Gut Hormone Peptide Research Articles

PYY3–36 “monkeys around” with energy balance

the last decade has witnessed an historic amount of effort and resources expended on the basic science of body weight regulation, and with good reason. The prevalence of obesity is escalating at alarming rates around the globe and will likely surpass tobacco as the leading cause of preventable death

Clarifying concepts about macronutrients’ effects on satiation and satiety

It seems that many people, including dietetics professionals and other nutrition experts, are unclear about some of the fundamental yet complex concepts behind the influence of dietary macronutrients (ie, protein, carbohydrate, and fat) on appetite regulation. Recent research has begun to unravel some of the more complicated physiological processes of appetite control and regulation generated by hormones such as leptin, ghrelin, and the gut hormone peptide YY3–35. Although the processes by which the macronutrients in our foods influence appetite regulation have been a topic of study for decades, they remain confusing and are often misunderstood. The objective of this article is to define the terminology commonly used to discuss the macronutrients’ roles in appetite regulation and to discuss the interrelated concepts and roles of taste, palatability, and energy density.

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 < 0.05) increased from a basal value of 15.6 ± 1.8 pM to a peak of 71.2 ± 11.6 pM after colectomy. Basal and postprandial plasma PYY concentrations were not significantly different from the results before surgery. Fasting, but not postprandial, plasma peptide YY after colectomy was significantly higher than that in healthy volunteers, 10.9 ± 0.9 pM. 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.

Stimulation of NPY Y2 receptors by PYY3-36 reveals divergent cardiovascular effects of endogenous NPY in rats on different dietary regimens.

In the present experiments the gut hormone peptide YY3-36 (PYY3-36), which inhibits neuropeptide Y (NPY) release, was used as a tool to study the cardiovascular effects of endogenous NPY under different dietary regimens in rats instrumented with a telemetry transmitter. In a first experiment, rats were placed on a standard chow diet ad libitum and in a second experiment on a high-fat diet ad libitum. After 6 wk, PYY3-36 (300 microg/kg) or vehicle was injected intraperitoneally. In a third experiment, PYY3-36 or vehicle was administered after 14 days of 50% restriction of a standard chow diet. In food-restricted rats, PYY3-36 increased mean arterial pressure (7 +/- 1 mmHg, mean +/- SE, P < 0.001 vs. saline, 1-way repeated-measures ANOVA with Bonferroni t-test) and heart rate (22 +/- 4 beats/min, P < 0.001) during 3 h after administration. Conversely, PYY3-36 did not influence mean arterial pressure (0 +/- 1 mmHg) and heart rate (-8 +/- 5 beats/min) significantly in rats on a high-fat diet. Rats fed standard chow diet ad libitum showed an intermediate response (mean arterial pressure 4 +/- 1 mmHg, P < 0.05, and heart rate 5 +/- 2 beats/min, not significant). Thus, in our studies, divergent cardiovascular responses to PYY3-36 were observed in rats on different dietary regimens. These findings suggest that the cardiovascular effects of PYY3-36 depend on the hypothalamic NPY release, which is increased after chronic food restriction and decreased during a high-fat diet.

Neurohormonal control of pancreatic exocrine secretion

The neurohormonal control of pancreatic exocrine secretion is a complex interaction of multiple pathways involving a large number of gut hormones, neurotransmitters, and neuropeptides. Recent studies have elucidated a role for cholecystokinin in the regulation of bicarbonate and fluid secretion from pancreatic duct cells and suggested that cholecystokinin stimulation of human pancreatic acinar cells is likely regulated by an indirect mechanism of stimulation of afferent neurons. Evidence supports the regulation of potassium channels in rat pancreatic acinar cells by the cyclic AMP-mediated agonist secretin. Mechanisms for the regulation of cholecystokinin and secretin release by releasing factors have also been elucidated. The area postrema has been implicated in the mediation of inhibition of pancreatic secretion by the gut hormones peptide YY and pancreatic polypeptide. The neurotransmitter serotonin has been demonstrated to play a role in acid-induced secretin release and in pancreatic secretion stimulated by luminal factors. The regulation of pancreatic exocrine secretion by purines, nitric oxide, and gamma-aminobutyric acid as well as by the neuropeptides pituitary adenylate cyclase-activating peptide, gastrin-releasing peptide, and substance P is reviewed. The role of the central nervous system in modulating pancreatic secretion is also described. This review highlights the recent advances in knowledge of the neurohormonal regulation of pancreatic exocrine secretion.

Effects of Abomasal Infusion of Long-Chain Fatty Acids on Splanchnic Metabolism of Pancreatic and Gut Hormones in Lactating Dairy Cows

Pancreatic and gut peptide hormones are potential mediators of the reduction in dry matter intake (DMI) often observed in lactating dairy cows fed supplemental fat. We investigated the effects of 7-d abomasal infusions of a rapeseed and sunflower oil mixture providing mostly unsaturated long-chain fatty acids (LCFA) on arterial concentration and splanchnic (portal-drained viscera [PDV] and liver) metabolism of insulin, pancreatic (PAN) and gut (GUT) glucagon, glucagon-like peptide-1 (7-36) amide (GLP-1), and cholecystokinin (CCK) in six cows at 55 (ELAC) and 111 (MLAC) d postpartum. Plasma flow for the PDV and liver were greater in ELAC and increased by oil infusion. Arterial concentrations of insulin and PAN were greater in MLAC, whereas arterial concentrations of GLP-1 and CCK were greater in ELAC. Abomasal oil infusion increased arterial concentration of GUT and GLP-1 but decreased arterial insulin concentration. These differences in peripheral hormone concentration were due largely to changes in their net PDV release and (or) liver removal. In addition, net liver removal of PAN was increased by oil infusion. There was no effect of oil infusion on splanchnic metabolism or arterial concentration of CCK. Lower concentrations of CCK in MLAC were attributable to net liver removal, emphasizing the importance of liver metabolism in determining peripheral concentrations of gut and pancreatic peptide hormones. Results of this study suggest a role for products of proglucagon processing (PAN, GUT, and GLP-1) as mediators of the reduction in DMI caused by postruminal supply of LCFA.

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.

Effect of Circulating Peptide YY on Gallbladder Emptying in Humans

Background: To further establish its role in the ileal brake mechanism, we determined the effect of the distal gut hormone peptide YY (PYY) on gallbladder motility and plasma gut hormones during the cephalic phase of meal stimulation. Methods: Eight healthy volunteers were studied in a randomized crossover design, with or without intravenous infusion of a physiological dose of PYY. On each occasion, subjects underwent modified sham feeding followed by real feeding. Results:

Neuropeptide Y Y1 receptor mediated mesenteric vasoconstriction in the pig in vivo

The object of the present study was to investigate the effects of the sympathetic cotransmitter neuropeptide Y (NPY), and the closely related gut hormone peptide YY (PYY), on splanchnic blood flow regulation in the anaesthetized pig in vivo. Systemic injections of NPY, PYY and the NPY Y 1 receptor agonist [Leu 31Pro 34]NPY (470 pmol kg −1 each) evoked pressor and mesenteric vasoconstrictor responses that were largely abolished by the selective NPY Y 1 receptor antagonist H 409/22 (60 nmol kg −1 min −1). In contrast, the NPY Y 2 receptor agonist N-acetyl[Leu 28Leu 31]NPY(24-36) (1.1 nmol kg −1), a dose of which potently evoked splenic NPY Y 2 receptor mediated (not affected by H 409/22) vasoconstriction, did not evoke any mesenteric vascular response. Mesenteric vascular responses to angiotensin II (10 pmol kg −1), α,β-methylene ATP (10 nmol kg −1) and the α 1-adrenoceptor agonist phenylephrine (15 nmol kg −1), were not inhibited by H 409/22. It is concluded that NPY and PYY evokes porcine mesenteric vasoconstriction mediated by the NPY Y 1 receptor subtype, as demonstrated by selective and specific inhibition exerted by the NPY Y 1 receptor antagonist H 409/22, in vivo.

Proximal and distal gut hormone secretion in slow transit constipation.

It has been suggested that slow transit constipation might be part of a panenteric disorder. Gastrointestinal peptides are involved in regulation of motility. In the present study we have evaluated whether plasma levels of proximal and distal gut hormones in the fasting state, and for 120 min after a solid meal in 29 patients with slow transit constipation are different from those obtained from 29 healthy controls. Plasma levels of the gut hormones cholecystokinin, gastrin, pancreatic polypeptide, motilin, neurotensin and peptide YY were determined using sensitive radioimmunoassays. In the patient group, oro-caecal transit time was determined by means of the hydrogen breath test on a separate test day. The results of transit were related with postprandial hormone secretion. Fasting plasma levels of cholecystokinin and pancreatic polypeptide were significantly (P < 0.05) increased in constipated patients. Postprandially, secretion of pancreatic polypeptide and cholecystokinin was significantly (P < 0.05) increased in the patients, while secretion of peptide YY was significantly (P < 0.05) reduced. Plasma motilin levels were not different between patients and controls. Altered postprandial hormone secretion was mainly observed in constipated patients with prolonged oro-caecal transit time. In patients with slow transit constipation, fasting and postprandial secretion of proximal gut hormones apart from motilin is increased and of distal gut hormones decreased, especially in those with severely delayed intestinal transit.

Cholecystokinin-a receptor messenger RNA expression in human pancreatic cancer

Cholecystokinin (CCK) is a gut peptide hormone known to stimulate postprandial gallbladder contraction and pancreatic enzyme secretion. It has also been shown to induce the growth of normal pancreas and of malignant and premalignant lesions in rodents. Although CCK has been shown to promote the growth of human adenocarcinoma cell lines, its role in the growth of human pancreatic adenocarcinomas in vivo is less clear. Localization of CCK receptors to neoplastic cells within resected human tissue specimens would be suggestive of its potential action as an in vivo promoter of human pancreatic cancer. Resected tissue specimens of pancreatic adenocarcinomas were therefore studied by both reverse transcriptase-polymerase chain reaction (RT-PCR) and in situ hybridization for the presence of CCK-A receptors. Ninety percent of studied tumors demonstrated CCK-A expression by RT-PCR, and this expression was localized to neoplastic cells by in situ hybridization. An increase in the expression of CCK receptors is a mechanism by which pancreatic malignancies may gain a significant growth stimulus.

Progress toward hormonal therapy of gastrointestinal cancer.

The authors discuss ongoing research to determine the mechanisms by which peptide hormones regulate growth of gastrointestinal cancer and ways in which this information might be used to develop noncytotoxic therapy. Approximately 100,000 people die of cancer of the gastrointestinal (GI) tract each year. Surgery is curative only when the tumor is localized. Chemotherapy and radiotherapy have limited efficacy for locally advanced or widespread disease. Various peptide hormones regulate the growth of these tumors. As for breast and prostate cancer, the growth regulatory effect of these hormones is being studied as a potential mechanism of hormonal therapy. Gut peptide hormones regulate the growth of GI malignancies through all-specific receptors and signal transduction pathways. Interruption or modification of these growth regulatory mechanisms may lead to specific noncytotoxic therapy. In combination with surgical extirpation, such hormonally based treatment may be curative of advanced GI cancer.

Gastroesophageal reflux disease is associated with enteric hormone abnormalities

Basal and postprandial levels of the foregut hormones gastrin, cholecystokinin (CCK), motilin, and pancreatic polypeptide, and the distal gut hormones neurotensin and peptide YY were measured in 20 patients with gastroesophageal reflux disease (GERD). GERD was defined by abnormal esophageal exposure to pH less than 4. Ten GERD patients had decreased lower esophageal sphincter (LES) pressure (mean: 4.5 nun Hg, range: 0.8 to 6.8 mm Hg), and 10 patients had normal LES pressures (mean: 14.1 mm Hg, range: 9.7 to 22.4 mm Hg). Eight age-matched healthy subjects were also studied. Basal levels of peptide YY were moderately decreased in GERD patients compared with controls irrespective of LES pressure. In patients with abnormal LES pressure, basal levels of motilin and the postprandial response of CCK were significantly decreased compared with controls; and basal levels of neurotensin and the postprandial response of gastrin were significantly increased compared with controls. Pancreatic polypeptide levels were similar in all groups. These gut hormone changes, which are more marked in patients with poor LES pressure, may reflect primary or secondary abnormalities in GERD.

Multiple neuropeptide Y receptors are involved in cardiovascular regulation. Peripheral and central mechanisms

1. 1. Neuropeptide Y (NPY) occurs in both the central and peripheral nervous system. In the periphery, NPY coexists with noradrenaline (NA) in perivascular sympathetic fibers. 2. 2. NPY has a vasopressor effect, reflecting direct vasoconstriction of blood vessels and potentiation of the NA-evoked response. NPY also suppresses the release of NA from sympathetic fibers. 3. 3. The post- and pre-junctional NPY receptors are referred to as Y 1 and Y 2, respectively. They recognize not only NPY but also the homologous gut hormone peptide YY (PYY). 4. 4. The Y 1 and Y 2 receptors have been characterized in numerous test systems using analogs of NPY/PYY. Already the deletion of the first N-terminal amino acid (NPY 2–36) results in a marked loss of potency at the Y 1 receptor. The Y 2 receptor is much less dependent upon an intact N-terminus, and a wide range of C-terminal NPY fragments retain quite high potency. 5. 5. Recently, yet another NPY receptor, Y 3, that is distinct from Y 1 and Y 2 in that it recognizes PYY poorly, has been demonstrated in the brainstem and in the periphery. 6. 6. Further attempts to characterize the various receptor types have relied on truncated and substituted analogs of NPY/PYY. Although such studies suggest the existence of at least three types of NPY receptors, the lack of antagonists has represented a problem. 7. 7. Since NPY may regulate cardiovascular functions via peripheral and central receptors its physiological and possibly pathophysiological significance has attracted much attention. 8. 8. The responsiveness to NPY seems to be altered in animal models of hypertension and elevated plasma levels of NPY have been found in patients under various conditions of stress and in primary hypertension. A number of studies have suggested that NPY may be a pathogenetic factor behind primary hypertension. 9. 9. Antagonists for the various NPY receptors would be useful for an analysis of which effects of these peptides are physiologically relevant. It is tempting to predict that both agonists and antagonists of the NPY receptors could be useful as drugs, for instance, in the treatment of primary hypertension.

Peptide YY, a new gut hormone (a mini-review)

This report describes our current knowledge of a new gut peptide hormone, peptide YY. The localization, action, and possible mechanisms that control release of peptide YY are described.

Adaptive increase in peptide YY and enteroglucagon after proctocolectomy and pelvic ileal reservoir construction

Functional results improve with time after proctocolectomy and pelvic ileal reservoir construction. We hypothesized that adaptive increases of circulating and tissue levels of the gut hormones peptide YY (PYY) and enteroglucagon may contribute to this improvement by slowing small bowel transit and increasing small bowel absorption. The specific aim of this study was to measure plasma and ileal mucosal concentrations of PYY and enteroglucagon in dogs 1 year after proctocolectomy and ileal reservoir-anal anastomosis. In the ileal reservoir dogs, postprandial PYY levels reached 238 +/- 31 pmol/liter compared with 93 +/- 33 pmol/liter in sham operated controls (P less than 0.001). Postprandial plasma enteroglucagon levels reached 199 +/- 53 pmol/liter in reservoir animals and 52 +/- 4 pmol/liter in controls (P less than 0.05). Tissue levels of PYY in the mucosa of the ileal reservoirs were 419 +/- 43 pmol/g compared with 133 +/- 23 pmol/g in normal terminal ileum (P less than 0.0001). Enteroglucagon levels were also elevated in reservoir mucosa (193 +/- 21 pmol/g vs. 113 +/- 9 pmol/g in controls, P less than 0.05). These data demonstrate that postprandial and tissue levels of PYY and enteroglucagon increase in dogs 1 year after construction of ileal reservoirs. The adaptive increase in PYY would slow small bowel transit and the increase in enteroglucagon would promote mucosal growth, each contributing to the improved functional results.

Gut hormone release by intraduodenal stimulation in duodenal ulcer patients.

After an overnight fast, plasma levels of gut peptide hormones were determined before and after intraduodenal stimulation (IDS) with glucose and citric acid in 8 patients with a recent endoscopically proved duodenal ulcer (DU) attack and in 8 healthy volunteers. The DU patients had a hyperacidic mean BAO of 6.6 and an average PAO of 41.8 mEq/h. In DU, basal secretin levels were similar to those in controls, and after IDS secretin release was not impaired. There was no defect of VIP liberation or of the neurotensin response (basal 21 +/- 7 vs 16 +/- 3, after IDS 68 +/- 28 vs 35 +/- 5 pmol/l) which could account for gastric acid hypersecretion. Although fasting GIP levels were significantly lower than in controls (16 +/- 2.5 vs 25 +/- 1.4 pmol/l), they did not correlate negatively with BAO. In contrast to former studies with oral test meals, integrated GIP release was rather reduced after IDS. Basal plasma levels of gastrin were significantly lower in DU (4.0 +/- 0.4 vs 12 +/- 2 pmol/l) and were inversely related to BAO (r = -0.82, p less than 0.02). From the present data, there is insufficient evidence for abnormal plasma levels of gut hormones as major etiologic factors for basal hyperchlorhydria in ordinary DU disease.

Temporal relationships of cholecystokinin release, pancreatobiliary secretion, and gastric emptying of a mixed meal

The influence of gastric emptying of nutrients on plasma cholecystokinin and pancreatobiliary functions is poorly understood. We therefore temporally related the emptying of fat, protein, and glucose of a mixed meal to release of the gut hormones cholecystokinin, pancreatic polypeptide, and peptide YY and outputs of trypsin, lipase, bilirubin, and bile salts. Five healthy volunteers with a multilumen duodenal tube ingested a mixed meal with phasespecific markers for the aqueous phase, liquid fat, solid fat, and solid protein phases. Duodenal passage was determined by intraduodenal infusion of a second set of phase-specific nonabsorbable markers. Plasma cholecystokinin levels and pancreatobiliary secretions rose to a maximum at 30–60 min and then gradually declined (p < 0.01) despite continued entry of protein and fat into the duodenum throughout the whole 4-h experimental period. High levels of both pancreatic polypeptide and peptide YY were observed in the last 2 h of the experiment. Release of factors capable of inhibiting cholecystokinin release and subsequently pancreatobiliary secretion may be responsible for the observed time-course.

Tubular adenoma of the human stomach. An immunohistochemical analysis of gut hormones, serotonin, carcinoembryonic antigen, secretory component, and lysozyme.

A total of 49 gastric tubular adenomas and 6 tubular adenomas with foci of adenocarcinoma from surgically resected stomachs were examined histologically and immunohistochemically for gut peptide hormones, serotonin, carcinoembryonic antigen (CEA), secretory component (SC), and lysozyme. A variety of endocrine cells were detected in tubular adenoma with mild to moderate atypia. Both the frequency and distribution density were highest for serotonin-containing EC cells, often showing hyperplasia, followed by glicentin-containing L cells, somatostatin-containing D cells and motilin-containing Mo cells in the order given. Adenoma cells with SC immunoreactivity were more dominant than those with CEA immunoreactivity. In tubular adenoma with severe atypia, endocrine cells were markedly decreased, whereas adenoma cells with CEA immunoreactivity were increased. The distribution density of lysozyme-containing cells in tubular adenoma of the intermediate zone and fundus was significantly higher than that of the antrum. In the subjacent mucosa of the adenoma, L cells and SC-positive epithelial cells were detected in 24 and 33 cases, respectively. These findings suggest that gastric tubular adenoma develops from intestinal metaplasia. In addition, gastric tubular adenoma showed a tendency to lose various intestinal markers with increase of histologic atypicality.

Postprandial effects of SMS 201-995 on gut hormones and glucose tolerance.

SMS 201-995 (5-100 micrograms) injected subcutaneously in normal and type-2 diabetic subjects 30 min before a test meal caused dose-related suppression of plasma concentrations of insulin, glucagon, and several regulatory gut peptide hormones (gastrin, gastric inhibitory peptide, pancreatic polypeptide, secretin, neurotensin, and motilin). Effective hormone suppression was achieved even at the lowest dose of 5 micrograms. In the normal subjects SMS caused postprandial hyperglycaemia, but there was no overall deterioration in glucose tolerance in the type-2 diabetic patients. This suggests that counterregulatory hormones play an important part in the metabolic disturbance of type-2 diabetes.