RESUMO
The vagus nerve and the celiaco-mesenteric ganglia (CMG) are required for reduction of meal size (MS) and prolongation of the intermeal interval (IMI) by intraperitoneal (ip) sulfated cholecystokinin-8 (CCK-8). However, recently we have shown that the gut regulates these responses. Therefore, reevaluating the role of the vagus and the CMG in the feeding responses evoked by CCK is necessary because the gut contains the highest concentration of enteric, vagal and splanchnic afferents and CCK-A receptors, which are required for reduction of food intake by this peptide, compared to other abdominal organs. To address this necessity, we injected sulfated CCK-8 (0, 0.1, 0.5, 1 and 3 nmol/kg) in the aorta, near the gastrointestinal sites of action of the peptide, in three groups of free-feeding rats (n = 10 rats per group), subdiaphragmatic vagotomy (VGX), celiaco-mesenteric ganglionectomy (CMGX) and sham-operated, and recorded seven feeding responses. In the sham group, CCK-8 reduced MS (normal chow), prolonged the intermeal interval (IMI, time between first and second meals), increased satiety ratio (SR, IMI/MS), shortened duration of first meal, reduced total (24 hrs) food intake and reduced number of meals relative to saline vehicle. Vagotomy attenuated all of the previous responses except IMI length and SR, and CMGX attenuated all of those responses. In conclusion, the feeding responses evoked by sulfated CCK-8 require, independently, the vagus nerve and the CMG.
Assuntos
Comportamento Animal/fisiologia , Colecistocinina/farmacologia , Comportamento Alimentar/fisiologia , Gânglios Simpáticos/fisiologia , Fragmentos de Peptídeos/farmacologia , Saciação/fisiologia , Simpatectomia , Vagotomia , Nervo Vago/fisiologia , Animais , Artéria Celíaca , Colecistocinina/administração & dosagem , Comportamento Alimentar/efeitos dos fármacos , Gânglios Simpáticos/cirurgia , Masculino , Fragmentos de Peptídeos/administração & dosagem , Ratos , Ratos Sprague-Dawley , Saciação/efeitos dos fármacos , Fatores de Tempo , Nervo Vago/cirurgiaRESUMO
We have shown that non-sulfated cholecystokinin-8 (NS CCK-8) reduces food intake in adult male Sprague Dawley rats by activating cholecystokinin-B receptor (CCK-BR). Here, we tested the hypothesis that the vagus nerve and the celiaco-mesenteric ganglia may play a role in this reduction. The hypothesis stems from the following facts. The vagus and the celiaco-mesenteric ganglia contain NS CCK-8, they express and have binding sites for CCK-BR, NS CCK-8 activates CCK-BR on afferent vagal and sympathetic fibers and the two structures link the gastrointestinal tract to central feeding nuclei in the brain, which also contain the peptide and CCK-BR. To test this hypothesis, three groups of free-feeding rats, vagotomy (VGX), celiaco-mesenteric ganglionectomy (CMGX) and sham-operated, received NS CCK-8 (0, 0.5 and 1 nmol/kg) intraperitoneally prior to the onset of the dark cycle and various feeding behaviors were recorded. We found that in sham-operated rats both doses of NS CCK-8 reduced meal size (MS), prolonged the intermeal interval (IMI, time between first and second meal), increased satiety ratio (SR = IMI/MS), reduced 24-h food intake and reduced the number of meals relative to saline control. In the VGX and the CMGX groups, all of the previous responses were attenuated. Consistent with our hypothesis, the findings of the current work suggest a role for the vagus nerve and the celiaco-mesenteric ganglia in the feeding responses evoked by NS CCK-8.
Assuntos
Comportamento Animal/fisiologia , Colecistocinina/metabolismo , Comportamento Alimentar/fisiologia , Gânglios Simpáticos/metabolismo , Fragmentos de Peptídeos/metabolismo , Nervo Vago/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Colecistocinina/administração & dosagem , Comportamento Alimentar/efeitos dos fármacos , Masculino , Fragmentos de Peptídeos/administração & dosagem , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND: Peptide tyrosine tyrosine 3-36 (peptide YY 3-36 or PYY 3-36) reduces food intake by unknown site(s). AIM: To test the hypothesis that the gastrointestinal tract contains sites of action regulating meal size (MS) and intermeal interval (IMI) length by PYY 3-36. METHODS: Peptide YY 3-36 (0, 1, 5, 10 and 20 nmol/kg) was injected in the aorta, the artery that supplies the gastrointestinal tract, prior to the onset of the dark cycle in free feeding male Sprague-Dawley rats and food intake was measured. Then, PYY 3-36 (25 nmol/kg) was injected intraperitoneally in these rats and Fos-like immunoreactivity (Fos-LI, a marker for neuronal activation) was quantified in the small intestinal enteric neurons, both myenteric and submucosal, and the dorsal vagal complex (DVC) of the hindbrain. RESULTS: PYY 3-36 reduced first MS, decreased IMI length, shortened duration of first meal and increased Fos-LI in enteric and DVC neurons. However, PYY 3-36 failed to change the size of the second meal, satiety ratio, latency to first meal, number of meals and 24 h intake relative to saline control. CONCLUSION: The gastrointestinal tract may contain sites of action regulating MS reduction by PYY 3-36.
Assuntos
Ingestão de Alimentos/efeitos dos fármacos , Sistema Nervoso Entérico/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Peptídeo YY/farmacologia , Animais , Avaliação Pré-Clínica de Medicamentos , Masculino , Ratos Sprague-DawleyRESUMO
We hypothesized that exogenous gastrin releasing peptide-29 (GRP-29), cholecystokinin-8 (CCK-8) and their combination reduce body weight (BW). To test this hypothesis, BW was measured in four groups of diet-induced obese (DIO) male rats infused in the aorta (close to the junctions of the celiac and cranial mesenteric arteries) with saline, CCK-8 (0.5 nmol/kg), GRP-29 (0.5 nmol/kg) and CCK-8+GRP-29 (0.5 nmol/kg each) once daily for a total of 23 days. We found that CCK-8, GRP-29 and CCK-8+GRP-29 reduce BW relative to saline control. In conclusion, CCK-8, GRP-29 and their combination reduce BW in the DIO rat model. If infused near their gastrointestinal sites of action CCK-8, GRP-29 and their combination may have a role in regulating BW.
Assuntos
Peso Corporal/efeitos dos fármacos , Colecistocinina/administração & dosagem , Peptídeo Liberador de Gastrina/administração & dosagem , Fármacos Gastrointestinais/administração & dosagem , Obesidade/tratamento farmacológico , Fragmentos de Peptídeos/administração & dosagem , Redução de Peso , Animais , Dieta/efeitos adversos , Quimioterapia Combinada , Infusões Parenterais , Masculino , Obesidade/etiologia , RatosRESUMO
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.
Assuntos
Artéria Celíaca/metabolismo , Colecistocinina/metabolismo , Ingestão de Alimentos/fisiologia , Comportamento Alimentar/fisiologia , Gabexato/análogos & derivados , Artéria Mesentérica Superior/metabolismo , Inibidores de Proteases/farmacologia , Receptor de Colecistocinina A/metabolismo , Animais , Ingestão de Alimentos/efeitos dos fármacos , Ésteres , Comportamento Alimentar/efeitos dos fármacos , Artéria Femoral/metabolismo , Gabexato/administração & dosagem , Gabexato/farmacologia , Guanidinas , Masculino , Inibidores de Proteases/administração & dosagem , Ratos , Ratos Sprague-Dawley , Fatores de TempoRESUMO
This confirmatory work is aimed to test that the hypothesis that the gastrin releasing peptide (GRP) receptor - the BB2 receptor - is necessary for reduction of meal size (MS) and prolongation of the intermeal interval (IMI) by the small and the large forms of GRP in the rat, GRP-10 and GRP-29, and to confirm the sites of action regulating such responses - the vascular bed of the celiac artery (CA, supplying stomach and upper duodenum). To pursue these aims we measured first MS and IMI length in response to GRP-10 and GRP-29 (0, 0.5nmol/kg) infused in the CA (n=8 rats) and the cranial mesenteric artery (CMA, supplying the small and part of the large intestine, n=8 rats) in near spontaneously free feeding rats pretreated with the BB2 receptor antagonist BW2258U89 (0.1mg/kg) in the same arteries prior to the onset of the dark cycle. We found that GRP-29, but not GRP-10, infused by the CA reduced MS and prolonged the IMI by decreasing meal latency and meal duration and the BB2 receptor antagonist BW2258U89 infused in the same artery attenuated these responses. These results suggest that the BB2 receptor is necessary for reduction of MS and prolongation of the IMI by exogenous GRP-29, and the vascular bed of the CA, stomach and upper duodenum, contains sites of action regulating these feeding responses.
Assuntos
Comportamento Alimentar/efeitos dos fármacos , Peptídeo Liberador de Gastrina/farmacologia , Oligopeptídeos/farmacologia , Receptores da Bombesina/antagonistas & inibidores , Animais , Bombesina/farmacologia , Artéria Celíaca/efeitos dos fármacos , Artéria Celíaca/fisiologia , Duodeno/efeitos dos fármacos , Duodeno/fisiologia , Comportamento Alimentar/fisiologia , Peptídeo Liberador de Gastrina/química , Masculino , Fragmentos de Peptídeos/farmacologia , Ratos , Ratos Sprague-Dawley , Estômago/efeitos dos fármacos , Estômago/fisiologiaRESUMO
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, 0.25nmol/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, 0.25nmol/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.
Assuntos
Colecistocinina/farmacologia , Comportamento Alimentar/efeitos dos fármacos , Trato Gastrointestinal/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Animais , Artéria Celíaca/efeitos dos fármacos , Artéria Celíaca/fisiologia , Ingestão de Alimentos/efeitos dos fármacos , Ingestão de Alimentos/fisiologia , Comportamento Alimentar/fisiologia , Trato Gastrointestinal/fisiologia , Masculino , Especificidade de Órgãos/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Sincalida/farmacologiaRESUMO
BACKGROUND: Roux-en-Y gastric bypass (RYGB) is the most effective method for the treatment of obesity, and metabolic disease RYGB may reduce body weight by altering the feeding responses evoked by the short-term satiety peptides. MATERIALS AND METHODS: Here, we measured meal size (MS, chow), intermeal interval (IMI) length, and satiety ratio (SR, IMI/MS; food consumed per a unit of time) by the small and the large forms of gastrin-releasing peptide (GRP) in rats, GRP-10 and GRP-29 (0, 0.1, 0.5 nmol/kg) infused in the celiac artery (CA, supplies stomach and upper duodenum) and the cranial mesenteric artery (CMA, supplies small and large intestine) in an RYGB rat model. RESULTS: GRP-10 reduced MS, prolonged the IMI, and increased the SR only in the RYGB group, whereas GRP-29 evoked these responses by both routes and in both groups. CONCLUSIONS: The RYGB procedure augments the feeding responses evoked by exogenous GRP, possibly by decreasing total food intake, increasing latency to the first meal, decreasing number of meals or altering the sites of action regulating MS and IMI length by the two peptides.
Assuntos
Comportamento Alimentar/efeitos dos fármacos , Derivação Gástrica , Peptídeo Liberador de Gastrina/farmacologia , Animais , Bombesina/administração & dosagem , Bombesina/farmacologia , Artéria Celíaca , Comportamento Alimentar/fisiologia , Peptídeo Liberador de Gastrina/administração & dosagem , Infusões Intra-Arteriais , Masculino , Artérias Mesentéricas , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/farmacologia , Ratos , Ratos Sprague-Dawley , Resposta de Saciedade/efeitos dos fármacos , Resposta de Saciedade/fisiologiaRESUMO
Three experiments were done to better assess the gastrointestinal (GI) site(s) of action of GLP-1 on food intake in rats. First, near-spontaneous nocturnal chow meal size (MS), intermeal intervals (IMI) length and satiety ratios (SR = MS/IMI) were measured after infusion of saline, 0.025 or 0.5 nmol/kg GLP-1 into the celiac artery (CA, supplying the stomach and upper duodenum), cranial mesenteric artery (CMA, supplying small and all of the large intestine except the rectum), femoral artery (FA, control) or portal vein (PV, control). Second, infusion of 0.5 nmol/kg GLP-1 was tested after pretreatment with the GLP-1 receptor (GLP-1R) antagonist exendin-4(3-39) via the same routes. Third, the regional distribution of GLP-1R in the rat GI tract was determined using rtPCR. CA, CMA and FA GLP-1 reduced first MS relative to saline, with the CMA route more effective than the others. Only CMA GLP-1 prolonged the IMI. None of the infusions affected second MS or later eating. CA and CMA GLP-1 increased the SR, with the CMA route more effective than the CA route. CMA exendin-4 (3-39) infusion reduced the effect of CMA GLP-1. Finally GLP-1R expression was found throughout the GI tract. The results suggest that exogenous GLP-1 acts in multiple GI sites to reduce feeding under our conditions and that GLP-1R in the area supplied by the CMA, i.e., the small and part of the large intestine, plays the leading role.
Assuntos
Comportamento Alimentar/efeitos dos fármacos , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Tamanho da Porção , Animais , Artéria Celíaca/efeitos dos fármacos , Artéria Celíaca/metabolismo , Exenatida , Artéria Femoral/efeitos dos fármacos , Artéria Femoral/metabolismo , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/metabolismo , Loci Gênicos , Receptor do Peptídeo Semelhante ao Glucagon 1/antagonistas & inibidores , Receptor do Peptídeo Semelhante ao Glucagon 1/genética , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/metabolismo , Peptídeos/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Saciação/efeitos dos fármacos , Peçonhas/farmacologiaRESUMO
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 0.25nmol/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 0.15nmol/kg given in the CA and 0.15 and 0.25nmol/kg given in the CMA prolonged the IMI, (4) CCK-58 (0.05, 0.15, 0.25nmol/kg) given in the CA and 0.25nmol/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.
Assuntos
Artéria Celíaca/metabolismo , Colagogos e Coleréticos/farmacologia , Colecistocinina/farmacologia , Comportamento Alimentar/fisiologia , Artéria Mesentérica Superior/metabolismo , Resposta de Saciedade/fisiologia , Animais , Colagogos e Coleréticos/administração & dosagem , Colecistocinina/administração & dosagem , Artéria Femoral/metabolismo , Masculino , Veia Porta/metabolismo , Ratos , Ratos Sprague-Dawley , Resposta de Saciedade/efeitos dos fármacosRESUMO
Recently, we reported that non-sulfated cholecystokinin-8 (NS CCK-8) reduces food intake by cholecystokinin-B receptors (CCK-BR). To examine a possible site of action for this peptide, and based on the fact that both NS CCK-8 and CCK-BR are found centrally and peripherally, in the current study we hypothesized that NS CCK-8 increases Fos-like immunoreactivity (Fos-LI, a neuronal activation marker) in the dorsal vagal complex (DVC) of the hindbrain and the myenteric and submucosal plexuses of the small intestine. We found that intraperitoneal NS CCK-8 (0.5â¯nmol/kg) increases Fos-LI in the DVC, the myenteric and the submucosal plexuses of the duodenum and the myenteric plexus of the jejunum. The findings suggest, but does not prove, a potential role for the DVC and the enteric neurons in the feeding responses evoked by NS CCK-8.
Assuntos
Comportamento Alimentar/fisiologia , Rombencéfalo/metabolismo , Sincalida/metabolismo , Animais , Encéfalo/metabolismo , Colecistocinina , Sistema Nervoso Entérico/metabolismo , Intestino Delgado , Masculino , Plexo Mientérico/metabolismo , Neurônios/metabolismo , Fragmentos de Peptídeos , Proteínas Proto-Oncogênicas c-fos/imunologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor de Colecistocinina B/metabolismo , Sincalida/fisiologia , Plexo Submucoso/metabolismo , Nervo Vago/metabolismoRESUMO
The current study measured seven feeding responses by non-sulfated cholecystokinin-8 (NS CCK-8) in freely fed adult male Sprague Dawley rats. The peptide (0, 0.5, 1, 3, 5 and 10â¯nmol/kg) was given intraperitoneally (ip) prior to the onset of the dark cycle, and first meal size (MS), second meal size, intermeal interval (IMI) length, satiety ratio (SRâ¯=â¯IMI/MS), latency to first meal, duration of first meal, number of meals and 24-hour food intake were measured. We found that NS CCK-8 (0.5 and 1.0â¯nmol/kg) reduced MS, prolonged IMI length and increased SR during the dark cycle. Furthermore, the specific CCK-B receptor antagonist L365, 260 (1â¯mg/kg, ip) attenuated these responses. These results support a possible role for NS CCK-8 in regulating food intake.
Assuntos
Colecistocinina/farmacologia , Ingestão de Alimentos/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Refeições , Fragmentos de Peptídeos/farmacologia , Animais , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
UNLABELLED: It has been shown in the rat that endogenous cholecystokinin (CCK), released in response to the non-nutrient trypsin inhibitor camostat, reduces food intake at meals and increases Fos-like immunoreactivity (Fos-LI; a marker for neuronal activation) in the dorsal vagal complex (DVC) of the hindbrain but not the myenteric plexus of the duodenum and jejunum. Experiment 1: We examined Fos-LI in the myenteric and the submucosal plexuses of the gut in response to orogastric gavage of camostat in rats. As we reported previously, camostat failed to increase Fos-LI in the myenteric plexus. We show here that camostat increased Fos-LI in the submucosal plexus of the duodenum and jejunum. Camostat also increased Fos-LI in the DVC. Experiment 2: Pretreatment with devazepide, a specific CCK(1) receptor antagonist abolished camostat-induced Fos-LI in the submucosal plexus and the DVC. Experiment 3: Bilateral subdiaphragmatic vagotomy reduced camostat-induced Fos-LI in the submucosal plexus approximately 40% and abolished it in the DVC. CONCLUSIONS: Activation of the submucosal plexus by cholecystokinin at the CCK(1) receptor accompanies stimulation of the dorsal vagal complex of the hindbrain and inhibition of food intake. Unlike the submucosal plexus, activation of the myenteric plexus is not necessary for cholecystokinin's influence on the dorsal vagal complex and food intake. The lack of activation in the myenteric plexus after camostat stimulation, in contrast to nutrient releasers of CCK such as oleate, suggests that intestinal stimulants can either release different amounts of CCK or cause release of CCK from I cells with different molecular forms of CCK. This would suggest that CCK-8 is released by camostat and is not able to travel to the myenteric plexus while a more stable form of CCK such as CCK-58 can travel to this site that is further away from the I cell.
Assuntos
Ingestão de Alimentos/efeitos dos fármacos , Gabexato/análogos & derivados , Trato Gastrointestinal/efeitos dos fármacos , Plexo Mientérico/metabolismo , Plexo Submucoso/efeitos dos fármacos , Animais , Colecistocinina/farmacologia , Devazepida/farmacologia , Ésteres , Gabexato/farmacologia , Trato Gastrointestinal/metabolismo , Guanidinas , Antagonistas de Hormônios/farmacologia , Modelos Biológicos , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores da Colecistocinina/fisiologia , Núcleo Solitário/efeitos dos fármacos , Plexo Submucoso/metabolismo , Nervo Vago/efeitos dos fármacosRESUMO
The enteric nervous system (ENS: myenteric and submucosal plexuses) of the gastrointestinal tract may have a role in the reduction of food intake by cholecystokinin (CCK). Exogenous cholecystokinin-8 (CCK-8) activates the myenteric plexus and the feeding control areas of the dorsal vagal complex (DVC) of the brainstem. An increasing number of reports, however, have shown that CCK-58 is the sole or the major circulating form of CCK in rat, human and dog, and that it is qualitatively different from CCK-8 in evoking various gastrointestinal physiological responses (e.g., contraction of the gallbladder and exocrine pancreatic secretion). In the current report, we compared the abilities of exogenous CCK-58 to activate the myenteric plexus and the dorsal vagal complex with those of exogenous CCK-8 by quantifying Fos-like immunoreactivity (Fos-LI; a marker for neuronal activation). We report that CCK-58 (1, 3, and 5 nmol/kg) increased Fos-LI in the myenteric plexus (p<0.001) and in the DVC (p<0.001) compared to the saline vehicle. The highest dose of CCK-58 increased Fos-LI more than an equimolar dose of CCK-8 in the myenteric plexus and the area postrema. Thus, CCK-8 and CCK-58 produce the same qualitative pattern of activation of central and peripheral neurons, but do not provoke identical quantitative patterns at higher doses. The different patterns produced by the two peptides at higher doses, in areas open to the circulation (myenteric plexus and area postrema) may reflect endocrine actions not observed at lower doses.
Assuntos
Colecistocinina/farmacologia , Plexo Mientérico/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Nervo Vago/efeitos dos fármacos , Animais , Colecistocinina/administração & dosagem , Relação Dose-Resposta a Droga , Comportamento Alimentar/efeitos dos fármacos , Imuno-Histoquímica , Plexo Mientérico/citologia , Plexo Mientérico/metabolismo , Fragmentos de Peptídeos/administração & dosagem , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Sprague-Dawley , Nervo Vago/citologia , Nervo Vago/metabolismoRESUMO
We purified and identified the peptide YY (PYY) forms present and determined their levels from a portion of the canine ileum directly adjacent to the cecum by a new extraction method designed to prevent and evaluate degradation of endogenous peptides. We used three reverse phase chromatography steps with radioimmunoassay of fractions for PYY-like-immunoreactivity (PYY-LI). The purified fractions underwent intact protein/peptide mass spectrometry identification and sequencing (i.e. "top-down" MS analysis). This analysis confirmed the identity of a new form of PYY, PYY(1-36)-Gly, which co-elutes with PYY(1-36)-NH(2) through all three of separation steps used. The PYY(1-36)-Gly form represents approximately 20% of the total PYY found in this region of the canine intestine. In addition, we also found that the PYY(3-36)-NH(2) form represents 6% of the total PYY in the canine ileo-cecal junction. The physiological implication of the Gly-extended form of PYY(1-36) warrants further investigation.
Assuntos
Íleo/química , Peptídeo YY/química , Peptídeo YY/isolamento & purificação , Sequência de Aminoácidos , Animais , Cães , Íleo/anatomia & histologia , Espectrometria de Massas , Dados de Sequência Molecular , Estrutura Molecular , Peptídeo YY/genética , Radioimunoensaio , Homologia de Sequência de Aminoácidos , Distribuição TecidualRESUMO
We compared the abilities of cholecystokinin-33 (CCK-33) and CCK-8 to reduce food intake and to activate feeding-related areas of the nervous system. (1) Overnight food-deprived rats were presented with a 10% sucrose solution, and intake was measured at 5-min intervals throughout a 90-min test beginning immediately after intraperitoneal injections of 1, 3, or 5 nMol/kg of CCK-33, CCK-8, or the vehicle control. In the initial 20 min (first meal), both peptides were equally effective, producing large reductions of food intake. Thereafter, however, CCK-33 was more effective than CCK-8, producing much more sustained reductions. Overall, both peptides reduced total food intake, but CCK-33 was more effective than CCK-8. (2) Possible roles for the myenteric plexus of the duodenum and the dorsal vagal complex (DVC) of the brainstem in the differential satiety effects of CCK-33 and CCK-8 were examined by quantifying CCK-33- and CCK-8-stimulated Fos-like immunoreactivity (Fos-LI) in each site. Consistent with the greater ability of CCK-33 to produce sustained inhibitions of food intake, CCK-33 produced more Fos-LI than CCK-8 in nearly every section of the sampled sites. The results demonstrate: (1) Different forms of CCK have different efficacies in reducing food intake; (2) CCK-33 produces a much more prolonged satiety action than CCK-8; and (3) the myenteric plexus and DVC may play roles in these differential satiety actions.
Assuntos
Depressores do Apetite/farmacologia , Colecistocinina/farmacologia , Ingestão de Alimentos/efeitos dos fármacos , Plexo Mientérico/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Nervo Vago/efeitos dos fármacos , Animais , Contagem de Células , Imuno-Histoquímica , Masculino , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Sprague-Dawley , Núcleo Solitário/citologia , Núcleo Solitário/efeitos dos fármacosRESUMO
To test the hypothesis that gastrin releasing peptide-29 (GRP-29) combined with glucagon like peptide-1 (7-36) (GLP-1 (7-36)) reduce body weight (BW) more than each of the peptides given individually, we infused the two peptides (0.5nmol/kg each) in the aorta of free feeding, diet-induced obese (DIO) male Sprague Dawley rats once daily for 25days and measured BW. We found that GRP-29 and GLP-1 reduce BW, GRP-29 reduced it more than GLP-1 and GRP-29+GLP-1 reduce BW more than each peptide given alone. This reduction was accompanied by decrease 24-hour food intake (normal rat chow), meal size (MS), duration of first meal and number of meals, and increase latency to the first meal, intermeal interval (IMI) and satiety ratio (IMI/MS, amount of food consumed per a unit of time). Furthermore, the peptides and their combination decreased 24-hour glucose levels. In conclusion, GRP-29+GLP-1 reduce BW more than each of the peptides given individually.
Assuntos
Peso Corporal/efeitos dos fármacos , Dieta , Peptídeo Liberador de Gastrina/farmacologia , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Obesidade/tratamento farmacológico , Animais , Ingestão de Alimentos/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Masculino , Fragmentos de Peptídeos/farmacologia , Ratos , Ratos Sprague-DawleyRESUMO
Intestinal epithelial tissue is constantly regenerated as a means to maintain proper tissue function. Previous studies have demonstrated that denervation of the parasympathetic or sympathetic nervous system to the intestine alters this process. However, results are inconsistent between studies, showing both increases and decreases in proliferation after denervation of the parasympathetic or sympathetic. The effect appears to correlate with (1) the timing post-denervation, (2) denervation-induced changes in food intake, (3) the denervation technique used, and (4) which intestinal segment is investigated. Thus, we proposed that parasympathetic or sympathetic denervation does not have an effect on intestinal epithelial regeneration when you (1) evaluate denervation after long-term denervation, (2) control for post-surgical changes in food intake, (3) use minimally invasive surgical techniques and (4) include a segmental analysis. To test this, adult male Sprague Dawley rats underwent parasympathetic denervation via subdiaphragmatic vagotomy, sympathetic denervation via celiacomesenteric ganglionectomy, a parasympathetic denervation sham surgery, or a sympathetic denervation sham surgery. Sham surgery ad libitum-fed groups and sham surgery pair-fed groups were used to control for surgically induced changes in food intake. Three weeks post-surgery, animals were sacrificed and tissue from the duodenum, jejunum, and ileum was excised and immunohistochemically processed to visualize indicators of proliferation (bromodeoxyuridine-positive cells) and apoptosis (caspase-3-positive cells). Results showed no differences between groups in proliferation, apoptosis, or total cell number in any intestinal segment. These results suggest that parasympathetic or sympathetic denervation does not have a significant long-term effect on intestinal epithelial turnover. Thus, intestinal epithelial regeneration is able to recover after autonomic nervous system injury. Impact statement This study investigates the long-term effect of autonomic denervation on intestinal epithelial cell turnover, as measured by proliferation, apoptosis, and total cell number. Although previous research has established that autonomic denervation can alter intestinal epithelial turnover under short-term conditions, here we establish for the first time that these changes do not persist long-term when you control for surgical-induced changes in food intake and use targeted denervation procedures. These findings add to the base of knowledge on autonomic control of tissue turnover, highlight the ability of the intestinal epithelium to recover after autonomic injury and reveal possible implications of the use of ANS denervation for disease treatment in humans.
Assuntos
Apoptose , Proliferação de Células , Células Epiteliais/fisiologia , Intestino Delgado/citologia , Parassimpatectomia , Simpatectomia , Animais , Bromodesoxiuridina/análise , Caspase 3/análise , Imuno-Histoquímica , Masculino , Ratos Sprague-Dawley , TempoRESUMO
The sites of action regulating meal size (MS) and intermeal interval (IMI) length by glucagon like peptide-1 (7-36) (GLP-1 (7-36)) and cholecystokinin-8 (CCK-8) reside in the areas supplied by the two major branches of the abdominal aorta, celiac and cranial mesenteric arteries. We hypothesized that infusing GLP-1 near those sites reduces body weight (BW) and adding CCK-8 to this infusion enhances the reduction. Here, we measured BW in diet-induced obese (DIO) male rats maintained and tested on normal rat chow and infused with saline, GLP-1 (0.5nmol/kg) and GLP-1+CCK-8 (0.5nmol/kg each) in the aorta once daily for 21days. We found that GLP-1 and GLP-1+CCK-8 decrease BW relative to saline vehicle and GLP-1+CCK-8 reduced it more than GLP-1 alone. Reduction of BW by GLP-1 alone was accompanied by decreased 24-h food intake, first MS, duration of first meal and number of meals, and an increase in latency to first meal. Reduction of BW by the combination of the peptides was accompanied by decrease 24-h food intake, first MS, duration of first meal and number of meals, and increase in the IMI length, satiety ratio and latency to first meal. In conclusion, GLP-1 reduces BW and CCK-8 enhances this reduction if the peptides are given near their sites of action.
Assuntos
Fármacos Antiobesidade/farmacologia , Colecistocinina/farmacologia , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Obesidade/tratamento farmacológico , Fragmentos de Peptídeos/farmacologia , Redução de Peso/efeitos dos fármacos , Animais , Aorta , Dieta Hiperlipídica , Modelos Animais de Doenças , Quimioterapia Combinada , Ingestão de Alimentos/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Masculino , Obesidade/fisiopatologia , Ratos Sprague-Dawley , Saciação/efeitos dos fármacos , Fatores de TempoRESUMO
Chemical sympathectomy with daily, intraperitoneal (IP) injections of guanethidine sulfate to adult rats, attenuated myenteric, but not dorsal vagal complex (DVC) Fos-like immunoreactivity (Fos-LI) by cholecystokinin-8 (CCK). This technique destroys only 60-70% of the sympathetic neurons, and spares the hormonal source of catecholamines, the adrenal medulla. The goal of the current study is to evaluate the effect of complete sympathectomy or destroying 100% of the sympathetic neurons by injecting guanethidine to 1-day-old pups (40 mg/kg daily for 5 weeks), and surgically removing the adrenal medulla. In the DVC, demedullation and sympathectomy-demedullation increased Fos-LI by CCK in the area postrema and nucleus of the solitary tract, but sympathectomy-demedullation increased it only in the area postrema. In the myenteric plexus, sympathectomy increased this response in the duodenum, and demedullation increased it in the duodenum and jejunum. On the other hand, sympathectomy-demedullation attenuated myenteric Fos-LI in the jejunum. These results indicate that catecholamines may play an inhibitory role on the activation of the DVC neurons by CCK. In the myenteric neurons, however, catecholamines may have both inhibitory and excitatory roles depending on the level of the intestine e.g., duodenum vs. jejunum. This may also indicate that CCK activates the enteric neurons by different mechanisms or through different pathways.