was not affected. As a result, the SR (IMI2/MS1), which is thought to represent the satiating property of food, was reliably greater following BN than following saline administration. The reduced food intake was accompanied by a significant increase in grooming behavior and a corresponding decrease in exploring. The amount of time spent resting (inactive) was similar following saline and all but the highest dose of BN. To demonstrate that the behavioral effects of BN were mediated by specific caudal brainstem BN receptors, 4th ventricle injections of [D-Phe12,Leu14]BN, a BN receptor antagonist, or saline preceded the 4th ventricle injection of 5 ng BN. Pretreatment with [D-Phe12,Leu14]BN reliably blocked the effects of BN on food intake and grooming.     

The feeding responses evoked by endogenous cholecystokinin are regulated by different gastrointestinal sites

The current study tested the hypothesis that cholecystokinin (CCK) A receptor (CCKAR) in areas supplied by the celiac artery (CA), stomach and upper duodenum, and the cranial mesenteric artery (CMA), small and parts of the large intestine, is necessary for reduction of meal size, prolongation of the intermeal interval (time between first and second meal) and increased satiety ratio (intermeal interval/meal size or amount of food consumed during any given unit of time) by the non-nutrient stimulator of endogenous CCK release camostat. Consistent with our previous findings camostat reduced meal size, prolonged the intermeal interval and increased the satiety ratio. Here, we report that blocking CCKAR in the area supplied by the celiac artery attenuated reduction of meal size by camostat more so than the cranial mesenteric artery route. Blocking CCKAR in the area supplied by the cranial mesenteric artery attenuated prolongation of the intermeal interval length and increased satiety ratio by camostat more so than the celiac artery route. Blocking CCKAR in the areas supplied by the femoral artery (control) failed to alter the feeding responses evoked by camostat. These results support the hypothesis that CCKAR in the area supplied by the CA is necessary for reduction of meal size by camostat whereas CCKAR in the area supplied by the CMA is necessary for prolongation of the intermeal interval and increased satiety ratio by this substance. Our results demonstrate that meal size and intermeal interval length by camostat are regulated through different gastrointestinal sites.     

The feeding responses evoked by cholecystokinin are mediated by vagus and splanchnic nerves

Total or selective branch vagotomy attenuates the reduction of cumulative food intake by cholecystokinin (CCK)-8 and CCK-33 respectively. However, the role of the sympathetic innervation of the gut and the role of the vagus nerve in feeding responses, which include meal size (MS) and intermeal interval (IMI), evoked by CCK-8 and CCK-33 have not been evaluated. Here, we tested the effects of total subdiaphragmatic vagotomy (VGX) and celiaco-mesenteric ganglionectomy (CMGX) on the previous feeding responses by CCK-8 and CCK-33 (0, 1, 3, and 5 nmol/kg given intraperitoneally). We found (1) that both peptides reduced meal size and CCK-8 (5 nmol) and CCK-33 (1 and 3 nmol) prolonged IMI, (2) that VGX attenuated the reduction of MS but failed to attenuate the prolongation of IMI by both peptides and (3) that CMGX attenuated the reduction of meal size by CCK-8 and the prolongation of IMI by both peptides. Therefore, the feeding responses evoked by CCK-8 require intact vagus and splanchnic nerves: the reduction of MS by CCK-33 requires an intact vagus nerve, and the prolongation of IMI requires the splanchnic nerve. These findings demonstrate the differential peripheral neuronal mediation of the feeding responses evoked by CCK-8 and CCK-33.