消化道酪酪肽的作用和受体分布

酪酪肽(PYY)是一种重要的胃肠激素，对消化道动力、分泌、粘膜上皮增殖等均有重要调节作用。酪酪肽的受体有多种亚型，在消化道的分布广泛。酪酪肽的作用机制复杂，涉及肠神经系统、中枢神经系统和其他胃肠激素。     

消化道酪酪肽的作用和受体分布

酪酪肽(PYY)是一种重要的胃肠激素,对消化道动力、分泌、粘膜上皮增殖等均有重要调节作用。酪酪肽的受体有多种亚型,在消化道的分布广泛。酪酪肽的作用机制复杂,涉及肠神经系统、中枢神经系统和其他胃肠激素。     

酪酪肽对人胰腺癌细胞生长的调节作用及其机制研究

目的：观察酪酪肽（PYY）对人胰腺癌细胞生长的抑制作用及其对细胞内环磷酸腺苷(cAMP)含量的影响。方法：采用^3H-胸腺嘧啶（^3H-TdR）掺入、放射免疫法，测定PYY对人胰腺癌细胞株SW－1990生长的调节作用及其对细胞内cAMP含量的影响。结果：PYY对SW－1990细胞的生长有显著抑制作用，随其浓度的增加或作用时间的延长而增强，并可减少细胞内cAMP的产生呈剂量依赖关系。结论:PYY树人胰腺癌细胞生长有抑制作用，其机制可能与通过降低细胞内cAMP含量有关。     

酪酪肽对实验性急性胰腺炎的治疗作用

目的探讨酪酪肽(Peptide YY,PYY)对实验性急性胰腺炎大鼠(AP)的治疗效果,并对其机制进行探讨。方法取40只SD大鼠,雌雄不限,随机分为胰腺炎组(n=20)和酪酪肽治疗组(n=20),急性胰腺炎模型采用经腹腔注射精氨酸完成,测定48 h后大鼠血清及胰腺组织匀浆中的丙二醛(MDA)含量,血清中肿瘤坏死因子-α含量,光镜下观察胰腺组织的病理变化。结果 PYY能有效减轻AP大鼠胰腺的病理损伤,与胰腺炎组相比,PYY组血清中及胰腺组织匀浆中的MDA含量下降,血清中肿瘤坏死因子-α的含量下降。结论 PYY可能通过抗氧自由基的生成,减轻组织的过氧化损伤,以及通过抑制某些细胞因子的作用而对急性胰腺炎发挥保护作用。     

贝那普利和氨氯地平对自发性高血压大鼠酪酪肽表达的影响

目的探讨贝那普利和氨氯地平对自发性高血压大鼠(SHR)酪酪肽(PYY)表达的影响。方法 14周龄雄性SHR 45只随机分为模型组(n=15)、贝那普利组(盐酸贝那普利灌服0.90 mg·kg~(-1)·d~(-1),n=15)、氨氯地平组(苯磺酸氨氯地平灌服0.45 mg·kg~(-1)·d~(-1),n=15),以同源雄性WKY大鼠作为正常对照(n=15),模型组及WKY组每日灌服同体积的蒸馏水,干预8 w后,应用酶联免疫法检测血清中PYY的含量,采用免疫组化法和RT-PCR法分别检测结肠中PYY及其mRNA的表达。结果干预8 w后,模型组血清中PYY及其mRNA表达量显著升高(P<0.05),与模型组比较,各给药组血清中PYY及其mRNA表达无显著性差异(P>0.05);与WKY组比较,模型组结肠组织中PYY及其mRNA表达显著升高(P<0.05),与模型组比较,贝那普利组与氨氯地平组结肠组织中PYY及其mRNA表达降低(P<0.05),与贝那普利组比较,氨氯地平组结肠组织中PYY及其mRNA表达显著降低(P<0.05)。结论 SHR大鼠结肠组织中PYY调节失衡,贝那普利、氨氯地平的降压作用很可能还通过调节PYY的表达而达到降压目的。     

血管活性肠肽与消化系肿瘤

血管活性肠肽(VIP)对消化系肿瘤细胞的增殖、分化有调节作用。在胃癌、结肠癌、胰腺癌细胞膜上存在特异性VIP受体;VIP对它们的增殖、分化调节有促进或抑制效应。这与VIP作用于受体后引起细胞内cAMP水平、ODC活性、c-myc基因表达改变有关。     

血管活性肠肽与消化系肿瘤

血管活性肠肽对消化系肿瘤细胞的增殖、分化有调节作用，在胃癌、结肠癌、胰腺癌细胞膜上存在特异性ＶＩＰ受体，ＶＩＰ对它们的增殖，分化调节有促进或抑制效应，这与ＶＩＰ作用于受体后引起细胞内ｃＡＭＰ水平，ＯＤＣ活性，ｃ－ｍｙｃ基因表达改变有关。     

胃肠肽和其他调节肽对肥胖患者的影响

控制进食和能量平衡信号可分为短期和长期两类。短期信号包括神经系统(如迷走神经)、营养物质以及来源于胃肠道的多肽激素，其作用根据进食多少和消化时间来变化，并不是脂肪组织储存能量的主要决定因素。长期信号由脂肪组织(如瘦素)或胰腺(如胰岛素)分泌，与基础能量储存相关，在较长一段时间内根据能量储存信息发生波动。长期信号通过作用于下丘脑、脑干和其他中枢系统神经元通路，使食物摄入和能量消耗匹配。因此，肥胖可能是外周和中枢能量平衡调节机制失衡的结果。     

胃肠肽类激素的研究进展

胃肠肽类激素是指传统的激素和许多可通过旁分泌、神经分泌、自分泌和外分泌等方式，介导细胞间信息传递，发挥激素和局部递质效应的胃肠肽。胃肠肽类激素包括胃肠激素、胃肠神经肽和生长因子3大类共计50余种。胃肠道已成为体内最大的内分泌器官。近年来，对胃肠激素的研究取得了前所未有的进展。在基础研究中，胃肠激素对疾病发病与预后的影响，     

Peptide YY ablation in mice leads to the development of hyperinsulinaemia and obesity

Aims/hypothesis Obese people exhibit reduced circulating peptide YY (PYY) levels, but it is unclear whether this is a consequence or cause of obesity. We therefore investigated the effect of Pyy ablation on energy homeostasis.Methods Body composition, i.p. glucose tolerance, food intake and hypothalamic neuropeptide expression were determined in Pyy knock-out and wild-type mice on a normal or high-fat diet.Results Pyy knock-out significantly increased bodyweight and increased fat mass by 50% in aged females on a normal diet. Male chow-fed Pyy ^−/− mice were resistant to obesity but became significantly fatter and glucose-intolerant compared with wild-types when fed a high-fat diet. Pyy knock-out animals exhibited significantly elevated fasting or glucose-stimulated serum insulin concentrations vs wild-types, with no increase in basal or fasting-induced food intake. Pyy knock-out decreased or had no effect on neuropeptide Y expression in the arcuate nucleus of the hypothalamus, and significantly increased proopiomelanocortin expression in this region. Male but not female knock-outs exhibited significantly increased growth hormone-releasing hormone expression in the ventromedial hypothalamus and significantly elevated serum IGF-I and testosterone levels. This sex difference in activation of the hypothalamo–pituitary somatotrophic axis by Pyy ablation may contribute to the resistance of chow-fed male knock-outs to late-onset obesity.Conclusions/interpretation PYY signalling is important in the regulation of energy balance and glucose homeostasis, possibly via regulation of insulin release. Therefore reduced PYY levels may predispose to the development of obesity, particularly with ageing or under conditions of high-fat feeding.The last two authors named contributed equally to the work.     

Time-Course of Morphologic Changes and Peptide YY Adaptation in Ileal Mucosa After Loop Ileostomy in Humans

PURPOSE The secretion mechanism of peptide YY involves systemic factors, such as humoral and neural stimuli, and local factors, such as intestinal peristalsis and intraluminal nutrients. This study was designed to survey the impact of local stimuli on the secretion of peptide YY under circumstances in which systemic stimuli are identical.METHODS Ileostomies were repaired within three months in a short-term group (14 patients) and after six months in a long-term group (14 patients). Mucosal peptide YY concentrations and cytomorphologic change, such as villus height, crypt depth, mucosal thickness, and villus index, were compared between proximal functioning ileum and a distal nonfunctioning ileal loop during ileostomy repair. In a control group of patients undergoing right hemicolectomy (21 cases), the normal distribution of peptide YY was measured in the mucosa throughout the distal ileum.RESULTS The peak of peptide YY concentration in the terminal ileum was 307.4 ± 21 pmol/g, 25 cm from the ileocecal valve, with lower levels both proximally and distally. The mucosa of the functioning ileum in the short-term group showed hypertrophy, but had returned to preoperative levels in the long-term group. The nonfunctioning mucosa in both groups underwent atrophic changes. The mucosal peptide YY content in functioning ileum in the short-term group was higher than that of distal nonfunctioning mucosa (363.9 ± 25.5 pmol/g vs. 284.1 ± 13 pmol/g, P < 0.05), suggesting adaptive upregulation. The increments of mucosal peptide YY content in this short-term group compared with the control group were 45.6 and 4.7 percent in the proximal and distal segments, respectively. In the long-term group, proximal and distal mucosal peptide YY were similar (256.6 ± 31.9 pmol/g vs. 254.9 ± 27.1 pmol/g, P > 0.05), and there was no increment in either (1.3 vs. 4.4 percent, P > 0.05).CONCLUSIONS The peak concentrations of PYY in the ileal mucosa are found 20 to 25 cm proximal to the ileocecal valve. In the short-term response of ileostomy, local stimulatory factors play a major role in the adaptation of mucosal PYY. In the defunctioned bowel without luminal stimulation, systemic stimulation was important for maintenance of mucosal PYY.Supported by the Siwon Institute and the Cancer Center of Pusan National Univerity Hospital at Busan, South Korea.Presented at the 19th World Congress of the International Society of University Colon and Rectal Surgeons, Osaka, Japan, April 14 to 18, 2002.     

Peptide YY levels are decreased by fasting and elevated following caloric intake but are not regulated by leptin

Aims/hypothesis Peptide YY (PYY) is a gut-derived hormone that has been shown to reduce short-term food intake in animals and humans. It has been proposed that deficiency of PYY contributes to obesity in humans. However, the physiology of PYY regulation by factors such as caloric restriction, or by other molecules important in energy homeostasis, e.g. leptin, remains to be fully elucidated. Materials and methods We evaluated the effect on PYY levels of: (1) caloric ingestion (a mixed meal) in five healthy normal-weight subjects; (2) fasting for 2 or 3 days in eight lean men and seven lean women respectively; and (3) recombinant human leptin administration at physiological replacement and pharmacological doses. Results PYY levels increased 50% after a mixed meal (p=0.01), and short-term complete fasting for 2 or 3 days decreased leptin and PYY levels to 20–30% and 40–60% of baseline, respectively (both p<0.05). However, recombinant human leptin administration at physiological doses to restore the fasting-induced decrease of leptin levels and at pharmacological doses over the short term had no effect on PYY levels. Conclusions/interpretation PYY increases after meal ingestion and decreases after fasting in a manner consistent with a meal-related signal of energy homeostasis. Importantly, circulating levels of this gut-secreted molecule are independent of regulation by leptin over the short term. These findings contribute towards our understanding of the homeostatic systems that regulate appetite in humans, including the possible redundancy of gastrointestinally secreted and adipocyte-secreted signals. This may be of importance for the future development of medications to treat obesity.     

Ileoanal pouch function and release of peptide YY

PURPOSE: This study evaluates peptide tyrosine-tyrosine (PYY), intestinal transit, fecal retention time, and anal sphincter manometry in colectomized patients with ileal pouch-anal anastomosis. METHODS: Plasma and pouch PYY, mouth-to-pouch transit time, fecal retention time, and anal canal pressures were studied in 27 patients with ileoanal pouches a mean of 50 (range, 3–84) months after loop ileostomy closure. RESULTS: Basal and peak postprandial plasma PYY were significantly reduced in patients with pouches compared with controls (P<0.0001). Pouch PYY was decreased compared with control ileal PYY (P=0.0003). No significant correlation was noted between intestinal transit and total integrated PYY response in patients with pouches (r=0.36;P=0.06). Fecal retention time was related to postprandial total integrated response of plasma PYY (r=0.43;P=0.02), mouth-to-pouch transit (r=0.87;P<0.0001), and resting (r=0.44;P=0.02) and squeeze (r=0.62;P=0.0006) anal sphincter pressures. CONCLUSIONS: Colectomized ileoanal patients with pouches showed decreased plasma and pouch PYY compared with controls. Intestinal transit was not significantly related to PYY release. However, prolonged pouch fecal retention was associated with greater PYY release, mouth-to-pouch transit, and anal sphincter pressures.Supported in part by the State of Nebraska Cancer and Smoking Related Diseases Program (LB595).Read at the meeting of The American Society of Colon and Rectal Surgeons, Montreal, Quebec, Canada, May 7 to 12, 1995. This article received the Research Forum Award.     

Antisecretory Mechanisms of Peptide YY in Rat Distal Colon

Peptide YY (PYY) is a potent regulator ofintestinal secretion. These studies investigated therole of Y1 and Y2 receptor subtypes in mediating theantisecretory effects of PYY on mucosa-submucosapreparations of rat distal colon. Addition of vasoactiveintestinal peptide (VIP) to these tissues resulted in a140 ± 18% increase in basal short-circuit current(I_sc) and the induction of Cl^-secretion. VIP-stimulated increases in I_sc were abolished bythe addition of each of PYY, (Pro³⁴)-PYY, aY1 receptor-selective agonist, and PYY-(3-36), anendogenous Y2 receptor-selective ligand. However, whentissue neural transmission was blocked with tetrodotoxin, neither PYY norits receptor subtype-selective analogs were able toinhibit VIP-stimulated increases in I_sc.These results suggest that in the rat distal colon, thesc antisecretory actions of PYY are mediated through acombination of Y1 and Y2 receptor subtypes or through anovel receptor subtype that is unable to discriminatebetween (Pro³⁴)-PYY and PYY-(3-36).     

Basal and Fat-Stimulated Plasma Peptide YY Levels in Celiac Disease

The distal gut hormone peptide YY (PYY) mediates feedback inhibition of gastric acid secretion, gastrointestinal motility, and pancreatic enzyme output. To investigate the influence of maldigestion on PYY, we determined plasma PYY levels in patients with celiac disease under basal conditions and in response to intraduodenal fat. Basal PYY was increased in untreated celiac patients (N = 13) compared to patients on a gluten free diet (N = 9) [15.6 (11.8–27.0) pM vs 12.2 (10.1–13.1) pM; P < 0.05] and compared to control subjects (N = 15) [9.5 (8.3–10.4) pM; P < 0.001]. Integrated PYY in response to intraduodenally infused predigested fat (1071 ± 293 pM 80 min) was significantly (P < 0.05) greater than in response to undigested fat (322 ± 223 pM 80 min) in six untreated celiacs. Plasma concentrations of PYY and cholecystokinin were strongly correlated (r = 0.79; P < 0.001). We conclude that basal PYY levels in untreated celiac disease are elevated, that predigestion of fat enhances PYY release in these patients, and that PYY secretion is correlated with CCK release.     

Peptide YY release after colectomy in slow transit constipation

Background: The gut hormone peptide YY is abundant in the colonic mucosa. Circulating PYY inhibits gastrointestinal motility and decreases food intake. The aim was to determine whether colectomy decreases PYY release in patients with slow transit constipation. Methods: Plasma PYY concentrations were measured in 10 patients with slow transit constipation before and 3–24 months after total abdominal colectomy with ileorectal anastomosis, and in 8 healthy controls. A liquid meal was infused intraduodenally to stimulate PYY release. Results: Postprandial PYY significantly (P?Conclusion. Despite removal of a major source of PYY‐secreting cells, colectomy with ileorectal anastomosis does not induce major impairment of PYY release in slow transit constipation.     

Effects of dipeptidyl peptidase IV on the satiety actions of peptide YY

Aims/hypothesis Dipeptidyl peptidase IV (DP IV) inhibitors are currently being developed to prolong the biological activity of insulinotropic peptides as a novel approach in the treatment of diabetes. We hypothesised that DP IV inhibition could attenuate the satiety actions of peptide YY (PYY) by altering the conversion of PYY(1–36) to PYY(3–36).Materials and methods The effects of PYY delivered by osmotic mini-pumps were assessed in rats treated with a DP IV inhibitor and in a rat model deficient in DP IV.Results Pharmacological levels of total PYY were found in the circulation after the exogenous administration of PYY(3–36). While both PYY(1–36) and PYY(3–36) reduced food intake in normal rats, PYY(1–36) was ineffective in rats deficient in DP IV. When re-fed after a 24-h fast, DP IV-deficient rats exhibited higher food intake and weight gain than normal rats. Moreover, unlike controls, there was no postprandial increase in PYY levels in DP IV-deficient rats. Despite these findings, administration of a DP IV inhibitor, Pro-boroPro, did not alter the acute anorectic effects of exogenous PYY(1–36) in normal rats. This could be the result of the protection of other appetite regulatory peptides or the generation of PYY(3–36) by remaining DP IV activity or other dipeptidyl peptidases.Conclusions/interpretation Although DP IV inhibition with Pro-boroPro attenuated the generation of PYY(3–36), our results indicate that short-term DP IV inhibition does not eliminate the satiety actions of exogenously administered PYY(1–36) at the doses tested.     

Peptide YY concentrations in normal ileum and colon and in idiopathic inflammatory bowel disease

Concentrations of the candidate endocrine and paracrine peptide, peptide YY, were measured by specific radioimmunoassay in tissue extracts prepared from normal ileum, normal colon, Crohn's disease, and ulcerative colitis. In both the ascending and descending colon, there were significantly decreased mean concentrations of peptide YY in Crohn's colitis and ulcerative colitis, compared to mean concentrations in normal colon. There was no age-related decrease of concentrations of peptide YY in normal colon. The decrease in concentrations of peptide YY in colon obtained from patients with inflammatory bowel disease did not appear related either to the duration of the clinical symptoms of the disease or to the severity of colonic inflammation. Further studies of the physiological function of peptide YY in man are needed to determine whether these findings might be useful in understanding a component of the pathophysiology of idiopathic inflammatory bowel disease.