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Stephen R Bloom - One of the best experts on this subject based on the ideXlab platform.

  • analogs of pancreatic polyPeptide and Peptide YY with a locked pp fold structure are biologically active
    2013
    Co-Authors: Natacha Germain, Mohammad A Ghatei, James Minnion, Tricia Tan, Joyceline C Shillito, Clare Gibbard, Stephen R Bloom
    Abstract:

    Pancreatic polyPeptide (PP), Peptide YY (PYY) and neuroPeptide Y (NPY), members of the PP-fold family share a high degree of sequence homology. Nuclear magnetic resonance (NMR) and X-ray crystallography studies have shown these Peptides can adopt a tightly organized tertiary structure called the PP-fold, which has long been assumed to be the active structure of this family of Peptides. To date, however, no studies have been completed with PYY and PP which confirm if the PP-fold structure is important for their physiological actions. The aim of the study was to test if PYY and PP locked into the PP-fold maintained biological activity. Therefore, we designed and produced analogs of PP and PYY in a cyclic conformation with two cysteine amino acid substitutions at the N-terminus and at position 27. These were oxidized to form a cysteine disulfide bond locking the Peptides into the PP-fold structure. Studies demonstrate that the cyclic analogs have both similar in vivo activity to their parent molecules, and affinity for the Y2 and Y4 receptors. Results suggest that the proposed PP and PYY-fold is likely to be their biologically active conformation.

  • selective ablation of Peptide YY cells in adult mice reveals their role in beta cell survival
    2012
    Co-Authors: Amir H Sam, Mohammad A Ghatei, Shanta J. Persaud, David Jl Gunner, Aileen King, Lucy Brooks, Klara Hostomska, Heather E Ford, Bo Liu, Stephen R Bloom
    Abstract:

    Background & Aims In the pancreas, Peptide YY (PYY) is expressed by a subpopulation of nonbeta cells in the islets of Langerhans. We investigated the function of these cells in the pancreas of adult mice. Methods We generated mice in which administration of diphtheria toxin (DT) led to specific ablation of PYY-expressing cells. We investigated the effects of loss of PYY cells on glucose homeostasis. Results Loss of PYY cells in adult mice resulted in severe hyperglycemia, which was associated with significant loss of pancreatic insulin and disruption of islet morphology. In vitro administration of DT to isolated islets significantly reduced numbers of PYY-expressing cells and levels of insulin. Administration of either pancreatic polyPeptide (a strong agonist of the receptor Y 4 ) or PYY 3–36 (a selective agonist of the receptor Y 2 ) did not restore loss of pancreatic insulin following administration of DT. However, a long-acting PYY analogue reduced the loss of insulin, and administration of this analogue reduced the hyperglycemia and insulin loss induced by streptozotocin in mice. Conclusions PYY appears to regulate beta cell function and survival via the receptor Y 1/2 . These findings might be developed to treat and prevent loss of beta cells in patients with diabetes mellitus.

  • eating slowly increases the postprandial response of the anorexigenic gut hormones Peptide YY and glucagon like Peptide 1
    2010
    Co-Authors: Alexander Kokkinos, Mohammad A Ghatei, Stephen R Bloom, Carel Le W Roux, Kleopatra Alexiadou, Nicholas Tentolouris, Royce P Vincent, Despoina Kyriaki, Despoina Perrea, Nicholas Katsilambros
    Abstract:

    Context: The rate at which people eat has been suggested to be positively associated with obesity, although appetite and related gut hormones have not been measured. Objective: The objective of the study was to determine whether eating the same meal at varying speeds elicits different postprandial gut Peptide responses. Design and Setting: This was a crossover study at a clinical research facility. Study Participants: Seventeen healthy adult male volunteers participated in the study. Intervention: A test meal consisting of 300 ml ice cream (675 kcal) was consumed in random order on two different sessions by each subject: meal duration took either 5 or 30 min. Main Outcome Measures: The postprandial response of the orexigenic hormone ghrelin and the anorexigenic Peptides Peptide YY and glucagon-like Peptide-1 over 210 min was assessed. Visual analog scales for the subjective feelings of hunger and fullness were completed throughout each session. Results: Peptide YY area under the curve (AUC) was higher aft...

  • ghrelin and Peptide YY pYY profiles in gastrointestinal tissues and the circulation of the rat during pregnancy and lactation
    2009
    Co-Authors: V J Taylor, M A Ghatei, Stephen R Bloom, Michael Patterson, Catherine A Wilson
    Abstract:

    Abstract Plasma and tissue profiles of gastrointestinal hormones ghrelin and Peptide YY (PYY) were investigated in different female rat reproductive states. Neither plasma nor tissue ghrelin concentrations were suppressed during pregnancy despite elevated leptin. The highest concentrations of stomach ghrelin were measured in late pregnancy. PYY concentrations in plasma, descending colon and rectum tissues were increased ( P

  • Peptide YY a gut hormone associated with anorexia during infectious diarrhea in children
    2008
    Co-Authors: Amy L Beck, Lilia Cabrera, William Pan, Vitaliano Cama, Jon S Friedland, Mohammad A Ghatei, Stephen R Bloom, Judy Lewis, Robert H Gilman
    Abstract:

    Objective To evaluate the effects of diarrhea on appetite among Peruvian children age 12 to 71 months and to assess whether elevated plasma levels of Peptide YY, tumor necrosis factor (TNF)-α, and interleukin (IL)-1β contribute to anorexia in this population. Study design A total of 46 Peruvian children with diarrhea and 46 healthy controls underwent an observed feeding trial that was repeated when cases were healthy. Blood samples were obtained from 30 cases and 30 controls at the first trial and from 30 cases at the second trial and assayed for Peptide YY, TNF-α, and IL-1β. Results In the cases, mean consumption was less when sick than when healthy. The mean plasma level of Peptide YY was higher for cases than controls and higher for cases when sick than when healthy. TNF-α levels were higher in cases than controls at visit 1 and also higher in cases when sick than when healthy. There were no differences in IL-1β levels between cases and controls or between cases when sick and healthy. Peptide YY levels in children with diarrhea correlated with the likelihood of them eating less when sick than when healthy. Conclusions Elevated serum Peptide YY may be a mechanism for anorexia in children with diarrhea.

Garth H Ballantyne - One of the best experts on this subject based on the ideXlab platform.

  • Peptide YY 1 36 and Peptide YY 3 36 part ii changes after gastrointestinal surgery and bariatric surgery
    2006
    Co-Authors: Garth H Ballantyne
    Abstract:

    Peptide YY (PYY) is secreted as a 36 amino acid, straight chain polyPeptide, and is found in greatest concentrations in the terminal ileum, colon and rectum. After secretion, dipeptidyl peptidase IV (DPP-IV) cleaves the N-terminal Tyrosine-Proline residues from PYY(1-36), producing PYY(3-36). PYY(1-36) acts at all four human Y receptors, Y1, Y2, Y4 and Y5, while PYY(336) is a specific Y2 receptor agonist. PYY participates in the regulation of appetite and weight balance through hypothalamic-based mechanisms. PYY(1-36) stimulates appetite and weight gain through Y1 and Y5 receptors. PYY(3-36) suppresses appetite and stimulates weight loss through Y2 receptors. GI diseases that cause malabsorption increase both basal and meal-stimulated PYY levels. In contrast, obesity decreases both basal and meal-stimulated PYY levels. Mutations in the human PYY and Y2 receptor genes may contribute to the development of obesity. Small bowel resection elevates PYY levels in humans. Colon resections increase PYY levels in animal models but not in man. PYY changes following bariatric operations are incompletely studied. Vertical banded gastroplasty, open Roux-en-Y gastric bypass and jejunoileal bypass significantly elevate basal and meal-stimulated PYY levels. In dogs with Pavlov pouches, Roux-en-Y duodenojejunostomy (duodenal switch) increases PYY levels compared to Roux-en-Y gastrojejunostomy. DPP-IV activity is increased in obese individuals and remains increased after biliopancreatic diversion. Thus, diseases or operations which cause malabsorption, elevate basal and meal-stimulated PYY levels. Bariatric operations also increase basal and meal-stimulated PYY levels. This suggests that the combination of increased PYY levels and elevated levels of DPP-IV observed after bariatric operations may generate increased circulating levels of PYY(3-36), leading to hypothalamic-mediated suppression of appetite and promotion of weight loss through Y2 receptor mediated mechanisms.

  • Peptide YY 1 36 and Peptide YY 3 36 part i distribution release and actions
    2006
    Co-Authors: Garth H Ballantyne
    Abstract:

    Peptide YY (PYY) is a 36 amino acid, straight chain polyPeptide, which is co-localized with GLP-1 in the L-type endocrine cells of the GI mucosa. PYY shares structural homology with neuroPeptide Y (NPY) and pancreatic polyPeptide (PP), and together form the NeuroPeptide Y Family of Peptides, which is also called the Pancreatic PolyPeptide-Fold Family of Peptides. PYY release is stimulated by intraluminal nutrients, including glucose, bile salts, lipids, short-chain fatty acids and amino acids. Regulatory Peptides such as cholecystokinin (CCK), vasoactive intestinal polyPeptide (VIP), gastrin and GLP-1 modulate PYY release. The proximal GI tract may also participate in the regulation of PYY release through vagal fibers. After release, dipeptidyl peptidase IV (DPP-IV; CD 26) cleaves the N-terminal tyrosine-proline residues forming PYY(3-36). PYY(1-36) represents about 60% and PYY(3-36) 40% of circulating PYY. PYY acts through Y-receptor subtypes: Y1, Y2, Y4 and Y5 in humans. PYY(1-36) shows high affinity to all four receptors while PYY(3-36) is a specific Y2 agonist. PYY inhibits many GI functions, including gastric acid secretion, gastric emptying, small bowel and colonic chloride secretion, mouth to cecum transit time, pancreatic exocrine secretion and pancreatic insulin secretion. PYY also promotes postprandial naturesis and elevates systolic and diastolic blood pressure. PYY(1-36) and PYY(3-36) cross the blood-brain barrier and participate in appetite and weight control regulation. PYY(1-36) acting through Y1- and Y5-receptors increases appetite and stimulates weight gain. PYY(3-36) acting through Y2-receptors on NPY-containing cells in the arcuate nucleus inhibits NPY release and, thereby, decreases appetite and promotes weight loss. PYY may play a primary role in the appetite suppression and weight loss observed after bariatric operations.

  • plasma and tissue alterations of Peptide YY and enteroglucagon in rats after colectomy
    1992
    Co-Authors: A P Vukasin, Thomas E Adrian, O Nilsson, Anton J Bilchik, Garth H Ballantyne, I M Modlin
    Abstract:

    Peptide YY (PYY) and enteroglucagon are produced by endocrine cells of the colonic mucosa. PYY inhibits upper gastrointestinal motility, and enteroglucagon is trophic for small bowel mucosa. Adaptive increase in the production and release of these Peptides may improve functional results after colorectal resections. We hypothesized that if segments of the colon were resected, then production and release of PYY and enteroglucagon would increase in the remaining segments of bowel. Animals which underwent colonic transections and partial resections had transient elevations of PYY up to 250 +/- 80 pmol/L, which dropped to control group levels in the second week following surgery. Rats with an abdominal colectomy had significantly greater PYY levels than all other groups from the third (208 +/- 30 pmol/L) to the thirty-eighth (100 +/- 16 pmol/L) week of the study. Circulating levels of enteroglucagon were elevated to 156 +/- 35 pmol/L in rats with a right hemicolectomy during the first week following surgery. Enteroglucagon levels did not significantly vary in the other groups studied. Both tissue PYY (413 +/- 33 pmol/gram) and tissue enteroglucagon (171 +/- 17 pmol/gram) were significantly elevated in the rectums of the rats with an abdominal colectomy, as compared to all other groups. The elevated tissue levels may thus account for the ability to maintain elevated plasma PYY. Double immunogold labeling of endocrine cells in the colorectal tissue for PYY and enteroglucagon revealed both Peptides within the same endocrine cells and secretory granules. These studies support the hypothesis that circulating levels of PYY are elevated after major colonic resections and suggest that L-type endocrine cells may participate in adaptive responses which improve intestinal function following colonic surgery.

  • Adaptive increase in Peptide YY and enteroglucagon after proctocolectomy and pelvic ileal reservoir construction
    1991
    Co-Authors: David N. Armstrong, Thomas E Adrian, Anton J Bilchik, Garth H Ballantyne, Marvin A. Mcmillen, Irvin M Modlin
    Abstract:

    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 < 0.001). Postprandial plasma enteroglucagon levels reached 199±53 pmol/liter in reservoir animals and 52±4 pmol/liter in controls ( P < 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 < 0.0001). Enteroglucagon levels were also elevated in reservoir mucosa (193 ±21 pmol/g vs . 113±9 pmol/g in controls , P < 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 .

H Rochlitz - One of the best experts on this subject based on the ideXlab platform.

  • effect of human body weight changes on circulating levels of Peptide YY and Peptide YY3 36
    2007
    Co-Authors: Juliane Kampe, Traci Kruthaupt, Stephen C Benoit, U Cuntz, H Rochlitz, Paul T Pfluger, Tamara R Castaneda, Torsten P Vahl, David A Dalessio
    Abstract:

    Background: Recent findings suggest that low plasma Peptide YY (PYY) levels may contribute to diet-induced human obesity and justify PYY replacement therapy. Although the pharmacological value of PYY is controversial, further study of the secretion of the precursor PYY1–36 and the pharmacologically active PYY3–36 is indicated to determine the potential role in energy balance regulation. Aim: Our objective was to determine the effects of acute and chronic changes in human body weight on circulating levels of the putative satiety hormone Peptide YY. Design: Total plasma PYY levels (PYY1–36 + PYY3–36) were measured in 66 lean, 18 anorectic, 63 obese, and 16 morbidly obese humans. In addition, total PYY was measured in 17 of the obese patients after weight loss and in the 18 anorectic patients after weight gain. Fasting PYY3–36 levels were measured in 17 lean and 15 obese individuals. Results: Fasting total plasma PYY levels were highest in patients with anorexia nervosa (80.9 ± 12.9 pg/ml, P < 0.05) compared...

Juliane Kampe - One of the best experts on this subject based on the ideXlab platform.

  • effect of human body weight changes on circulating levels of Peptide YY and Peptide YY3 36
    2007
    Co-Authors: Juliane Kampe, Traci Kruthaupt, Stephen C Benoit, U Cuntz, H Rochlitz, Paul T Pfluger, Tamara R Castaneda, Torsten P Vahl, David A Dalessio
    Abstract:

    Background: Recent findings suggest that low plasma Peptide YY (PYY) levels may contribute to diet-induced human obesity and justify PYY replacement therapy. Although the pharmacological value of PYY is controversial, further study of the secretion of the precursor PYY1–36 and the pharmacologically active PYY3–36 is indicated to determine the potential role in energy balance regulation. Aim: Our objective was to determine the effects of acute and chronic changes in human body weight on circulating levels of the putative satiety hormone Peptide YY. Design: Total plasma PYY levels (PYY1–36 + PYY3–36) were measured in 66 lean, 18 anorectic, 63 obese, and 16 morbidly obese humans. In addition, total PYY was measured in 17 of the obese patients after weight loss and in the 18 anorectic patients after weight gain. Fasting PYY3–36 levels were measured in 17 lean and 15 obese individuals. Results: Fasting total plasma PYY levels were highest in patients with anorexia nervosa (80.9 ± 12.9 pg/ml, P < 0.05) compared...

Rachel L Batterham - One of the best experts on this subject based on the ideXlab platform.

  • the role of gut hormone Peptide YY in energy and glucose homeostasis twelve years on
    2014
    Co-Authors: Sean Manning, Rachel L Batterham
    Abstract:

    Although the role of Peptide YY (PYY) as a regulator of energy homeostasis was first highlighted only in 2002, our understanding of the physiological role of PYY has since rapidly advanced. In recent years, insights from mechanistic studies in patients undergoing bariatric surgery, from pancreatic islet research, from functional neuroimaging studies, and from exercise research have greatly added to the field, and these areas provide the focus of discussion for this narrative review. We critically discuss recent findings relating to the role of PYY in mediating the beneficial effects of bariatric surgery, the role of PYY in glucose homeostasis, the role of hepatoportal PYY in mediating its central physiological effects, the specific modulation of brain regions by PYY, and the exercise-induced PYY response.

  • the role of Peptide YY in appetite regulation and obesity
    2009
    Co-Authors: Efthimia Karra, Keval Chandarana, Rachel L Batterham
    Abstract:

    The last decade has witnessed a marked increase in our understanding of the importance of gut hormones in the regulation of energy homeostasis. In particular, the discovery that the gut hormone Peptide YY 3–36 (PYY3–36) reduced feeding in obese rodents and humans fuelled interest in the role of PYY3–36 in body weight regulation. Pharmacological and genetic approaches have revealed that the Y2-receptor mediates the anorectic effects of PYY3–36 whilst mechanistic studies in rodents identified the hypothalamus, vagus and brainstem regions as potential sites of action. More recently, using functional brain imaging techniques in humans, PYY3–36 was found to modulate neuronal activity within hypothalamic and brainstem, and brain regions involved in reward processing. Several lines of evidence suggest that low circulating PYY concentrations predispose towards the development and or maintenance of obesity. Subjects with reduced postprandial PYY release exhibit lower satiety and circulating PYY levels that correlate negatively with markers of adiposity. In addition, mice lacking PYY are hyperphagic and become obese. Conversely, chronic PYY3–36 administration to obese rodents reduces adiposity, and transgenic mice with increased circulating PYY are resistant to diet-induced obesity. Moreover, there is emerging evidence that PYY3–36 may partly mediate the reduced appetite and weight loss benefits observed post-gastric bypass surgery. Taken together these findings, coupled with the retained responsiveness of obese subjects to the effects of PYY3–36, suggest that targeting the PYY system may offer a therapeutic strategy to help treat obesity.

  • attenuated Peptide YY release in obese subjects is associated with reduced satiety
    2006
    Co-Authors: C Le W Roux, Katie Wynne, Michael Patterson, Royce P Vincent, Rachel L Batterham, Simon Aylwin, Cynthiamichelle Borg, Aysha Kent, James Gardiner, M A Ghatei
    Abstract:

    The responses of the gut hormone Peptide YY (PYY) to food were investigated in 20 normal-weight and 20 obese humans in response to six test meals of varying calorie content. Human volunteers had a graded rise in plasma PYY (R2 = 0.96; P < 0.001) during increasing calorific meals, but the obese subjects had a lower endogenous PYY response at each meal size (P < 0.05 at all levels). The ratio of plasma PYY1–36 to PYY3–36 was similar in normal-weight and obese subjects. The effect on food intake and satiety of graded doses of exogenous PYY3–36 was also evaluated in 12 human volunteers. Stepwise increasing doses of exogenous PYY3–36 in humans caused a graded reduction in food intake (R2 = 0.38; P < 0.001). In high-fat-fed (HF) mice that became obese and low-fat-fed mice that remained normal weight, we measured plasma PYY, tissue PYY, and PYY mRNA levels and assessed the effect of exogenous administered PYY3–36 on food intake in HF mice. HF mice remained sensitive to the anorectic effects of exogenous ip PYY3–...

  • the gut hormone Peptide YY regulates appetite
    2003
    Co-Authors: Rachel L Batterham, Stephen R Bloom
    Abstract:

    The gut hormone Peptide YY (PYY) belongs to the pancreatic polyPeptide (PP) family along with PP and neuroPeptide Y (NPY). These Peptides mediate their effects through the NPY receptors of which there are several subtypes (Y1, Y2, Y4, and Y5). The L cells of the gastrointestinal tract are the major source of PYY, which exists in two endogenous forms: PYY(1-36) and PYY(3-36). The latter is produced by the action of the enzyme dipeptidyl peptidase-IV (DPP-IV). PYY(1-36) binds to and activates at least three Y receptor subtypes (Y1, Y2, and Y5), whereas PYY(3-36) is more selective for Y2 receptor (Y2R). The hypothalamic arcuate nucleus, a key brain area regulating appetite, has access to nutrients and hormones within the peripheral circulation. NPY neurons within the arcuate nucleus express the Y2R. In response to food ingestion plasma PYY(3-36) concentrations rise within 15 min and plateau by approximately 90 min. The peak PYY(3-36) level achieved is proportional to the calories ingested, suggesting that PYY(3-36) may signal food ingestion from the gut to appetite-regulating circuits within the brain. We found that peripheral administration of PYY(3-36) inhibited food intake in rodents and increased C-Fos immunoreactivity in the arcuate nucleus. Moreover, direct intra-arcuate administration of PYY(3-36) inhibited food intake. We have shown that Y2R null mice are resistant to the anorectic effects of peripherally administered PYY(3-36), suggesting that PYY(3-36) inhibits food intake through the Y2R. In humans, peripheral infusion of PYY(3-36), at a dose which produced normal postprandial concentrations, significantly decreased appetite and reduced food intake by 33% over 24 h. These findings suggest that PYY(3-36) released in response to a meal acts via the Y2R in the arcuate nucleus to physiologically regulate food intake.