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.

Wahab PJ, et al. Dig Dis Sci 2001 Nov;46(11):2504-9

Normal feeding behavior, body weight and leptin response require the
neuropeptide Y Y2 receptor

Neuropeptide Y (NPY), a 36-amino-acid peptide widely expressed in the brain is involved in many physiological responses, including hypothalamic control of food intake and cardiovascular homeostasis. NPY mediates its effects through binding to the Y1, Y2 and Y5 G-protein-coupled receptors. Little is known of the role of the Y2 receptor in mediating the different NPY effects. We inactivated the Y2 receptor subtype in mice and found that these mice developed increased body weight, food intake and fat deposition. The null mutant mice showed an attenuated response to leptin administration but a normal response to NPY-induced food intake and intact regulation of re-feeding and body weight after starvation. An absence of the Y2 receptor subtype also affected the basal control of heart rate, but did not influence blood pressure. These findings indicate an inhibitory role for the Y2 receptor subtype in the central regulation of body weight and control of food intake.

Naveilhan P., et al. Nat Med 1999 Oct;5(10):1188-93

Gastrointestinal transit in relation to gut endocrine cells in animal models of human diabetes

Gastrointestinal transit was measured in non-obese diabetic (NOD) mice, as an animal model of human diabetes type 1, and in obese diabetic mice, as an animal model of human diabetes type 2. The endocrine cells known to correlate to gastrointestinal transit, namely secretin, serotonin, Peptide YY (PYY) and enteroglucagon cells, were identified by immunocytochemistry and quantified by computer image analysis in different segments of the gut. Gastrointestinal transit was significantly accelerated in NOD mice and slower in obese diabetic mice than in controls. The density of duodenal secretin and serotonin as well as colonic PYY and enteroglucagon cells in NOD mice was significantly higher than that of control mice. On the other hand, the density of duodenal secretin and serotonin cells was significantly lower in obese diabetic mice than in controls. It was concluded that changes in duodenal secretin and colonic serotonin, PYY and enteroglucagon cells may play a role in accelerated gastrointestinal transit in NOD mice and delayed gastrointestinal transit in obese diabetic mice.

El-Salhy M. Ups J Med Sci 2002;107(1):23-33

Human placenta and fetal membranes contain peptide YY1-36 and peptide YY3-36

Extracts of human term amniotic, placental, and chorion/decidua tissue contained, respectively, 4.36 +/- 2.79 (pmol/g wet wt; mean +/- S.E.M.: n = 5). 2.78 +/- 0.5 (n = 5) and 0.68 +/- 0.68 (n = 5) peptide YY (PYY)-like immunoreactivity. Using a specific PYY antiserum, gel filtration chromatography and reverse-phase high performance liquid chromatography (HLPC), amniotic, placental and fetal intestinal tissue extracts were demonstrated to contain PYY-like immunoreactivity consisting of equal amounts of PYY1-36 and PYY3-36. The presence of pancreatic polypeptide was not detected in any of the extracts. Positive immunohistochemical staining for PYY was seen in extravillous trophoblasts in the decidual septa and fetal membranes, the syncytiotrophoblast and cytotrophoblasts, amniotic epithelial cells and in maternal decidual stromal cells. Positive staining for PYY was found at the earliest date examined (9.5 weeks) and remained present throughout pregnancy to term. PYY1-36 and PYY3-36 may play important roles in human pregnancy, acting via endocrine or paracrine mechanisms.

Xiao Q,et al. J Endocrinol 1998 Mar;156(3):485-92

Autoradiographic distribution of [125I]Leu31,Pro34]PYY and [125I]PYY3-36 binding sites in the rat brain evaluated with two newly developed Y1 and Y2 receptor radioligands

The peptide YY derivatives [Leu31,Pro34]PYY and PYY3-36 are highly selective Y1 and Y2 agonists, devoid of activity on the Y3 receptor subtype [Dumont et al. (1994) Molec. Brain Res., 26:3220-3324]. These selective ligands were iodinated and used to evaluate the respective quantitative autoradiographic distribution of the Y1 and Y2 receptor subtypes in the rat brain, excluding a potential contamination from Y3 receptor. Specific [125I][Leu31,Pro34]PYY (Y1), and [125I]PYY3-36 (Y2) binding sites are detected in various brain regions, but each showed a differential distribution profile. Y1/[125I][Leu31,Pro34]PYY sites are especially concentrated in superficial layers of the cortex, the olfactory tubercle, islands of Calleja, tenia tecta, molecular layer of the dentate gyrus, several thalamic nuclei, and the posterior part of the medial mammaliary nucleus. These areas generally contained only low densities of Y2/[125I]PYY3-36 binding sites. In contrast, [125I]PYY3-36 binding is most abundant in multiple other regions including the lateral septum, piriform cortex, triangular septal nucleus, bed nucleus of the stria terminalis, oriens layer and stratum radiatum of the dorsal hippocampus, ventral tegmental area, substantia nigra, dorsal raphe nucleus, and the granular cell layer of the cerebellum. Few areas of the rat brain contained significant amounts of both [125I][Leu31,Pro34]PYY and [125I]PYY3-36 binding sites such as the anterior olfactory nuclei, oriens layer and stratum radiatum of the ventral hippocampus, nucleus tractus solitarius, area postrema, and inferior olive. Taken together, these results and the use of two selective radioligands demonstrate further the discrete, differential distribution of the Y1 and Y2 receptor subtypes in the rat brain.

Dumont Y., et al. Synapse 1996 Feb;22(2):139-58

Characterization of neuropeptide Y binding sites in rat brain membrane preparations using [125I][Leu31,Pro34]peptide YY and [125I]peptide YY3-36 as selective Y1 and Y2 radioligands

The peptide YY (PYY)-derivatives [Leu31,Pro34]PYY and PYY3-36 were respectively developed as selective Y1 and Y2 radioligands devoid of affinity for the Y3 receptor subtype. Each analog was iodinated by the chloramine T method after a purification by reverse-phase high-performance liquid chromatography. Both radioligands bind with high affinity, low capacity and in a time-dependent and saturable manner to specific sites present in rat frontoparietal cortical or hippocampal membrane preparations. [125I][Leu31,Pro34]PYY demonstrated apparent affinities (Kd) of 0.42 +/- 0.07 and 0.22 +/- 0.08 nM and maximal capacities (Bmax) of 185 +/- 14 and 33 +/- 4 fmol/mg of protein to a single class of sites in cortical and hippocampal membrane homogenates, respectively. Conversely, [125I]PYY3-36 apparently bound to a greater amount of sites in hippocampal (Bmax of 109 +/- 13 fmol/mg of protein; Kd of 0.13 +/- 0.03 mM) compared with cortical (Bmax of 33 +/- 5 fmol/mg of protein; Kd of 0.37 +/- 0.06 nM) membrane preparations, which suggests the differential enrichment of these two brain regions with a given neuropeptide Y (NPY) receptor subtype. The comparative ligand selectivity profile of these two radiolabeled PYY derivatives confirmed this hypothesis and revealed that, although the rat frontoparietal cortex is enriched with Y1 sites, Y2, receptor binding sites are most abundant in the hippocampus.

Dumont Y., et al. J Pharmacol Exp Ther 1995 Feb;272(2):673-80