Disease relevance of PYY

• In humans and dogs the effects of NPY or PYY were abolished by treatment of cells with Bordetella pertussis toxin, clearly indicating the involvement of a Gi protein in the antilipolytic effects [1].
• Thus, higher plasma PYY following JIB may contribute to reduced food intake and contribute to weight loss [2].
• 3-(3-(Benzothiazol-6-yl)ureido)-1-N-(3-(N'-(3-isopropylureido++ +))benzyl )-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (21), which was one of the most potent derivatives, competitively inhibited specific [(125)I]peptide YY (PYY) binding to Y1 receptors in human neuroblastoma SK-N-MC cells (K(i) = 5.1 nM) [3].
• While obese subjects have appropriate reductions in orexigenic ghrelin, other gut-hormone disturbances may contribute to obesity such as reduced anorexigenic PYY and PP [4].
• Furthermore, in the patients with colonic inertia, the percentages of strongly and moderately stained PYY-positive cells were higher in the right-side colon than in the left (P < 0.01) [5].

Psychiatry related information on PYY

• Intraventricular administration of pNPY, hNPY, NPY-A and PYY over a dose range of 0.5 to 10 micrograms evoked feeding behavior to a varying extent [6].
• During the last two decades, NPY body fluid concentrations and NPY/PYY brain receptor numbers have been demonstrated to be altered during the course of Alzheimer's disease [7].
• Leptin, neuropeptide Y, and peptide YY in long-term recovered eating disorder patients [8].
• Postprandial changes in gastric volume and PYY were independent predictors of satiation (both P = .01) [9].
• The discovery, anatomy, and physiology of ghrelin and peptide YY are discussed, focusing on the adaptive changes in diseases such as obesity and anorexia nervosa [10].
• Fasting total plasma PYY levels were highest in patients with anorexia nervosa (80.9 +/- 12.9 pg/ml, P < 0.05) compared with lean (52.4 +/- 4.6 pg/ml), obese (43.9 +/- 3.8 pg/ml), or morbidly obese (45.6 +/- 11.2 pg/ml) subjects [11].

High impact information on PYY

• XVI. International Union of Pharmacology recommendations for the nomenclature of neuropeptide Y, peptide YY, and pancreatic polypeptide receptors [12].
• Further studies are needed to characterize the pharmacological nature of the receptor mediating the inhibitory effect of NPY and PYY in fat cells [1].
• In dog fat cells NPY and PYY inhibited adenosine deaminase-, isoproterenol- and forskolin-induced lipolysis [1].
• Neuropeptide Y and peptide YY inhibit lipolysis in human and dog fat cells through a pertussis toxin-sensitive G protein [1].
• Conclusions: Overweight or obesity are associated with lower postprandial gastric volumes and normal PYY levels [9].

Chemical compound and disease context of PYY

• RESULTS: After substantial body weight loss (36.8 +/- 3.6%) induced by gastric bypass, the PYY response to an oral glucose tolerance test was significantly higher than in controls (p = 0.01) [13].
• Out of the six argyrophil carcinoids, five were argyrophil, non-argentaffin carcinoids; three consisted almost totally of PYY cells; one consisted of 60% PYY cells, 40% So cells and a few Gli cells; and one consisted of Ser cells alone [14].
• In the gastric mucosa, PYY binds to Y1 receptors in the enterochromaffin-like cells to inhibit gastrin-stimulated histamine release and calcium signaling via a pertussis toxin-sensitive pathway [15].
• Pancreatic cancer cells received 500 pmol of PYY or BIM-43004 for 24 hours prior to 5-fluorouracil (5-FU; 10 micrograms/mL) and leucovorin (40 micrograms/mL) administration [16].
• Compound 1 competitively inhibited [125I]peptide YY (PYY) binding to Y1 receptors in human neuroblastoma SK-N-MC cells with Ki of 6.4 +/- 1.0 nM, while it had no effect on [125I]PYY binding to Y2 or Y5 receptors even at 1 microM [17].
• The markedly reduced ghrelin levels in addition to increased PYY levels after LSG, are associated with greater appetite suppression and excess weight loss compared with LRYGBP [18].

Biological context of PYY

• This study indicates that, in addition to alpha 2-adrenergic agonists, NPY and PYY are also involved in the regulation of lipolysis in human and dog adipose tissue as powerful antilipolytic agents [1].
• Reverse transcriptase-polymerase chain reaction analysis indicated expression also in human cultured vascular smooth muscle cells, supporting the view that the Y1 receptor is associated with NPY/PYY-evoked vasoconstriction [19].
• We now report the isolation of a human Y2 (hhY2) receptor cDNA by expression cloning from a human hippocampal cDNA library, using a 125I-PYY binding assay. hhY2 cDNA encodes a predicted protein of 381 amino acids with low amino acid identity to the human Y1 receptor (31% overall; 41% transmembrane) [20].
• Considering the high degree of sequence homology of pNPY and pPYY (>80%) and the fact, that their binding affinities at all receptor subtypes are high and, more importantly, rather similar, it is much more likely that PYY and NPY are recognized by the Y receptors from the membrane-bound state [21].
• In binding experiments the chimeric peptides were all about equipotent with NPY and PYY in displacing [125I]-PYY from Y1 and Y2 binding sites on SK-N-MC cells and rat hippocampus respectively [22].

Anatomical context of PYY

• The PYY and RPP antisera labeled groups of neurons and fibers in the rhombencephalic and mesencephalic reticular formation [23].
• One of the PYY/RPP-ir cell groups, located in the anterior rhombencephalic reticular nucleus, had a projection to the dorsolateral spinal cord [23].
• NPY is expressed exclusively in neurons, whereas PYY and PP are produced primarily in gut endocrine cells [24].
• Moreover, the antagonist 1) considerably reversed the PYY-induced reduction of short-circuit current in rat jejunum mucosa in Ussing chamber and 2) completely abolished the antisecretory action of PYY on vasoactive intestinal peptide (VIP)-induced fluid secretion in rat jejunum in vivo [25].
• BIIE0246 completely abolished the inhibition of cAMP production by PYY in crypt cells and transfected CHO cells [25].

Associations of PYY with chemical compounds

• Because (a) NPY has been shown to be colocalized with noradrenaline in peripheral as well as central catecholaminergic neurons, and (b) alpha 2-adrenergic receptors of adipocytes play a major role in the regulation of lipolysis, we investigated the effect of NPY and PYY on isolated fat cells [1].
• 4. Y(1) receptor antagonists, BIBP3226 and BIBO3304 both increased basal I(sc) levels per se and inhibited subsequent PYY and Pro(34)PYY but not hPP or PYY(3 - 36) responses [26].
• The frequency of PYY-containing cells and the 5-HT-containing cells in the ascending colon was significantly increased in the constipated patients [27].
• However, as different from the Y1-like LP-PYY binding, but similar to the binding of the Y2-selective ligand [125I]human peptide YY(3-36) (hPYY(3-36)), the PP binding showed a low sensitivity to guanosine polyphosphates [28].
• 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 [29].
• Our data does not support PYY being relevant in the changes in glucose homeostasis occurring after this type of bariatric surgery [30].

Physical interactions of PYY

• 1229U91 potently displaced [125I]-peptide YY (PYY) binding to human NPY Y1 receptors (IC50 = 0.245+/-0.004 nM, n = 4). but displayed little affinity for the human NPY Y2 and Y5 receptors (IC50 > 1000 nM) [31].
• Saturable 125I-porcine PYY binding sites in all regions of the dogfish brain closely resembled the mammalian Y1 NPY receptor subtype in specificity for these substances [32].
• PYY induced expression of tetraspanins and intestinal fatty acid binding protein (I-FABP) may be part of a mechanism whereby FFA modulate expression of differentiation dependent proteins in the mucosa [33].

Enzymatic interactions of PYY

• Dipeptidyl peptidase-IV hydrolyzes PYY at the Pro2-Ile3 bond, producing PYY-(3-36), which is a Y2 receptor-selective ligand [34].

Co-localisations of PYY

• GLU was colocalized with PYY and NPY in a few cells in a small peripheral area in the big islet and a few intermediate islets [35].

Regulatory relationships of PYY

• PYY inhibited the vagal action more effectively than did NPY [36].
• In the Y1-7 clone, BIBP 3226 fully inhibited the reductions in VIP-stimulated SCC induced by 30 nM PYY, with an IC50 of 27.2 nM and 30 nM BIBP 3226 caused a parallel rightward shift on the PYY concentration-response curve, with an approximate pKB of 8 [37].
• Distension tended to increase integrated plasma PYY from 77 +/- 30 pM min to 128 +/- 40 pM min in the first hour after the meal (P = 0.08) and it suppressed integrated plasma PP from 1133 +/- 248 pM min to 269 +/- 284 pM min in the second hour (P < 0.05) [38].
• PYY inhibits upper gastrointestinal secretory and motor functions [39].
• This pathway further requires protein kinase C with EGFR TK inhibition blocking PYY-induced protein kinase Cepsilon (PKCepsilon) translocation to the cell membrane [40].

Other interactions of PYY

• FAT infusion was associated with a marked, and progressive, suppression of plasma ghrelin from t = 60 min (P < 0.001) and stimulation of PYY from t = 30 min (P < 0.01) [41].
• 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 [29].
• In obese unoperated patients, the density of PYY and secretin cells was decreased compared with the JIB-patients and the density of the GIP cells compared with both other groups [42].
• However, other peptides capable of inhibiting gastric acid secretion in vivo, such as CCK, VIP, and PYY, were unable to induce any inhibition of the parietal cell response to db-cAMP or histamine in the isolated gastric gland preparation irrespective of the species studied [43].
• The levels of VIP, substance P and NPY were higher in the ascending colon than in the descending colon, whereas the opposite pattern was seen for PYY [44].

Analytical, diagnostic and therapeutic context of PYY

• RESULTS: Compared with lean and obese controls, patients following Roux-en-Y gastric bypass (RYGB) had increased postprandial plasma PYY and GLP-1 favoring enhanced satiety [2].
• Pools of clones were transiently expressed in COS-1 cells, and 125I-PYY binding pools were identified by autoradiography [45].
• A second weaker hybridization signal also found on chromosome 17q11 and results obtained by Southern blot analysis suggest that the entire PYY-PPY region has undergone a further duplication event [46].
• Peptide YY (PYY) and fish pancreatic peptide Y (PY) expression in the brain of the sea bass (Dicentrarchus labrax) as revealed by in situ hybridization [47].
• Immunocytochemistry revealed PYY- and EG-like immunoreactivity in 20-30% of tumor cells [48].

References