peptide-yy and Disease-Models--Animal

Obesity is a disease that develops as a result of long-term positive energy balance. In recent years, the influence of gut microflora composition, as a potential factor affecting the energy balance and contributing to fat accumulation, has been studied. It seems that bacteria can affect host energy balance through several mechanisms, such as increased fermentation of undigested polysaccharides and obtaining extra energy from the portion of food, reduced expression of FIAF (fasting-induced adipocyte factor) in the enterocytes with inhibitory activity towards intestinal lipoprotein lipase, and the increased release of peptide YY that slows the intestinal motility. It is also believed that changes in the composition of gut microflora may be one of the factors that induce systemic microinflammation in the obese, an important link in the pathogenesis of obesity related complications, including dyslipidaemia, hypertension and type 2 diabetes. However, the results of previous studies are inconclusive. Many of them have been carried out in an animal model and were not confirmed in studies involving humans. These discrepancies may be due to different composition of the diet, distinct physiological gut microflora and the methodology used in these studies. The present article reviews the current literature on the potential role of gut microflora in the pathogenesis of obesity.

Topics: Angiopoietin-Like Protein 4; Angiopoietins; Animals; Diabetes Mellitus, Type 2; Diet; Disease Models, Animal; Dyslipidemias; Energy Metabolism; Enterocytes; Gastrointestinal Motility; Gastrointestinal Tract; Humans; Hypertension; Intestines; Lipase; Microbiota; Obesity; Peptide YY

Peptide YY (PYY) 3-36, the main circulatory form of PYY, plays important roles in gastrointestinal motility, secretion, and absorption. However, it is unknown whether PYY 3-36 has underlying functions in colitis. The Crohn's disease (CD)-like mouse model in which CD is induced by trinitrobenzene sulfonic acid (TNBS) was established and utilized to investigate this potential role for PYY 3-36. The results showed that the expression of colonic mucosal PYY and PYY receptors Y1, Y2, Y4 were significantly increased in mice with TNBS-induced colitis. In vitro, PYY 3-36 remarkably inhibited the production of proinflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) from lipopolysaccharide (LPS)-induced macrophages. In vivo, a high concentration of PYY 3-36 robustly decreased the weight loss and death rate and attenuated the pathological colon tissue damage observed in mice with TNBS-induced colitis. Further studies uncovered that PYY 3-36 treatment reduced the levels of colon myeloperoxidase (MPO) and both colonic and systemic TNF-α and IL-6 observed in murine colitis. Furthermore, flow cytometric analysis showed PYY 3-36 altered the proportion of Th1/Th2 splenocytes in the disease model of colitis. Collectively, these results suggest that PYY 3-36 may be a promising candidate for the improvement of colitis, reflected by the attenuation of colon inflammatory responses observed in experimental murine colitis.

Topics: Animals; Colitis; Crohn Disease; Cytokines; Disease Models, Animal; Interleukin-6; Mice; Mice, Inbred BALB C; Peptide YY; Trinitrobenzenesulfonic Acid; Tumor Necrosis Factor-alpha

Complex interactions between keratinocytes and various cell types, such as inflammatory cells and stromal cells, contribute to the pathogenesis of chronic inflammatory skin lesions. In proinflammatory cytokine‒mediated disease settings, IL-9 plays a pathological role in inflammatory dermatitis. However, IL-9‒related mechanisms remain incompletely understood. In this study, we established tamoxifen-induced keratinocyte-specific IL-9RA-deficient mice (K14

Topics: Animals; Dermatitis; Disease Models, Animal; Imiquimod; Inflammation; Interleukin-9; Keratinocytes; Mice; Peptide YY; Psoriasis; Skin

The hypothalamus is an important brain region for the regulation of energy balance. Roux-en-Y gastric bypass (RYGB) surgery and gut hormone-based treatments are known to reduce body weight, but their effects on hypothalamic gene expression and signaling pathways are poorly studied.. Diet-induced obese male Wistar rats were randomized into the following groups: RYGB, sham operation, sham + body weight-matched (BWM) to the RYGB group, osmotic minipump delivering PYY3-36 (0.1 mg/kg/day), liraglutide s.c. (0.4 mg/kg/day), PYY3-36 + liraglutide, and saline. All groups (except BWM) were kept on a free choice of high- and low-fat diets. Four weeks after interventions, hypothalami were collected for RNA sequencing.. While rats in the RYGB, BWM, and PYY3-36 + liraglutide groups had comparable reductions in body weight, only RYGB and BWM treatment had a major impact on hypothalamic gene expression. In these groups, hypothalamic leptin receptor expression as well as the JAK-STAT, PI3K-Akt, and AMPK signaling pathways were upregulated. No significant changes could be detected in PYY3-36 + liraglutide-, liraglutide-, and PYY-treated groups.. Despite causing similar body weight changes compared to RYGB and BWM, PYY3-36 + liraglutide treatment does not impact hypothalamic gene expression. Whether this striking difference is favorable or unfavorable to metabolic health in the long term requires further investigation.

Topics: Animals; Body Weight; Caloric Restriction; Disease Models, Animal; Energy Metabolism; Gastric Bypass; Gastrointestinal Hormones; Gene Expression; Hypothalamus; Liraglutide; Male; Obesity; Peptide Fragments; Peptide YY; Rats; Rats, Wistar; Signal Transduction; Transcriptome

Olfactory receptor 78 (Olfr78), which is also known as a receptor for short-chain fatty acids (SCFAs) produced via gut microbial fermentation from indigestible polysaccharides such as dietary fibers, is expressed in the enteroendocrine cells of the colon. However, the role of Olfr78 in gut hormone secretion remains unknown. Here, we aimed to investigate the function and mechanism of action of Olfr78 in vivo and in vitro. Toward this, we assessed the expression of Olfr78 in several tissues, affinity of Olfr78 to various monocarboxylates, and the secretion of anorexigenic gut hormone peptide YY (PYY) via Olfr78 using various molecular and biochemical techniques. Olfr78 was abundantly expressed in the colon and mouse enteroendocrine cell line STC-1 and showed specific affinity to SCFAs such as acetate and propionate, but not butyrate, in a monocarboxylate ligand screening assay using a heterologous expression system. Acetate promoted PYY secretion in STC-1 cells via Olfr78-protein kinase A signaling, whereas the effects were abolished by Olfr78 RNA interference. Colonic SCFAs production via oral administration of fructo-oligosaccharide significantly increased plasma PYY levels, whereas this effect was abolished in Olfr78-deficient and germ-free mice. These results suggested that the SCFA receptor Olfr78 is important for anti-obesity and anorexigenic effects of the gut microbiota and dietary fibers.

Topics: Animals; Anorexia; Cells, Cultured; Disease Models, Animal; Enteroendocrine Cells; Fatty Acids, Volatile; Gastrointestinal Microbiome; Intestinal Mucosa; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Peptide YY; Receptors, Odorant

The trichothecene mycotoxins contaminate cereal grains and have been related to alimentary toxicosis resulted in emetic response. This family of mycotoxins comprises type A to D groups of toxic sesquiterpene chemicals. Diacetoxyscirpenol (DAS), one of the most toxic type A trichothecenes, is considered to be a potential risk for human and animal health by the European Food Safety Authority. Other type A trichothecenes, T-2 toxin and HT-2 toxin, as well as type B trichothecene deoxynivalenol (DON), have been previously demonstrated to induce emetic response in the mink, and this response has been associated with the plasma elevation of neurotransmitters peptide YY (PYY) and serotonin (5-hydroxytryptamine, 5-HT). However, it is found that not all the type A and type B trichothecenes have the capacity to induce PYY and 5-HT. It is necessary to identify the roles of these two emetogenic mediators on DAS-induced emesis. The goal of this study was to determine the emetic effect of DAS and relate this effect to PYY and 5-HT, using a mink bioassay. Briefly, minks were fasted one day before experiment and given DAS by intraperitoneally and orally dosing on the experiment day. Then, emetic episodes were calculated and blood collection was employed for PYY and 5-HT test. DAS elicited robust emetic responses that corresponded to upraised PYY and 5-HT. Blocking the neuropeptide Y2 receptor (NPY2R) diminished emesis induction by PYY and DAS. The serotonin 3 receptor (5-HT3R) inhibitor granisetron totally restrained the induction of emesis by serotonin and DAS. In conclusion, our findings demonstrate that PYY and 5-HT have critical roles in DAS-induced emetic response.

Topics: Animals; Antiemetics; Disease Models, Animal; Female; Granisetron; Mink; Peptide YY; Receptors, Gastrointestinal Hormone; Receptors, Serotonin, 5-HT3; Secretory Pathway; Serotonin; Serotonin 5-HT3 Receptor Antagonists; Trichothecenes; Up-Regulation; Vomiting

Roux-en-Y gastric bypass (RYGB) modifies various aspects of eating behavior in morbidly obese individuals to cause marked and lasting weight loss and improvements in metabolic health, but the underlying mechanisms remain poorly understood.. To assess the relative contributions of the gut hormones glucagon-like peptide 1 (GLP-1) and peptide tyrosine tyrosine 3-36 (PYY. University hospital, Würzburg, Germany.. HF diet-induced obese male Wistar rats underwent RYGB (n = 11) or sham (n = 7) surgeries and were subsequently maintained on a choice of low-fat (10% calories from fat) and HF (60% calories from fat) diets. From postoperative weeks 4 to 6, acute feeding studies were performed in which the selective GLP-1 receptor antagonist exendin-9 (30 μg/kg), the second-generation selective Y2 receptor antagonist JNJ-31020028 (10 mg/kg), or a combination of both drugs was administered intraperitoneally.. During the observational period weight, adiposity and total food intake were lower while postprandial plasma GLP-1 and peptide tyrosine tyrosine levels were higher for RYGB-operated compared with sham-operated rats. There was a gradual shift in preference from HF to low-fat food in RYGB-operated rats by postoperative week 3. Single antagonist treatments had a relatively modest impact on HF food preference in rats from both surgical groups. However, dual antagonist treatment caused a striking increase in HF food preference specifically in RYGB-operated rats.. GLP-1 and peptide tyrosine tyrosine 3-36 reduce HF food preference additively after RYGB supporting the use of gut hormone combination strategies for healthier feeding behavior.

Topics: Animals; Diet, High-Fat; Disease Models, Animal; Feeding Behavior; Food Preferences; Gastric Bypass; Glucagon-Like Peptide 1; Male; Obesity, Morbid; Peptide Fragments; Peptide YY; Rats; Rats, Wistar

Sleeve gastrectomy with ileal transposition has been shown to be superior to sleeve gastrectomy alone for promoting weight loss in rat and porcine models. The absence of a mouse model for this procedure has impeded efforts to understand the molecular physiology underlying its efficacy. This study demonstrates the long-term survivability of sleeve gastrectomy with ileal transposition in mice.. In this study of technical feasibility, a sleeve gastrectomy with ileal transposition (SGIT), sleeve gastrectomy (SG), or sham surgery (SH) was performed on 7- to 8-week-old C57Bl/6J mice (n = 8 for each). To evaluate long-term survivability, mice were placed on an obesogenic diet and weighed weekly for 10 weeks. The intestinal identity of the transposed segment was assessed with gene expression analysis of duodenal-, jejunal-, and ileal-specific hormones using quantitative polymerase chain reaction.. Overall, SGIT better prevented weight gain than the SG or sham procedures (10-week post-operative weight: SH 45.3 ± 1.0 g, SG 41.25 ± 1.6 g, SGIT 35.4 ± 0.8 g). Gene expression pattern analysis of three markers of intestinal identity (gastrin, cholecystokinin, and peptide YY) suggests that the ileal identity of the transposed segment is maintained 10 weeks after transposition.. We demonstrate for the first time a reproducible mouse model of sleeve gastrectomy with ileal transposition. Future studies utilizing this model will expand our understanding of the molecular pathways through which the hindgut regulates satiety.

Topics: Animals; Biomarkers; Blood Glucose; Cholecystokinin; Disease Models, Animal; Feasibility Studies; Gastrectomy; Gastrins; Gene Expression; Ileum; Mice, Inbred C57BL; Peptide YY; Random Allocation; RNA; Weight Loss

Duodenal-jejunal bypass (DJB) has been proven effective in glycemic control in various type 2 diabetes (T2DM) rat models. "Hindgut hypothesis" and "foregut hypothesis" are two prevailing theories to elucidate the weight-independent anti-diabetic mechanisms of DJB, however, which mechanism plays the dominant role that has not been illuminated.. This paper aims to verify that exclusion of the foregut leads to loss of weight and remission of type 2 diabetes without expedited delivery of nutrients to the distal bowel.. Thirty-five diabetic rats induced by high-fat diet (HFD) and low dose of streptozotocin (STZ) were randomly assigned to the control, sham-DJB (S-DJB), DJB, ileal bypass (ILB), and DJB combined with ILB (DJB-ILB) groups. Effects of surgeries on body weight, food intake, blood glucose, glucose-stimulated insulin, and gastrointestinal hormones secretion were evaluated at indicated time points.. Compared to the control and S-DJB groups, the DJB group had significant and sustained glycemic control independent of weight loss. Excluding part of the distal ileum did not reverse the diabetic control that followed DJB surgery. The glucagon-like peptide 1 (GLP-1) and PYY levels were significantly increased after DJB. Although GLP-1 and PYY are mainly secreted by L cells in the distal ileum, excluding part of the ileum did not decrease the levels of GLP-1 and PYY after DJB.. The beneficial effects of DJB in glycemic control could not be reversed by excluding the distal ileum.

Topics: Anastomosis, Surgical; Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Disease Models, Animal; Duodenum; Glucagon-Like Peptide 1; Ileum; Jejunum; Male; Obesity, Morbid; Peptide YY; Rats; Rats, Wistar

Short bowel syndrome (SBS) patients developing hyperphagia have a better outcome. Gastrointestinal endocrine adaptations help to improve intestinal functions and food behaviour. We investigated neuroendocrine adaptations in SBS patients and rat models with jejuno-ileal (IR-JI) or jejuno-colonic (IR-JC) anastomosis with and without parenteral nutrition. Circulating levels of ghrelin, PYY, GLP-1, and GLP-2 were determined in SBS rat models and patients. Levels of mRNA for proglucagon, PYY and for hypothalamic neuropeptides were quantified by qRT-PCR in SBS rat models. Histology and immunostaining for Ki67, GLP-1 and PYY were performed in SBS rats. IR-JC rats, but not IR-JI, exhibited significantly higher crypt depths and number of Ki67-positive cells than sham. Fasting and/or postprandial plasma ghrelin and PYY concentrations were higher, or tend to be higher, in IR-JC rats and SBS-JC patients than in controls. Proglucagon and Pyy mRNA levels were significantly enhanced in IR-JC rats. Levels of mRNA coding hypothalamic orexigenic NPY and AgRP peptides were significantly higher in IR-JC than in sham rats. We demonstrate an increase of plasma ghrelin concentrations, major changes in hypothalamic neuropeptides levels and greater induction of PYY in SBS-JC rats and patients suggesting that jejuno-colonic continuity creates a peculiar environment promoting further gut-brain adaptations.

Topics: Adult; Aged; Agouti-Related Protein; Anastomosis, Surgical; Animals; Colon; Disease Models, Animal; Feeding Behavior; Female; Ghrelin; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Humans; Hyperphagia; Hypothalamus; Intestinal Mucosa; Jejunum; Ki-67 Antigen; Male; Middle Aged; Neuropeptide Y; Peptide YY; Proglucagon; Rats; Rats, Wistar; Real-Time Polymerase Chain Reaction; RNA, Messenger; Short Bowel Syndrome

Laparoscopic sleeve gastrectomy (SG) and gastric banding (GB) are popular bariatric procedures for treating morbid obesity. This study aimed to investigate changes in the hypothalamic feeding center after these surgeries in a diet-induced obese rat model.. Obesity was induced in 60 Sprague-Dawley rats using a high-energy diet for 6 weeks. These rats were divided into four groups: the sham-operated (SO) control, pair-fed (PF) control, SG and GB groups. Six weeks after the surgery, metabolic parameters, the plasma levels of leptin, ghrelin, peptide YY (PYY) and glucagon-like peptide-1 (GLP-1) and the hypothalamic mRNA expressions of neuropeptide Y (NPY) and pro-opiomelanocortin (POMC) were measured.. Compared with those observed in the SO group, the body and fat tissue weights were significantly decreased and the metabolic parameters were significantly improved in the PF, SG and GB groups 6 weeks after surgery. The plasma ghrelin levels were significantly lower and the PYY and GLP-1 levels were significantly higher in the SG group than in the PF, GB and SO groups. Compared with that seen in the PF and GB groups, the hypothalamic mRNA expression of NPY was significantly lower and the expression of POMC was significantly higher in the SG group.. SG may affect the neurological pathway associated with appetite in the hypothalamus and thereby control ingestive behavior.

Topics: Animals; Bariatric Surgery; Disease Models, Animal; Feeding Behavior; Gastrectomy; Ghrelin; Glucagon-Like Peptide 1; Hypothalamus; Leptin; Male; Neuropeptide Y; Obesity, Morbid; Peptide YY; Pro-Opiomelanocortin; Rats, Sprague-Dawley; RNA, Messenger

In addition to classic functions of facilitating hepatobiliary secretion and intestinal absorption of lipophilic nutrients, bile acids (BA) are also endocrine factors and regulate glucose and lipid metabolism. Recent data indicate that antiobesity bariatric procedures e.g. Roux-en-Y gastric bypass surgery (RYGB), which also remit diabetes, increase plasma BAs in humans, leading to the hypothesis that BAs may play a role in diabetes resolution following surgery. To investigate the effect of RYGB on BA physiology and its relationship with glucose homeostasis, we undertook RYGB and SHAM surgery in Zucker diabetic fatty (ZDF) and normoglycemic Sprague Dawley (SD) rats and measured plasma and fecal BA levels, as well as plasma glucose, insulin, Glucagon like peptide 1 (GLP-1) and Peptide YY (PYY), 2 days before and 3, 7, 14 and 28 days after surgery. RYGB decreased body weight and increased plasma GLP-1 in both SD and ZDF rats while decreasing plasma insulin and glucose in ZDF rats starting from the first week. Compared to SHAM groups, both SD-RYGB and ZDF-RYGB groups started to have increases in plasma total BAs in the second week, which might not contribute to early post-surgery metabolic changes. While there was no significant difference in fecal BA excretion between SD-RYGB and SD-SHAM groups, the ZDF-RYGB group had a transient 4.2-fold increase (P<0.001) in 24-hour fecal BA excretion on post-operative day 3 compared to ZDF-SHAM, which paralleled a significant increase in plasma PYY. Ratios of plasma and fecal cholic acid/chenodeoxycholic acid derived BAs were decreased in RYGB groups. In addition, tissue mRNA expression analysis suggested early intestinal BA reabsorption and potentially reduced hepatic cholic acid production in RYGB groups. In summary, we present novel data on RYGB-mediated changes in BA metabolism to further understand the role of BAs in RYGB-induced metabolic effects in humans.

Topics: Animals; Bile Acids and Salts; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Disease Models, Animal; Gastric Bypass; Gastric Inhibitory Polypeptide; Gene Expression Profiling; Glucagon-Like Peptide 1; Insulin; Organ Specificity; Peptide YY; Rats

Cardiovascular disease remains a burden for Westernized countries. Peptide YY (PYY) raises blood pressure, yet its role has not yet been determined in diseased arteries. This study aimed at identifying PYY and eNOS in diseased blood vessels and to determine which blood vessels respond to PYY. New Zealand White rabbits were fed an atherogenic diet (n = 6, 0.5% cholesterol + 1% methionine + 5% peanut oil) and control animals fed a normal diet (n = 6) for 4 weeks. Immunohistochemistry was used to determine the localization of PYY and eNOS in the aorta. The aorta, carotid, renal, iliac, inferior mesenteric, and renal interlobular arteries were removed, mounted in organ baths, and subjected to doses of PYY (10(-9) -10(-7) mol/L) and then acetylcholine (10(-6) mol/L). Immunohistochemistry of the aorta shows PYY staining in plaque macrophages, smooth muscle cells and endothelium, and these cells co-expressed eNOS. PYY caused a minor vasoconstrictive response in all blood vessels studied but was blunted in arteries from control animals. Acetylcholine caused relaxation of PYY constricted blood vessels. This data clearly shows that PYY is present in atherosclerotic plaque and is a minor constrictor of the vasculature tree. Further studies aimed at understanding the role of PYY in cardiovascular disease are warranted.

Topics: Animals; Arteries; Atherosclerosis; Disease Models, Animal; Endothelium, Vascular; Male; Organ Culture Techniques; Peptide YY; Rabbits; Vasoconstriction

Kainate-induced seizures constitute a model of temporal lobe epilepsy where prominent changes are observed in the hippocampal neuropeptide Y (NPY) system. However, little is known about the functional state and signal transduction of the NPY receptor population resulting from kainate exposure. Thus, in this study, we explored functional NPY receptor activity in the mouse hippocampus and neocortex after kainate-induced seizures using NPY-stimulated [(35) S]GTPγS binding. Moreover, we also studied levels of [(125) I]-peptide YY (PYY) binding and NPY, Y1, Y2, and Y5 receptor mRNA in these kainate-treated mice. Functional NPY binding was unchanged up to 12 h post-kainate, but decreased significantly in all hippocampal regions after 24 h and 1 week. Similarly, a decrease in [(125) I]-PYY binding was found in the dentate gyrus (DG) 1 week post-kainate. However, at 2 h, 6 h, and 12 h, [(125) I]-PYY binding was increased in all regions, and in the CA1 also at 24 h post-kainate. NPY mRNA levels were prominently increased in hippocampal regions, reaching maximum at 12 and 24 h. Y1 and Y5 mRNA levels were lowered in the DG at 24 and 2 h, respectively, while Y2 mRNA levels were elevated at 24 h in the DG and CA3. This study confirms rat kainate studies by showing pronounced adaptive changes in the mouse hippocampus both with regard to NPY synthesis and NPY receptor synthesis and binding, which may contribute to regulating neuronal seizure susceptibility after kainate. However, the potential seizure-suppressant effects of increased NPY gene expression at late time points post-kainate could be attenuated by the novel finding of reduced NPY-receptor G-protein activation.

Topics: Animals; Autoradiography; Disease Models, Animal; Epilepsy, Temporal Lobe; Guanosine 5'-O-(3-Thiotriphosphate); Hippocampus; Kainic Acid; Male; Mice; Neocortex; Neuropeptide Y; Peptide YY; Receptors, Neuropeptide Y; RNA, Messenger; Seizures; Time Factors

Cholecystokinin (CCK)-induced suppression of feeding is mediated by vagal sensory neurons that are destroyed by the neurotoxin capsaicin (CAP). Here we determined whether CAP-sensitive neurons mediate anorexic responses to intravenous infusions of gut hormones peptide YY-(3-36) [PYY-(3-36)] and glucagon-like peptide-1 (GLP-1). Rats received three intraperitoneal injections of CAP or vehicle (VEH) in 24 h. After recovery, non-food-deprived rats received at dark onset a 3-h intravenous infusion of CCK-8 (5, 17 pmol·kg⁻¹·min⁻¹), PYY-(3-36) (5, 17, 50 pmol·kg⁻¹·min⁻¹), or GLP-1 (17, 50 pmol·kg⁻¹·min⁻¹). CCK-8 was much less effective in reducing food intake in CAP vs. VEH rats. CCK-8 at 5 and 17 pmol·kg⁻¹·min⁻¹ reduced food intake during the 3-h infusion period by 39 and 71% in VEH rats and 7 and 18% in CAP rats. In contrast, PYY-(3-36) and GLP-1 were similarly effective in reducing food intake in VEH and CAP rats. PYY-(3-36) at 5, 17, and 50 pmol·kg⁻¹·min⁻¹ reduced food intake during the 3-h infusion period by 15, 33, and 70% in VEH rats and 13, 30, and 33% in CAP rats. GLP-1 at 17 and 50 pmol·kg⁻¹·min⁻¹ reduced food intake during the 3-h infusion period by 48 and 60% in VEH rats and 30 and 52% in CAP rats. These results suggest that anorexic responses to PYY-(3-36) and GLP-1 are not primarily mediated by the CAP-sensitive peripheral sensory neurons (presumably vagal) that mediate CCK-8-induced anorexia.

Topics: Animals; Anorexia; Behavior, Animal; Capsaicin; Cholecystokinin; Disease Models, Animal; Energy Intake; Feeding Behavior; Glucagon-Like Peptide 1; Infusions, Intravenous; Injections, Intraperitoneal; Intestinal Mucosa; Intestine, Small; Male; Neuritis; Neurons, Afferent; Peptide Fragments; Peptide YY; Rats; Vagus Nerve; Vagus Nerve Diseases

Deoxynivalenol (DON, vomitoxin), a trichothecene mycotoxin produced by Fusarium sp. that frequently occurs in cereal grains, has been associated with human and animal food poisoning. Although a common hallmark of DON-induced toxicity is the rapid onset of emesis, the mechanisms for this adverse effect are not fully understood. Recently, our laboratory has demonstrated that the mink (Neovison vison) is a suitable small animal model for investigating trichothecene-induced emesis. The goal of this study was to use this model to determine the roles of two gut satiety hormones, peptide YY3-36 (PYY3-36) and cholecystokinin (CCK), and the neurotransmitter 5-hydroxytryptamine (5-HT) in DON-induced emesis. Following ip exposure to DON at 0.1 and 0.25mg/kg bw, emesis induction ensued within 15-30min and then persisted up to 120min. Plasma DON measurement revealed that this emesis period correlated with the rapid distribution and clearance of the toxin. Significant elevations in both plasma PYY3-36 (30-60min) and 5-HT (60min) but not CCK were observed during emesis. Pretreatment with the neuropeptide Y2 receptor antagonist JNJ-31020028 attenuated DON- and PYY-induced emesis, whereas the CCK1 receptor antagonist devezapide did not alter DON's emetic effects. The 5-HT3 receptor antagonist granisetron completely suppressed induction of vomiting by DON and the 5-HT inducer cisplatin. Granisetron pretreatment also partially blocked PYY3-36-induced emesis, suggesting a potential upstream role for this gut satiety hormone in 5-HT release. Taken together, the results suggest that both PYY3-36 and 5-HT play contributory roles in DON-induced emesis.

Topics: Animals; Antiemetics; Benzamides; Cholecystokinin; Devazepide; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Granisetron; Mink; Peptide Fragments; Peptide YY; Piperazines; Serotonin; Serotonin Antagonists; Time Factors; Trichothecenes; Vomiting

There is a growing interest in modulating gut microbiota with diet in the context of obesity. The purpose of the present study was to evaluate the dose-dependent effects of prebiotics (inulin and oligofructose) on gut satiety hormones, energy expenditure, gastric emptying and gut microbiota. Male lean and obese JCR:LA-cp rats were randomised to either of the following: lean 0 % fibre (LC), lean 10 % fibre (LF), lean 20 % fibre (LHF), obese 0 % fibre (OC), obese 10 % fibre (OF) or obese 20 % fibre (OHF). Body composition, gastric emptying, energy expenditure, plasma satiety hormone concentrations and gut microbiota (using quantitative PCR) were measured. Caecal proglucagon and peptide YY mRNA levels were up-regulated 2-fold in the LF, OF and OHF groups and 3-fold in the LHF group. Ghrelin O-acyltransferase mRNA levels were higher in obese v. lean rats and decreased in the OHF group. Plasma ghrelin response was attenuated in the LHF group. Microbial species measured in the Bacteroidetes division decreased, whereas those in the Firmicutes increased in obese v. lean rats and improved with prebiotic intake. Bifidobacterium and Lactobacillus increased in the OHF v. OC group. Bacteroides and total bacteria negatively correlated with percentage of body fat and body weight. Enterobacteriaceae increased in conjunction with glucose area under the curve (AUC) and glucagon-like peptide-1 AUC. Bacteroides and total bacteria correlated positively with ghrelin AUC yet negatively with insulin AUC and energy intake (P < 0·05). Several of the mechanisms through which prebiotics act (food intake, satiety hormones and alterations in gut microbiota) are regulated in a dose-dependent manner. The combined effects of prebiotics may have therapeutic potential for obesity.

Topics: Acyltransferases; Animals; Bacteroidetes; Disease Models, Animal; Gastrointestinal Tract; Gene Expression Regulation; Ghrelin; Glucagon-Like Peptide 1; Gram-Negative Bacteria; Gram-Positive Bacteria; Inulin; Male; Obesity; Oligosaccharides; Peptide YY; Prebiotics; Proglucagon; Random Allocation; Rats; Rats, Inbred Strains; RNA, Messenger; Satiety Response

Ileal interposition (IT), in which the distal ileum is transposed isoperistaltically into the proximal jejunum, is considered as a procedure for metabolic or antidiabetes surgery. Our aim was to study the effects of IT on glycemic control, fat metabolism, and hormonal changes in obese rats with spontaneous diabetes.. Animals were divided into either an IT or a sham (SH) group. They underwent an oral glucose tolerance test (OGTT) before and 4 and 8 weeks after the operation. All animals were killed 10 weeks after operation for analyses of tissue weight (liver, pancreas, epididymal fat, brown fat), immunoblotting of uncoupling protein-1 (UCP1) protein in brown adipose tissue (BAT), and fasting plasma levels of glucose, insulin, glucagon-like peptide (GLP)-1, peptide YY (PYY), glucose-dependent insulinotropic polypeptide (GIP), and leptin.. Body weight increased postoperatively in both groups compared with preoperative weight, but it did not differ between the 2 groups. Eight weeks postoperatively, integrated blood glucose levels during the OGTT were decreased in IT compared with SH (P < .05). Fasting plasma levels of insulin, GLP-1, and GIP did not differ between the 2 groups, but PYY levels were higher in the IT animals (P < .01). The weight of epididymal and BATs, homeostasis model assessment insulin resistance, and fasting plasma leptin levels were decreased in the IT group (P < .05). Expression of UCP1 was higher in IT than SH animals (P < .05).. These results suggest that IT improves glucose and lipid metabolism by decreasing insulin resistance and epididymal fat, and increased expression of UCP1 in BAT might be among the mechanisms responsible.

Topics: Adipose Tissue, Brown; Animals; Body Weight; Comorbidity; Diabetes Mellitus; Disease Models, Animal; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose; Ileum; Insulin Resistance; Ion Channels; Jejunum; Leptin; Lipid Metabolism; Male; Mitochondrial Proteins; Obesity; Peptide YY; Rats, Inbred OLETF; Uncoupling Protein 1

Bariatric surgical procedures, including the laparoscopic adjustable gastric band (LAGB), are currently the only effective treatments for morbid obesity, however, there is no clear understanding of the mechanisms underpinning the efficacy of LAGB. The aim of this study is to examine changes in activation of the sensory neuronal pathways and levels of circulating gut hormones associated with inflation of an AGB.. The trajectory within the central nervous system of polysynaptic projections of sensory neurons innervating the stomach was determined using the transsynaptically transported herpes simplex virus (HSV). Populations of HSV-infected neurons were present in the brainstem, hypothalamus and cortical regions associated with energy balance. An elevation of Fos protein was present within the nucleus of the solitary tract, a region of the brainstem involved in the control of food intake, following acute and chronic band inflation. Two approaches were used to test (1) the impact of inflation of the band alone (on a standard caloric background) or (2) the impact of a standard caloric meal (on the background of the inflated band) on circulating gut hormones. Importantly, there was a significant elevation of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) following oral gavage of a liquid meal in animals with pre-inflated bands. There was no impact of inflation of the band alone on circulating GLP-1, PYY or ghrelin in animals on a standard caloric background.. These data are consistent with the notion that the LAGB exerts its effects on satiety, reduced food intake and reduced body weight by the modulation of both neural and hormonal responses with the latter involving an elevation of meal-related levels of GLP-1 and PYY. These data are contrary to the view that the surgery is purely 'restrictive'.

Topics: Animals; Brain; Caloric Restriction; Disease Models, Animal; Eating; Gastric Mucosa; Gastroplasty; Ghrelin; Glucagon-Like Peptide 1; Laparoscopy; Male; Obesity, Morbid; Peptide YY; Rats; Rats, Sprague-Dawley; Satiation; Sensory Receptor Cells; Signal Transduction; Simplexvirus; Stomach; Weight Loss

This study investigated the effects of peripheral administration of ghrelin and PYY(3-36) on food intake and plasma and tissue fasting and postprandial ghrelin and PYY(3-36) levels in normal-weight (NW) and diet-induced-obese (DIO) rats.. In experiment one, NW and DIO rats received a single intraperitoneal injection of saline, PYY(3-36) or ghrelin; food intake was measured for 4 h. In experiment two, total plasma ghrelin and PYY(3-36), gastric fundus ghrelin, and ascending colon PYY(3-36) were measured either after a 20-h fast or 2 h after refeeding in NW and DIO rats by radioimmunoassay.. Compared to the NW rats, findings in the DIO rats revealed: (i) a reduced sensitivity to both the anorectic effect of exogenous PYY(3-36) and the orexigenic effect of exogenous ghrelin; (ii) the postprandial plasma ghrelin levels were significantly higher; and (iii) refeeding decreased endogenous plasma ghrelin levels by 53% in the NW rats and 39% in DIO rats. Refeeding increased the plasma PYY(3-36) level by 58% in the NW rats versus 9% in the DIO rats (P=0.003).. Compared with regular rats, DIO rats exhibit blunted responses in food intake to exogenous ghrelin and PYY(3-36). Although endogenous ghrelin and PYY(3-36) in DIO rats are not altered in the fasting state, their responses to food ingestion are blunted in comparison with regular rats.

Topics: Animals; Blood Glucose; Body Weight; Colon; Diet; Disease Models, Animal; Eating; Fasting; Gastric Fundus; Ghrelin; Injections, Intraperitoneal; Male; Obesity; Peptide Fragments; Peptide YY; Postprandial Period; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Time Factors

Intrauterine growth restriction (IUGR) is associated with a substantially greater incidence of metabolic syndrome in adulthood. Animal studies have shown that IUGR offspring are hyperphagic during the early postnatal period and therefore exhibit obesity. The molecular mechanisms underlying food intake regulation in the gastrointestinal tract have not been clarified in IUGR. In the present study, we utilized a rat model of IUGR by restricting the food intake of the mother (50% of the normal intake, ad libitum; FR group) from day 7 of gestation until delivery. Pups from undernourished mothers were fostered by control mothers. We examined the food intake and assessed the gene expressions of ghrelin, peptide YY (PYY), and cholecystokinin (CCK) in the alimentary tract of male newborns (postnatal day1) and adult offspring (age, 7 months). Compared to the offspring whose mothers received the standard diet ad libitum (CON offspring), FR offspring were hyperphagic from the weaning time until the end of the experiment, and resulted in a heavier final weight. Both newborn and adult FR offspring had higher ghrelin gene expression in the stomach and higher ghrelin plasma levels than did the controls. Although the gastrointestinal gene expressions and plasma levels of the anorexic peptides, PYY and CCK, were elevated in the FR newborns, they decreased in the FR adults. Our findings suggest that the altered gene expressions of orexigenic and anorexigenic gut peptides in the gastrointestinal tract in the maternal undernutrition-induced IUGR offspring provide a potential mechanism to explain hyperphagia and obesity seen in these offspring.

Topics: Adult; Animals; Animals, Newborn; Body Weight; Cholecystokinin; Disease Models, Animal; Eating; Female; Fetal Growth Retardation; Gastrointestinal Tract; Gene Expression; Gene Expression Regulation, Developmental; Ghrelin; Humans; Hyperphagia; Male; Peptide YY; Rats; Rats, Sprague-Dawley; Up-Regulation

Peptide YY (PYY)(3-36), a neuropeptide Y (NPY) Y2 receptor agonist, is a powerful inhibitor of intestinal secretion. Based on this anti-secretory effect, NPY Y2 receptor agonists may be useful as novel anti-diarrheal agents, but anti-diarrheal efficacy has yet to be determined. We therefore examined the anti-diarrheal efficacy of PYY(3-36) and a selective Y2 receptor agonist, N-acetyl-[Leu28, Leu31]-NPY(24-36), in experimental mouse models of diarrhea. Intraperitoneal administration of PYY(3-36) (0.01-1mg/kg) and N-acetyl-[Leu28, Leu31]-NPY(24-36) (10mg/kg) significantly inhibited diarrhea (increase in wet fecal weight and diarrhea score) induced by dimethyl-prostaglandin E2, 5-hydroxytryptamine, and castor oil. Anti-diarrheal activities of PYY(3-36) and N-acetyl-[Leu28, Leu31]-NPY(24-36) were comparable to the effects of loperamide (1mg/kg), a widely used anti-diarrheal drug. To clarify the anti-diarrheal mechanisms of NPY Y2 receptor agonists, we investigated the effects of PYY(3-36) and N-acetyl-[Leu28, Leu31]-NPY(24-36) on intestinal fluid secretion and colonic transit. PYY(3-36) (1mg/kg) and N-acetyl-[Leu28, Leu31]-NPY(24-36) (10mg/kg) significantly reduced dimethyl-prostaglandin E2-induced intestinal fluid accumulation in conscious mice, suggesting that NPY Y2 receptor agonists inhibit diarrhea, at least in part, by reducing intestinal secretion. In addition, PYY(3-36) (0.01-1mg/kg) and N-acetyl-[Leu28, Leu31]-NPY(24-36) (10mg/kg) potently inhibited normal fecal output, suggesting that NPY Y2 receptor activation inhibits colonic motor function and NPY Y2 receptor agonists inhibit diarrhea partly by slowing colonic transit. These results indicate that NPY Y2 receptor agonists inhibit diarrhea in mice by not only reducing intestinal fluid secretion, but also slowing colonic transit, and illustrate the therapeutic potential of NPY Y2 receptor agonists as effective treatments for diarrhea.

Topics: Animals; Antidiarrheals; Diarrhea; Disease Models, Animal; Gastrointestinal Transit; Humans; Intestinal Secretions; Loperamide; Male; Mice; Mice, Inbred C57BL; Peptide Fragments; Peptide YY; Receptors, Neuropeptide Y

The lack of potent, selective, brain penetrant Y(2) receptor antagonists has hampered in vivo functional studies of this receptor.. Here, we report the in vitro and in vivo characterization of JNJ-31020028 (N-(4-{4-[2-(diethylamino)-2-oxo-1-phenylethyl]piperazin-1-yl}-3-fluorophenyl)-2-pyridin-3-ylbenzamide), a novel Y(2) receptor antagonist.. The affinity of JNJ-31020028 was determined by inhibition of the PYY binding to human Y(2) receptors in KAN-Ts cells and rat Y(2) receptors in rat hippocampus. The functional activity was determined by inhibition of PYY-stimulated calcium responses in KAN-Ts cells expressing a chimeric G protein Gqi5 and in the rat vas deferens (a prototypical Y(2) bioassay). Ex vivo receptor occupancy was revealed by receptor autoradiography. JNJ-31020028 was tested in vivo with microdialysis, in anxiety models, and on corticosterone release.. JNJ-31020028 bound with high affinity (pIC(50) = 8.07 +/- 0.05, human, and pIC(50) = 8.22 +/- 0.06, rat) and was >100-fold selective versus human Y(1), Y(4), and Y(5) receptors. JNJ-31020028 was demonstrated to be an antagonist (pK(B) = 8.04 +/- 0.13) in functional assays. JNJ-31020028 occupied Y(2) receptor binding sites (approximately 90% at 10 mg/kg) after subcutaneous administration in rats. JNJ-31020028 increased norepinephrine release in the hypothalamus, consistent with the colocalization of norepinephrine and neuropeptide Y. In a variety of anxiety models, JNJ-31020028 was found to be ineffective, although it did block stress-induced elevations in plasma corticosterone, without altering basal levels, and normalized food intake in stressed animals without affecting basal food intake.. These results suggest that Y(2) receptors may not be critical for acute behaviors in rodents but may serve modulatory roles that can only be elucidated under specific situational conditions.

Topics: Administration, Oral; Animals; Anorexia; Anti-Anxiety Agents; Anxiety; Autoradiography; Benzamides; Binding, Competitive; Calcium; CHO Cells; Corticosterone; Cricetinae; Cricetulus; Disease Models, Animal; Dose-Response Relationship, Drug; Eating; Feeding Behavior; Hippocampus; Humans; Injections, Intravenous; Injections, Subcutaneous; Male; Mice; Microdialysis; Norepinephrine; Peptide YY; Permeability; Piperazines; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Neuropeptide Y; Transfection; Vas Deferens

The main reason why enterocyte proliferative effects of peptide YY (PYY) have not been detected in rats undergoing massive small intestinal resection after feeding may have been the background activity of markedly increased endogenous PYY released from L cells in the distal gut in response to the intraluminal nutrients. The purpose of the present study was to evaluate the effects of PYY on enterocyte proliferation in a rat model of distal bowel resection (DBR) with total enteral nutrition (TEN). Male, adult Sprague-Dawley rats were assigned into three experimental groups: sham rats underwent bowel transection and reanastomosis, DBR rats underwent the resection of 40 cm distal small intestine and colon, and DBR-PYY rats underwent distal bowel resection as above, and were treated with PYY(1-36) from day 2 to day 14 postoperatively. During days 2-14 postoperatively, all animals received isocaloric TEN. At the endpoints, plasma PYY levels and parameters of enterocyte proliferation were determined. Compared with the sham group, DBR rats demonstrated a significant decrease in plasma PYY levels, and a significant increase in intestinal bowel and mucosal weight, mucosal DNA and protein content, villus height and crypt depth, and crypt cell proliferation index. Administration of PYY (DBR-PYY group) led to a significant increase in plasma PYY levels, intestinal bowel and mucosal weight, mucosal DNA and protein content, villus height and crypt depth, and crypt cell proliferation index in comparison with the DBR untreated group. We conclude that administration of PYY increases the plasma PYY levels, and PYY induces enterocyte proliferation with TEN after distal bowel resection.

Topics: Animals; Cell Proliferation; Disease Models, Animal; Enteral Nutrition; Enterocytes; Follow-Up Studies; Intestine, Small; Male; Peptide YY; Postoperative Period; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Short Bowel Syndrome; Treatment Outcome

Chronic administration of anorexigenic substances to experimental animals by injections or continuous infusion typically produces either no effect or a transient reduction in food intake and body weight. Our aim here was to identify an intermittent dosing strategy for intraperitoneal infusion of peptide YY(3-36) [PYY(3-36)] that produces a sustained reduction in daily food intake and adiposity in diet-induced obese rats. Rats (665+/-10 g body wt, 166+/-7 g body fat) with intraperitoneal catheters tethered to infusion swivels had free access to a high-fat diet. Vehicle-treated rats (n=23) had relatively stable food intake, body weight, and adiposity during the 9-wk test period. None of 15 PYY(3-36) dosing regimens administered in succession to a second group of rats (n=22) produced a sustained 15-25% reduction in daily food intake for >5 days, although body weight and adiposity were reduced across the 9-wk period by 12% (594+/-15 vs. 672+/-15 g) and 43% (96+/-7 vs. 169+/-9 g), respectively. The declining inhibitory effect of PYY(3-36) on daily food intake when the interinfusion interval was >or=3 h appeared to be due in part to an increase in food intake between infusions. The declining inhibitory effect of PYY(3-36) on daily food intake when the interinfusion interval was <3 h suggested possible receptor downregulation and tolerance to frequent PYY(3-36) administration; however, food intake significantly increased when PYY(3-36) treatments were discontinued for 1 day following apparent loss in treatment efficacies. Together, these results demonstrate the development of a potent homeostatic response to increase food intake when PYY(3-36) reduces food intake and energy reserves in diet-induced obese rats.

Topics: Adiposity; Animals; Appetite Depressants; Behavior, Animal; Body Weight; Dietary Fats; Disease Models, Animal; Drug Administration Schedule; Eating; Homeostasis; Infusions, Parenteral; Male; Obesity; Peptide Fragments; Peptide YY; Rats; Rats, Sprague-Dawley; Time Factors

Peptide YY (PYY) is produced by endocrine cells in the lower gastrointestinal tract. The main functions of PYY are antisecretory effects in the colon and inhibition of gastrointestinal motility. We chose PYY as an index of the intrinsic factor in diarrhea and examined the influence of changes induced in a diarrhea rat model by administration of 4 types of laxative and loperamide hydrochloride (loperamide) as an agent for the treatment of diarrhea. A specific radioimmunoassay was performed to determine plasma and intestinal mucosal PYY concentrations. PYY in the rat intestinal tissue extract was distributed at a high density in the lower intestinal mucosa. In the diarrhea rat model, multiple changes in PYY concentrations in the intestinal mucosa and plasma were observed. In rats administered castor oil and sodium picosulfate, the intestinal mucosal PYY levels significantly decreased in a dose-dependent manner. Plasma PYY levels significantly decreased only in rats administered magnesium citrate. Next, we examined the influence of loperamide administration on the intestinal mucosa and plasma PYY concentrations in these rats. Loperamide administration resulted in multiple changes in plasma and intestinal mucosa PYY concentrations, along with an improvement in the diarrhea. Our research showed that the endocrine hormone PYY is involved in the onset of diarrhea, the course of the condition, and the manifestation of medicinal effects in the lower intestine.

Topics: Animals; Antidiarrheals; Diarrhea; Disease Models, Animal; Dose-Response Relationship, Drug; Gastrointestinal Motility; Intestinal Mucosa; Loperamide; Peptide YY; Radioimmunoassay; Rats; Rats, Wistar

Few studies have reported the changes in the peptide YY (PYY) levels in the intestinal tissue of rats with ulcerative colitis (UC) following oral administration of mesalazine and prednisolone. We investigated the effects of these drugs on the intestinal mucosal PYY levels in a rat model of UC. We confirmed that the PYY levels in the rat intestinal mucosal tissue were high in the lower intestinal tract. The leukocyte count and hemoglobin levels approached the normal values after administering mesalazine or prednisolone to rats treated with 3% dextran sulfate sodium (DSS). The PYY levels in the caecum and colon decreased significantly after administering DSS but increased when mesalazine was administered in a tissue-specific manner. Unlike mesalazine, the PYY levels increased in the ileum in addition to the colon and rectum after administering prednisolone. However, neither of the drugs induced any changes in the plasma PYY levels. These findings indicate that changes in the intestinal tissue PYY levels may be partially involved in the improvement of DSS-induced UC in rats following the administration of these drugs.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Colitis, Ulcerative; Dextran Sulfate; Disease Models, Animal; Intestinal Mucosa; Male; Mesalamine; Peptide YY; Prednisolone; Rats; Rats, Wistar

To characterize the gastrointestinal tract at the onset and in well-established obesity.. Lean (+/?) and obese (cp/cp) male JCR:LA-cp rats lacking a functional leptin receptor were killed at 3.5 weeks and 9 months of age and plasma concentrations of satiety hormones determined. The small intestine, colon, and stomach were measured, weighed, and mRNA levels of satiety genes quantified.. At the onset of obesity, obese rats had greater intestine, colon, and liver mass when adjusted for body weight compared to lean rats. Conversely, adult rats with established obesity had lower intestine and colon mass and length after adjustment for body weight. Early changes in gene expression included decreased ghrelin mRNA levels in stomach and increased peptide YY (PYY) mRNA levels in duodenum of young obese rats. After massive accumulation of adipose tissue had occurred, adult obese rats had increased proglucagon and ghrelin mRNA expression in the proximal intestine. In the distal small intestine, obese rats had lower proglucagon, ghrelin, and PYY mRNA levels. Finally, at the onset and in well-established obesity, obese rats had higher plasma insulin, amylin, glucagon like peptide-1 (GLP-1), and PYY, a finding, with the exception of insulin, unique to this model. Plasma total ghrelin levels were significantly lower at the onset of obesity and established obesity compared to the lean rats.. Several defects are manifested in the obese gut early on in the disease before the accumulation of large excesses of body fat and represent potential targets for early intervention in obesity.

Topics: Amyloid; Animals; Body Weight; Colon; Disease Models, Animal; Energy Metabolism; Female; Gastric Mucosa; Gastrointestinal Hormones; Ghrelin; Glucagon-Like Peptide 1; Insulin; Insulin Secretion; Intestine, Small; Islet Amyloid Polypeptide; Liver; Male; Obesity; Peptide YY; Proglucagon; Rats; Rats, Inbred Strains; RNA, Messenger; Satiety Response; Stomach

A couple of papers indicate that patients with depression show a decrease in serum neuropeptide Y (NPY). To study the role of NPY in depression, we examined the effects of infusion of NPY into the hippocampus of learned helplessness (LH) rats (an animal model of depression). Infusion of NPY into the cerebral ventricle of LH rats showed antidepressant-like effects. Infusion of NPY into the CA3 region, but not the dentate gyrus (DG), produced antidepressant-like effects in the LH paradigm. Infusion of NPY did not affect locomotor activity or aversive learning ability. Coadministration of BIBO3304 (a Y1 receptor antagonist) with NPY to the CA3 region blocked the antidepressant-like effects of NPY, whereas coadministration of NPY with BIIE0246 (a Y2 receptor antagonist) to the CA3 region failed to block antidepressant-like effects. Furthermore, infusions of [Leu(31) Pro(34)]PYY (a Y1 and Y5 receptor agonist) alone and BIIE0246 alone into the CA3 region produced the antidepressant-like effects in LH rats. These results suggest that infusion of NPY into the CA3 region of hippocampus of LH rats produces antidepressant-like activity through Y1 receptors and attenuating effects through Y2 receptors.

Topics: Animals; Antidepressive Agents; Arginine; Avoidance Learning; Behavior, Animal; Benzazepines; Depression; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Exploratory Behavior; Helplessness, Learned; Hippocampus; Injections, Intraventricular; Male; Neuropeptide Y; Peptide YY; Rats; Rats, Sprague-Dawley; Reaction Time; Receptors, G-Protein-Coupled; Receptors, Neuropeptide

Peptide YY (PYY) and pancreatic polypeptide (PPY) are members of the neuropeptide Y peptide family. The neuropeptide Y receptor signaling pathway has been implicated in a number of physiologic processes, including the regulation of energy balance and bone mass. To investigate the contribution of endogenous PYY and PPY to these processes, we generated both Pyy- and Ppy-deficient mice.. Pyy(-/-) and Ppy(-/-) mice and their respective wild-type littermates were studied from 8 weeks to 9 months of age. Food intake, metabolic parameters, and locomotor activity were monitored using indirect calorimetry. Body composition and bone parameters were analyzed using dual energy x-ray absorptiometry, histomorphometry, and vertebral compression testing.. Studies in these mice showed an osteopenic phenotype specific to the Pyy-deficient line, which included a reduction in trabecular bone mass and a functional deficit in bone strength. Furthermore, female Pyy(-/-) mice showed a greater sensitivity to ovariectomy-induced bone loss compared with wild-type littermates. No food intake or metabolic phenotype was apparent in male or female Pyy(-/-) mice on standard chow. However, female Pyy(-/-) mice on a high-fat diet showed a greater propensity to gain body weight and adiposity. No metabolic or osteopenic phenotype was observed in Ppy-deficient mice.. These results indicate that endogenous PYY plays a critical role in regulating bone mass. In comparison, its role in regulating body weight is minor and is confined to situations of high-fat feeding.

Topics: Absorptiometry, Photon; Adiposity; Animals; Body Composition; Body Weight; Bone and Bones; Bone Density; Bone Diseases, Metabolic; Dietary Fats; Disease Models, Animal; Energy Metabolism; Female; Gene Deletion; Male; Mice; Mice, Transgenic; Ovariectomy; Peptide YY; Phenotype; Spine

A major problem in treating obesity is high rates of relapse to maladaptive food-taking habits during dieting. This relapse is often provoked by acute re-exposure to palatable food, food-associated cues, or stress. We used a reinstatement model, commonly used to study relapse to abused drugs, to explore the effect of peptide YY3-36 (PYY3-36) on reinstatement of high-fat (35%, 45 mg pellets) food seeking induced by acute exposure to the pellets (pellet priming), a cue previously associated with pellet delivery (pellet cue), or yohimbine (2 mg/kg, a pharmacological stressor). Rats were placed on a restricted diet (16 g of chow per day) and lever-pressed for the pellets for 9-12 sessions (6 h/d, every 48 h); pellet delivery was paired with a tone-light cue. They were then given 10-20 extinction sessions wherein lever presses were not reinforced with the pellets and subsequently tested for reinstatement of food seeking. Systemic PYY3-36 injections (100-200 microg/kg) decreased pellet priming- and pellet cue-induced reinstatement of food seeking but not yohimbine-induced reinstatement. Arcuate nucleus (Arc) injections of PYY3-36 (0.4 microg per side) decreased pellet priming-induced reinstatement. The attenuation of pellet priming-induced reinstatement by systemic PYY3-36 was reversed by systemic (2 mg/kg) but not Arc (0.5 microg per side) injections of the Y2 receptor antagonist BIIE0246. Arc PYY3-36 injections did not decrease pellet cue-induced reinstatement. Finally, systemic PYY3-36 injections had minimal effects on ongoing food self-administration or heroin priming- or heroin cue-induced reinstatement of heroin seeking. These data identify an effect of systemic PYY3-36 on relapse to food seeking that is independent of Y2 receptor activation in Arc and suggest that PYY3-36 should be considered for the treatment of relapse to maladaptive food-taking habits during dieting.

Topics: Animals; Dietary Fats; Disease Models, Animal; Feeding Behavior; Male; Obesity; Peptide Fragments; Peptide YY; Rats; Rats, Long-Evans; Secondary Prevention

The gut hormone peptide YY (PYY) was recently proposed to comprise an endogenous satiety factor. We have studied acute anorectic functions of PYY(3-36) in mice and rats, as well as metabolic effects of chronic PYY(3-36) administration to diet-induced obese (DIO) mice and rats. A single intraperitoneal injection of PYY(3-36) inhibited food intake in mice, but not in rats. We next investigated the effects of increasing doses (100, 300, and 1,000 microg.kg-1.day-1) of PYY(3-36) administered subcutaneously via osmotic minipumps on food intake and body weight in DIO C57BL/6J mice. Whereas only the highest dose (1,000 microg.kg-1.day-1) of PYY(3-36) significantly reduced food intake over the first 3 days, body weight gain was dose dependently reduced, and on day 28 the group treated with 1,000 microg.kg-1.day-1 PYY(3-36) weighed approximately 10% less than the vehicle-treated group. Mesenteric, epididymal, retroperitoneal, and inguinal fat pad weight was dose dependently reduced. Subcutaneous administration of PYY(3-36) (250 and 1,000 microg.kg-1.day-1) for 28 days reduced body weight and improved glycemic control in glucose-intolerant DIO rats. Neither 250 nor 1,000 microg/kg PYY(3-36) elicited a conditioned taste aversion in male rats.

Topics: Animals; Blood Glucose; Body Weight; Disease Models, Animal; Drug Administration Routes; Eating; Feeding Behavior; Insulin; Male; Mice; Mice, Inbred C57BL; Motor Activity; Obesity; Peptide Fragments; Peptide YY; Rats; Rats, Sprague-Dawley; Rats, Wistar; Rodentia; Taste

Dietary protein enhances satiety and promotes weight loss, but the mechanisms by which appetite is affected remain unclear. We investigated the role of gut hormones, key regulators of ingestive behavior, in mediating the satiating effects of different macronutrients. In normal-weight and obese human subjects, high-protein intake induced the greatest release of the anorectic hormone peptide YY (PYY) and the most pronounced satiety. Long-term augmentation of dietary protein in mice increased plasma PYY levels, decreased food intake, and reduced adiposity. To directly determine the role of PYY in mediating the satiating effects of protein, we generated Pyy null mice, which were selectively resistant to the satiating and weight-reducing effects of protein and developed marked obesity that was reversed by exogenous PYY treatment. Our findings suggest that modulating the release of endogenous satiety factors, such as PYY, through alteration of specific diet constituents could provide a rational therapy for obesity.

Topics: Animals; Appetite Regulation; Body Weight; Dietary Proteins; Disease Models, Animal; Enteroendocrine Cells; Feeding Behavior; Food, Formulated; Gastrointestinal Tract; Hormones; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Obesity; Peptide YY; Satiety Response; Up-Regulation

Pancreatic polypeptide (PP) belongs to a family of peptides including neuropeptide Y and peptide YY. We examined the role of PP in the regulation of body weight as well as the therapeutic potential of PP.. We measured food intake, gastric emptying, oxygen consumption, and gene expression of hypothalamic neuropeptides, gastric ghrelin, and adipocytokines in mice after administering PP intraperitoneally. Peptide gene expression was also examined in PP-overexpressing mice. Vagal and sympathetic nerve activities were recorded after intravenous administration in rats. Effects of repeated administrations of PP on energy balance and on glucose and lipid metabolism were examined in both ob/ob obese mice and fatty liver Shionogi (FLS)-ob/ob obese mice.. Peripherally administered PP induced negative energy balance by decreasing food intake and gastric emptying while increasing energy expenditure. The mechanism involved modification of expression of feeding-regulatory peptides (decrease in orexigenic neuropeptide Y, orexin, and ghrelin along with an increase in anorexigenic urocortin) and activity of the vagovagal or vagosympathetic reflex arc. PP reduced leptin in white adipose tissue and corticotropin-releasing factor gene expression. The expression of gastric ghrelin and hypothalamic orexin was decreased in PP-overexpressing mice. Repeated administrations of PP decreased body weight gain and ameliorated insulin resistance and hyperlipidemia in both ob/ob obese mice and FLS-ob/ob obese mice. Liver enzyme abnormalities in FLS-ob/ob obese mice were also ameliorated by PP.. These observations indicate that PP may influence food intake, energy metabolism, and the expression of hypothalamic peptides and gastric ghrelin.

Topics: Animals; Body Weight; Carrier Proteins; Disease Models, Animal; Eating; Energy Metabolism; Gastric Emptying; Gene Expression; Ghrelin; Hypothalamus; Injections, Intraperitoneal; Intracellular Signaling Peptides and Proteins; Male; Mice; Neuropeptide Y; Neuropeptides; Obesity; Orexins; Oxygen Consumption; Pancreatic Polypeptide; Peptide Hormones; Peptide YY

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.

Topics: Animals; Diabetes Mellitus, Type 2; Disease Models, Animal; Enteroendocrine Cells; Gastrointestinal Transit; Glucagon-Like Peptides; Humans; Image Processing, Computer-Assisted; Mice; Mice, Inbred BALB C; Mice, Obese; Peptide YY; Secretin; Serotonin

The aim of the study was to investigate the effect of ileojejunal transposition, in which the distal ileum is interposed isoperistaltically into the proximal jejunum, on gastric emptying, gastrointestinal motility, and fecal water content in dogs with total colectomy.. Dogs were divided into three groups: dogs with intact colons (control), total colectomy alone (sham operated group), or total colectomy and ileojejunal transposition group. The alimentary tract was reconstructed by ileal J-pouch-rectal anastomosis. Gastric emptying was measured by a validated freeze-drying method, and gastrointestinal motility was measured by strain gauge force transducers. Plasma peptide YY was measured by specific radioimmunoassay. Fecal water content was measured in dogs with total colectomy.. Gastric emptying of solids in the ileojejunal transposition group was delayed longer than 120 minutes after meal ingestion compared with that in the sham operated group. The duration of the digestive state was prolonged in the ileojejunal transposition group, only when compared with the control group. Plasma peptide YY was increased in the ileojejunal transposition group compared with the sham operated group. Fecal water content was decreased in the ileojejunal transposition group compared with the sham operated group.. Ileojejunal transposition delays gastric emptying of solids and decreases fecal water content in dogs with total colectomy, indicating that ileojejunal transposition might be able to improve intractable watery diarrhea after total colectomy.

Topics: Animals; Colectomy; Colon; Diarrhea; Disease Models, Animal; Dogs; Feces; Gastric Emptying; Gastrointestinal Motility; Ileum; Jejunoileal Bypass; Jejunum; Peptide YY; Time Factors

Whether or not peptide YY (PYY)-induced hyperphagia is modified by the histaminergic system in the brain is not yet known.. We investigated the effect on feeding of intracerebroventricular (ICV) administration of a specific histamine H3 receptor antagonist prior to ICV administration of PYY in rats.. PYY (1, 3, and 10 micrograms/10 microL) strongly induced feeding behavior in a dose-dependent manner in sated rats. The 4-hour food intake induced by 3 micrograms/10 microL of PYY was equal to that induced by a 16-hour fast. The ICV administration of thioperamide (40.8, 122.4, and 408.5 micrograms/10 microL) did not suppress the 4-hour food intake induced by 16-hour fasting; however, thioperamide produced dose-dependent and strong inhibition of hyperphagia induced by a 3-microgram dose of PYY.. These results suggest that the effect of PYY on appetite is different than that induced by fasting and may involve a histaminergic mechanism.

Topics: Analysis of Variance; Animals; Appetite Regulation; Bulimia; Disease Models, Animal; Dose-Response Relationship, Drug; Drinking; Eating; Fasting; Histamine Antagonists; Hyperphagia; Injections, Intraventricular; Male; Peptide YY; Piperidines; Rats; Rats, Wistar; Receptors, Histamine H3; Satiation; Time Factors

Receptor autoradiography with the Y2 receptor ligand 125I-peptide YY3-36 and in situ hybridization were applied to investigate changes in neuropeptide tyrosine-Y2 receptor expression after kainic acid-induced recurrent seizures in the rat hippocampus. In the strata oriens and radiatum of CA1 to CA3, which are densely innervated by Y2 receptor-bearing Schaffer collateral terminals, a transient 2-fold increase in Y2 receptor affinity was observed after 4-12 hr, with a later slow decline. No change was seen in Y2 mRNA expression in CA2/CA3 pyramidal cells, from which Schaffer collaterals originate. Conversely, in granule cells of the dentate gyrus, markedly elevated Y2 mRNA concentrations were observed (by 740% in the dorsal hippocampus) 24-48 hr after kainate injection. At the same time, a marked and lasting (up to 6 months) increase in the number of Y2 receptor sites (by 800%) was seen in the dentate hilus, which is innervated densely by mossy fibers. The early increase in Y2 receptor affinity in Schaffer collaterals was accompanied by a 60% decrease in the EC50 of peptide YY3-36 in inhibiting K(+)-stimulated glutamate release in hippocampal slices from kainic acid-treated rats. Our data indicate transient up-regulation of presynaptic Y2 receptors in Schaffer collaterals by a change in affinity and a permanent de novo synthesis of presynaptic Y2 receptors in granule cells/mossy fibers. These changes may cause augmented presynaptic inhibition of glutamate release from different hippocampal sites and, in conjunction with increased concentrations of neuropeptide tyrosine in mossy fibers, may represent an endogenous reactive anticonvulsant mechanism.

Topics: Animals; Autoradiography; Behavior, Animal; Binding, Competitive; Disease Models, Animal; Epilepsy, Temporal Lobe; Excitatory Amino Acid Agonists; Glutamic Acid; In Situ Hybridization; Iodine Radioisotopes; Kainic Acid; Kinetics; Male; Mossy Fibers, Hippocampal; Peptide Fragments; Peptide YY; Pyramidal Cells; Rats; Rats, Sprague-Dawley; Receptors, Neuropeptide Y; RNA, Messenger; Up-Regulation