peptide-yy and Anorexia

The changes in PYY in several gastrointestinal disorders and their possible clinical implications are reviewed. The changes in PYY seem to be an adaptive response to alterations in the patho-physiological condition caused by the disease. This becomes evident in gastrointestinal disorders such as diabetes gastroenteropathy, inflammatory bowel diseases, celiac disease, systemic sclerosis and post-intestinal resection state. On the other hand, changes in PYY in chronic idiopathic slow transit constipation appear to be primary and could be one of the etiologic factors of the disease. PYY does not seem to be involved in colorectal carcinoma. Although gastrointestinal dysmotility in neuro-muscular diseases is evident, PYY is not affected. The changes in PYY in gastrointestinal disorders could be beneficial in clinical practice. Thus, in cases where an increase or decrease in PYY is desirable, a diet that increases or decreases PYY synthesis and release can be followed, or a receptor agonist or antagonist can be utilized.

Topics: Anorexia; Celiac Disease; Colorectal Neoplasms; Gastrointestinal Diseases; Humans; Inflammatory Bowel Diseases; Neuromuscular Diseases; Peptide YY

This study investigated the effects of continuous moderate-intensity exercise (MIE) and high-intensity interval exercise (HIIE) in combination with short exposure to hypoxia on appetite and plasma concentrations of acylated ghrelin, peptide YY (PYY), and glucagon-like peptide-1 (GLP-1). Twelve healthy males completed four, 2.6 h trials in a random order: (1) MIE-normoxia, (2) MIE-hypoxia, (3) HIIE-normoxia, and (4) HIIE-hypoxia. Exercise took place in an environmental chamber. During MIE, participants ran for 50 min at 70% of altitude-specific maximal oxygen uptake (V˙O2max) and during HIIE performed 6 × 3 min running at 90% V˙O2max interspersed with 6 × 3 min active recovery at 50% V˙O2max with a 7 min warm-up and cool-down at 70% V˙O2max (50 min total). In hypoxic trials, exercise was performed at a simulated altitude of 2980 m (14.5% O2). Exercise was completed after a standardised breakfast. A second meal standardised to 30% of participants' daily energy requirements was provided 45 min after exercise. Appetite was suppressed more in hypoxia than normoxia during exercise, post-exercise, and for the full 2.6 h trial period (linear mixed modelling, p <0.05). Plasma acylated ghrelin concentrations were lower in hypoxia than normoxia post-exercise and for the full 2.6 h trial period (p <0.05). PYY concentrations were higher in HIIE than MIE under hypoxic conditions during exercise (p = 0.042). No differences in GLP-1 were observed between conditions (p > 0.05). These findings demonstrate that short exposure to hypoxia causes suppressions in appetite and plasma acylated ghrelin concentrations. Furthermore, appetite responses to exercise do not appear to be influenced by exercise modality.

Topics: Acylation; Adult; Altitude; Anorexia; Appetite; Appetite Regulation; Eating; Energy Intake; Energy Metabolism; Ghrelin; Glucagon-Like Peptide 1; Humans; Male; Meals; Oxygen; Oxygen Consumption; Peptide YY; Physical Exertion; Rest; Running

Peptide YY(3-36) (PYY(3-36)) is a gut hormone with anorectic action that also affects energy expenditure. Anorexia and malnutrition are often observed in patients with decompensated liver cirrhosis (LC), whereas patients with LC after insertion of transjugular portosystemic stent shunts (TIPS) show normal eating behavior. The underlying mechanism of anorexia in decompensated LC and its resolution in patients with TIPS is still unclear. We thus investigated fasting and postprandial PYY(3-36) serum levels in patients with decompensated LC, patients with compensated LC with in situ TIPS, and healthy controls.. We analyzed fasting PYY(3-36) levels in six patients with decompensated LC (four men and two women, 55 ± 11 y of age), nine patients with TIPS (seven men and two women, 48 ± 11 y of age), and 10 controls (eight men and two women, 43 ± 9 y of age) postprandially after a standardized meal of 300 kcal and during 1-h continuous parenteral nutrition. Energy expenditure was determined by indirect calorimetry.. At baseline PYY(3-36) was comparable in controls and patients with TIPS (91 ± 10 and 89 ± 25 ng/L) but was increased in patients with decompensated LC (165 ± 44 ng/L, P < 0.01). Although the cumulative postprandial PYY(3-36) increase was similar in controls (mean 2089 ng/240 min per liter) and patients with decompensated LC (mean 1735 ng/240 min per liter), no postprandial PYY(3-36) increase was observed in patients with TIPS (mean -579 ng/240 min per liter). Parenteral nutrition did not significantly affect PYY(3-36) levels in any group. Fasting PYY(3-36) values were negatively related to resting energy expenditure (r = -0.443, P = 0.030). PYY(3-36) was not associated to liver parameters (e.g., bilirubin, alanine aminotransferase).. Our results demonstrate an abnormal neuroendocrine regulation of PYY(3-36) in patients with decompensated LC and those with TIPS.

Topics: Adult; Aged; Anorexia; Basal Metabolism; Case-Control Studies; Fasting; Female; Humans; Liver Cirrhosis; Male; Malnutrition; Middle Aged; Parenteral Nutrition; Peptide YY; Portasystemic Shunt, Transjugular Intrahepatic; Postprandial Period

Malnutrition is very prevalent among patients with chronic renal failure. The role of derangements in the gut-brain axis for regulation of appetite in the genesis of anorexia of these patients has not been adequately investigated. Design. Following a randomized, crossover design, we analysed plasma levels of peptide YY (PYY)(1-36) and PYY(3-36) both fasting and after a standardized oral mixed meal or intraperitoneal glucose infusion in 10 stable uraemic patients undergoing peritoneal dialysis and 8 healthy controls, matched for age, gender and body mass index. Main results. Median baseline plasma levels of PYY(1-36) in the different provocation tests oscillated between 406 and 460 pg/mL in patients, as compared with 73 and 100 pg/mL in controls (P < 0.001). Corresponding values for PYY(3-36) oscillated between 235 and 267 pg/mL in patients, versus 56 and 70 pg/mL in controls (P < 0.001). The association of high levels of PYY(3-36) and normal levels of acylated ghrelin (when compared with healthy controls) configurated a markedly pro-anorexigenic pattern in patients. Neither oral intake nor intraperitoneal glucose resulted in significant changes in plasma levels of PYY(1-36) or PYY(3-36) in subjects with renal failure, in contrast with the expected postprandial rise observed in healthy controls (41% for PYY(1-36), P = 0.04 and 32% for PYY(3-36), P = 0.02, median values).. Baseline plasma levels of PYY(1-36) or PYY(3-36) are markedly elevated in patients with renal failure undergoing peritoneal dialysis. Provocation studies disclose a marked disregulation in the postprandial secretion of these anorexigenic peptides, when compared with healthy controls. These findings may contribute to clarify the complex pathogenesis of anorexia of chronic renal failure.

Topics: Adult; Aged; Anorexia; Appetite; Case-Control Studies; Chronic Disease; Cross-Over Studies; Dialysis Solutions; Female; Food, Formulated; Glucose; Humans; Infusions, Parenteral; Male; Malnutrition; Middle Aged; Peptide YY; Peritoneal Dialysis; Renal Insufficiency

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

Topics: Animals; Anorexia; CHO Cells; Cricetulus; Glucagon-Like Peptide-1 Receptor; HEK293 Cells; Humans; Liraglutide; Macaca mulatta; Mice; Mice, Inbred C57BL; Obesity; Peptide YY; Vomiting

T-2 toxin, a potent type A trichothecene mycotoxin, is produced by various Fusarium species and can negatively impact animal and human health. Although anorexia induction is a common hallmark of T-2 toxin-induced toxicity, the underlying mechanisms for this adverse effect are not fully understood. The goal of this study was to determine the roles of two gut satiety hormones, glucose-dependent insulinotropic polypeptide (GIP) and Peptide YY

Topics: Animals; Anorexia; Appetite Depressants; Biomarkers; Dose-Response Relationship, Drug; Eating; Female; Gastric Inhibitory Polypeptide; Mice; Peptide Fragments; Peptide YY; Random Allocation; Satiety Response; T-2 Toxin

Peptide YY 3-36 (PYY3-36) is known as a critical satiety factor that reduces food intake both in rodents and humans. Although the anorexic effect of PYY3-36 is assumed to be mediated mainly by the Y2 receptor, the involvement of other Y-receptors in this process has never been conclusively resolved. Amongst them, the Y5 receptor (Y5R) is the most likely candidate to also be a target for PYY3-36, which is considered to counteract the anorectic effects of Y2R activation. In the present study, we show that short-term treatment of diet-induced obese wild-type (WT) and Y5R knockout mice (Y5KO) with PYY3-36 leads to a significantly reduced food intake in both genotypes, which is more pronounced in Y5R KO mice. Interestingly, chronic PYY3-36 infusion via minipumps to WT mice causes an increased cumulative food intake, which is associated with increased body weight gain. By contrast, lack of Y5R reversed this effect. Consistent with the observed increased body weight and fat mass in WT-treated mice, glucose tolerance was also impaired by chronic PYY3-36 treatment. Again, this was less affected in Y5KO mice, suggestive of a role of Y5R in the regulation of glucose homeostasis. Taken together, our data suggest that PYY3-36 mediated signalling via Y5 receptors may counteract the anorectic effects that it mediates via the Y2 receptor (Y2R), consequently lowering bodyweight in the absence of Y5 signalling. These findings open the potential of combination therapy using PYY3-36 and Y5R antagonists to enhance the food intake reducing effects of PYY3-36.

Topics: Animals; Anorexia; Body Weight; Bone and Bones; Diet, High-Fat; Eating; Glucose; Homeostasis; Mice, Knockout; Obesity; Peptide Fragments; Peptide YY; Receptors, Neuropeptide Y

Ghrelin is an important gut-derived hormone with an appetite stimulatory role, while most of the intestinal hormones, including cholecystokinin (CCK), peptide YY (PYY) and glucagon-like peptide-1 (GLP-1), are appetite-inhibitors. Whether these important peptides with opposing roles on food intake interact to regulate energy balance in fish is currently unknown. The aim of this study was to characterize the putative crosstalk between ghrelin and CCK, PYY and GLP-1 in goldfish (Carassius auratus). We first determined the localization of CCK, PYY and GLP-1 in relation to ghrelin and its main receptor GHS-R1a (growth hormone secretagogue 1a) in the goldfish intestine by immunohistochemistry. Colocalization of ghrelin/GHS-R1a and CCK/PYY/GLP-1 was found primarily in the luminal border of the intestinal mucosa. In an intestinal explant culture, a significant decrease in prepro-cck, prepro-pyy and proglucagon transcript levels was observed after 60min of incubation with ghrelin, which was abolished by preincubation with the GHS-R1a ghrelin receptor antagonist [D-Lys3]-GHRP-6 (except for proglucagon). The protein expression of PYY and GLP-1 was also downregulated by ghrelin. Finally, intraperitoneal co-administration of CCK, PYY or GLP-1 with ghrelin results in no modification of food intake in goldfish. Overall, results of the present study show for the first time in fish that ghrelin exerts repressive effects on enteric anorexigens. It is likely that these interactions mediate the stimulatory effects of ghrelin on feeding and metabolism in fish.

Topics: Animals; Anorexia; Appetite; Appetite Depressants; Cholecystokinin; Eating; Female; Ghrelin; Glucagon-Like Peptide 1; Goldfish; Intestinal Mucosa; Intestines; Male; Oligopeptides; Peptide YY; Protein Precursors; Receptors, Ghrelin

Trichothecences, secondary metabolites produced by Fusarium, are serious health risks to humans and animals worldwide. Although type A trichothecence-induced food refusal has been observed, the mechanism underlying the anorexia caused by these compounds is not fully understood. In this study, we hypothesized that anorexia induced by type A trichothecenes, including T-2 toxin (T-2), HT-2 toxin (HT-2), diacetoxyscirpenol (DAS), and neosolaniol (NEO), in mice corresponds to the changes in the gut satiety hormones peptide YY3-36 (PYY3-36) and glucose-dependent insulinotropic polypeptide (GIP) in plasma. A well-characterized mouse food refusal model was used in this assay. Oral exposure to or intraperitoneal (ip) injection of 1 mg/kg bw T-2, HT-2, DAS, or NEO resulted in dramatically decreased food intake, and PYY3-36 and GIP concentrations were elevated accordingly. Specifically, the PYY3-36 and GIP concentrations peaked at 2 h following oral exposure to these 4 toxins individually, although the durations were not identical. After ip administration of T-2 or HT-2, PYY3-36 significantly increased within 6 h. However, no significant difference was found in the DAS and NEO groups. The GIP levels peaked within 2, 2, 0.5, and 0.5 h, respectively, and remained increased up to 6, 6, 2, and 6 h, respectively, following T-2, HT-2, DAS, or NEO ip exposure. The increase in GIP was greater than that of PYY3-36 after exposure to the 4 toxins using 2 administration routes. Together, these findings suggest that PYY3-36 and GIP play a role in T-2-, HT-2-, DAS-, and NEO-induced anorexia.

Topics: Animals; Anorexia; Female; Gastric Inhibitory Polypeptide; Mice; Mycotoxins; Peptide Fragments; Peptide YY; T-2 Toxin; Trichothecenes

Food contamination by the trichothecene mycotoxin deoxynivalenol (DON, vomitoxin) has the potential to adversely affect animal and human health by suppressing food intake and impairing growth. In mice, the DON-induced anorectic response results from aberrant satiety hormone secretion by enteroendocrine cells (EECs) of the gastrointestinal tract. Recent in vitro studies in the murine STC-1 EEC model have linked DON-induced satiety hormone secretion to activation of calcium-sensing receptor (CaSR), a G-coupled protein receptor, and transient receptor potential ankyrin-1 (TRPA1), a TRP channel. However, it is unknown whether similar mechanisms mediate DON's anorectic effects in vivo. Here, we tested the hypothesis that DON-induced food refusal and satiety hormone release in the mouse are linked to activation of CaSR and TRPA1. Oral treatment with selective agonists for CaSR (R-568) or TRPA1 (allyl isothiocyanate (AITC)) suppressed food intake in mice, and the agonist's effects were suppressed by pretreatment with corresponding antagonists NPS-2143 or ruthenium red (RR), respectively. Importantly, NPS-2143 or RR inhibited both DON-induced food refusal and plasma elevations of the satiety hormones cholecystokinin (CCK) and peptide YY

Topics: Animals; Anorexia; Appetite Depressants; Appetite Stimulants; Behavior, Animal; Cholecystokinin; Drug Therapy, Combination; Energy Intake; Environmental Pollutants; Female; Models, Biological; Peptide Fragments; Peptide YY; Random Allocation; Receptors, Calcium-Sensing; Receptors, G-Protein-Coupled; Satiety Response; Transient Receptor Potential Channels; Trichothecenes; TRPA1 Cation Channel

Deoxynivalenol (DON), a trichothecene mycotoxin that commonly contaminates cereal grains, is a public health concern because of its adverse effects on the gastrointestinal and immune systems. The objective of this study was to compare effects of DON on anorectic responses in aged (22 mos) and adult (3 mos) mice. Aged mice showed increased feed refusal with both acute i.p. (1 mg/kg and 5 mg/kg) and dietary (1, 2.5, 10 ppm) DON exposure in comparison to adult mice. In addition to greater suppression of food intake from dietary DON exposure, aged mice also exhibited greater but transient body weight suppression. When aged mice were acutely exposed to 1 mg/kg bw DON i.p., aged mice displayed elevated DON and DON3GlcA tissue levels and delayed clearance in comparison with adult mice. Acute DON exposure also elicited higher proinflammatory cytokine and satiety hormone responses in the plasma of the aged group compared with the adult group. Increased susceptibility to DON-induced anorexia in aged mice relative to adult mice suggests that advanced life stage could be a critical component in accurate human risk assessments for DON and other trichothecenes.

Topics: Aging; Animals; Anorexia; Body Weight; Cholecystokinin; Cytokines; Eating; Male; Mice, Inbred C57BL; Peptide YY; Satiety Response; Tissue Distribution; Trichothecenes

Cereal grain contamination by trichothecene mycotoxins is known to negatively impact human and animal health with adverse effects on food intake and growth being of particular concern. The head blight fungus Fusarium graminearum elaborates five closely related 8-ketotrichothecene congeners: (1) deoxynivalenol (DON), (2) 3-acetyldeoxynivalenol (3-ADON), (3) 15-acetyldeoxynivalenol (15-ADON), (4) fusarenon X (FX), and (5) nivalenol (NIV). While anorexia induction in mice exposed intraperitoneally to DON has been linked to plasma elevation of the satiety hormones cholecystokinin (CCK) and peptide YY₃₋₃₆ (PYY₃₋₃₆), the effects of oral gavage of DON or of other 8-keotrichothecenes on release of these gut peptides have not been established. The purpose of this study was to (1) compare the anorectic responses to the aforementioned 8-ketotrichothecenes following oral gavage at a common dose (2.5 mg/kg bw) and (2) relate these effects to changes plasma CCK and PYY₃₋₃₆ concentrations. Elevation of plasma CCK markedly corresponded to anorexia induction by DON and all other 8-ketotrichothecenes tested. Furthermore, the CCK1 receptor antagonist SR 27897 and the CCK2 receptor antagonist L-365,260 dose-dependently attenuated both CCK- and DON-induced anorexia, which was consistent with this gut satiety hormone being an important mediator of 8-ketotrichothecene-induced food refusal. In contrast to CCK, PYY₃₋₃₆ was moderately elevated by oral gavage with DON and NIV but not by 3-ADON, 15-ADON, or FX. Taken together, the results suggest that CCK plays a major role in anorexia induction following oral exposure to 8-ketotrichothecenes, whereas PYY₃₋₃₆ might play a lesser, congener-dependent role in this response.

Topics: Administration, Oral; Animals; Anorexia; Chemokines, CC; Cholecystokinin; Female; Mice; Mycotoxins; Peptide Fragments; Peptide YY; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; Trichothecenes

Cancer-associated anorexia and cachexia are a multifactorial condition described by a loss of body weight and muscle with anorexia, asthenia, and anemia. Moreover, they correlate with a high mortality rate, poor response to chemotherapy, poor performance status, and poor quality of life. Cancer cachexia is regulated by proinflammatory cytokines such as interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor- α (TNF- α). In addition, glucagon like peptide-1 (GIP-1), peptide YY (PYY), ghrelin, and leptin plays a crucial role in food intake. In this study, we investigated the therapeutic effects of one of the traditional herbal medicines, Sipjeondaebo-tang (Juzen-taiho-to in Japanese; SJDBT), on cancer anorexia and cachexia in a fundamental mouse cancer anorexia/cachexia model, CT-26 tumor-bearing mice. SJDBT was more significantly effective in a treatment model where it was treated after anorexia and cachexia than in a prevention model where it was treated before anorexia and cachexia on the basis of parameters such as weights of muscles and whole body and food intakes. Moreover, SJDBT inhibited a production of IL-6, MCP-1, PYY, and GLP-1 and ameliorated cancer-induced anemia. Therefore, our in vivo studies provide evidence on the role of SJDBT in cancer-associated anorexia and cachexia, thereby suggesting that SJDBT may be useful for treating cancer-associated anorexia and cachexia.

Topics: Animals; Anorexia; Body Weight; Cachexia; Cell Line, Tumor; Chemokine CCL2; Drugs, Chinese Herbal; Ghrelin; Glucagon-Like Peptide 1; Inflammation; Interleukin-6; Intestinal Mucosa; Leptin; Male; Mice; Mice, Inbred BALB C; Muscles; Neoplasm Transplantation; Neoplasms; Peptide YY; Plant Preparations; Tumor Necrosis Factor-alpha

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

The mycotoxin deoxynivalenol (DON) elicits robust anorectic and emetic effects in several animal species. However, less is known about the potential for naturally occurring and synthetic congeners of this trichothecene to cause analogous responses. Here we tested the hypothesis that alterations in DON structure found in the plant metabolite deoxynivalenol-3-glucoside (D3G) and two pharmacologically active synthetic DON derivatives, EN139528 and EN139544, differentially impact their potential to evoke food refusal and emesis. In a nocturnal mouse food consumption model, oral administration with DON, D3G, EN139528, or EN139544 at doses from 2.5 to 10 mg/kg BW induced anorectic responses that lasted up to 16, 6, 6, and 3 h, respectively. Anorectic potency rank orders were EN139544>DON>EN139528>D3G from 0 to 0.5 h but DON>D3G>EN139528>EN139544 from 0 to 3 h. Oral exposure to each of the four compounds at a common dose (2.5 mg/kg BW) stimulated plasma elevations of the gut satiety peptides cholecystokinin and to a lesser extent, peptide YY3-36 that corresponded to reduced food consumption. In a mink emesis model, oral administration of increasing doses of the congeners differentially induced emesis, causing marked decreases in latency to emesis with corresponding increases in both the duration and number of emetic events. The minimum emetic doses for DON, EN139528, D3G, and EN139544 were 0.05, 0.5, 2, and 5 mg/kg BW, respectively. Taken together, the results suggest that although all three DON congeners elicited anorectic responses that mimicked DON over a narrow dose range, they were markedly less potent than the parent mycotoxin at inducing emesis.

Topics: Animals; Anorexia; Cholecystokinin; Dose-Response Relationship, Drug; Eating; Female; Glucosides; Intestinal Mucosa; Intestines; Mice, Inbred Strains; Mink; Molecular Structure; No-Observed-Adverse-Effect Level; Peptide Fragments; Peptide YY; Trichothecenes; Vomiting

Peptide YY(3-36) [PYY(3-36)] is postulated to act as a hormonal signal from gut to brain to inhibit food intake. PYY(3-36) potently reduces food intake when administered systemically or into the brain. If action of endogenous PYY(3-36) is necessary for normal satiation to occur, then pharmacological blockade of its receptors should increase food intake. Here, we determined the effects of iv infusion of Y1, Y2, and Y5 receptor antagonists (BIBP 3226, BIIE 0246, CGP 71683) during the first 3 h of the dark period on food intake in non-food-deprived rats. Our results showed that 1) Y2 receptor blockade reversed the anorexic response to iv infusion of PYY(3-36) but did not increase food intake when administered alone; 2) Y1 and Y5 receptor antagonists neither attenuated PYY(3-36)-induced anorexia nor altered food intake when given alone; and 3) Y2 receptor blockade attenuated anorexic responses to gastric infusions of casein hydrolysate and long-chain triglycerides, but not maltodextrin. Previous work showed that Y2 antagonist BIIE 0246 does not penetrate the blood-brain barrier. Together, these results support the hypothesis that gut PYY(3-36) action at Y2 receptors peripheral to the blood brain barrier plays an essential role in mediating satiety responses to gastric delivery of protein and long-chain triglycerides, but not polysaccharide.

Topics: Animals; Anorexia; Cholecystokinin; Eating; Hunger; Intubation, Gastrointestinal; Islet Amyloid Polypeptide; Male; Peptide Fragments; Peptide YY; Polysaccharides; Protein Hydrolysates; Rats; Rats, Sprague-Dawley; Receptors, Gastrointestinal Hormone; Satiety Response; Triglycerides

Consumption of deoxynivalenol (DON), a trichothecene mycotoxin known to commonly contaminate grain-based foods, suppresses growth of experimental animals, thus raising concerns over its potential to adversely affect young children. Although this growth impairment is believed to result from anorexia, the initiating mechanisms for appetite suppression remain unknown. Here, we tested the hypothesis that DON induces the release of satiety hormones and that this response corresponds to the toxin's anorectic action. Acute ip exposure to DON had no effect on plasma glucagon-like peptide-1, leptin, amylin, pancreatic polypeptide, gastric inhibitory peptide, or ghrelin; however, the toxin was found to robustly elevate peptide YY (PYY) and cholecystokinin (CCK). Specifically, ip exposure to DON at 1 and 5mg/kg bw induced PYY by up to 2.5-fold and CCK by up to 4.1-fold. These responses peaked within 15-120 min and lasted up to 120 min (CCK) and 240 min (PPY), corresponding with depressed rates of food intake. Direct administration of exogenous PYY or CCK similarly caused reduced food intake. Food intake experiments using the NPY2 receptor antagonist BIIE0246 and the CCK1A receptor antagonist devazepide, individually, suggested that PYY mediated DON-induced anorexia but CCK did not. Orolingual exposure to DON induced plasma PYY and CCK elevation and anorexia comparable with that observed for ip exposure. Taken together, these findings suggest that PYY might be one critical mediator of DON-induced anorexia and, ultimately, growth suppression.

Topics: Administration, Oral; Animals; Anorexia; Appetite Depressants; Appetite Regulation; Arginine; Behavior, Animal; Benzazepines; Chemokines, CC; Cholecystokinin; Devazepide; Dose-Response Relationship, Drug; Eating; Female; Food Contamination; Injections, Intraperitoneal; Mice; Mycotoxins; Peptide YY; Receptors, Cholecystokinin; Receptors, Neuropeptide Y; Satiation; Time Factors; Trichothecenes

To assess whether endocrine dysfunction may cause derangement in energy homeostasis in patients undergoing hemodialysis (HD), we profiled hormones, during a 3-day period, from the adipose tissue and the gut and the nervous system around the circadian clock in 10 otherwise healthy HD patients and 8 normal controls. The protocol included a 40-h fast. We also measured energy-protein intake and output and assessed appetite and body composition. We found many hormonal abnormalities in HD patients: 1) leptin levels were elevated, due, in part, to increased production, and nocturnal surge in response to daytime feeding, exaggerated. 2) Peptide YY (PYY), an anorexigenic gut hormone, was markedly elevated and displayed an augmented response to feeding. 3) Acylated ghrelin, an orexigenic gut hormone, was lower and did not exhibit the premeal spike as observed in the controls. 4) neuropeptide Y (NPY), a potent orexigenic peptide, was markedly elevated and did not display any circadian variation. 5) Norepinephrine, marginally elevated, did not exhibit the normal nocturnal dip. By contrast, α-melanocyte-stimulating hormone and glucagon-like peptide-1 were not different between the two groups. Despite these hormonal abnormalities, HD patients maintained a good appetite and had normal body lean and fat mass, and there was no evidence of increased energy expenditure or protein catabolism. We explain the hormonal abnormalities as well as the absence of anorexia on suppression of parasympathetic activity (vagus nerve dysfunction), a phenomenon well documented in dialysis patients. Unexpectedly, we noted that the combination of high leptin, PYY, and NPY with suppressed ghrelin may increase arterial blood pressure, impair vasodilatation, and induce cardiac hypertrophy, and thus could predispose to adverse cardiovascular events that are the major causes of morbidity and mortality in the HD population. This is the first report attempting to link hormonal abnormalities associated with energy homeostasis to adverse cardiovascular outcome in the HD patients.

Topics: Adult; Anorexia; Appetite; Body Composition; Cardiovascular Diseases; Circadian Rhythm; Endocrine System Diseases; Energy Metabolism; Fasting; Female; Ghrelin; Homeostasis; Humans; Leptin; Male; Middle Aged; Neuropeptide Y; Norepinephrine; Peptide YY; Protein-Energy Malnutrition; Renal Dialysis; Renal Insufficiency; Risk Factors

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

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)-alpha, and interleukin (IL)-1beta contribute to anorexia in this population.. 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-alpha, and IL-1beta.. 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-alpha 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-1beta 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.. Elevated serum peptide YY may be a mechanism for anorexia in children with diarrhea.

Topics: Anorexia; Appetite; Case-Control Studies; Child, Preschool; Diarrhea; Female; Gastrointestinal Hormones; Humans; Infant; Interleukin-1beta; Intestinal Mucosa; Male; Peptide YY; Treatment Outcome; Tumor Necrosis Factor-alpha

Acute administration of peptide YY(3-36) [PYY(3-36)] results in a reduction in food intake in several different vertebrates. However, long-term continuous administration of PYY(3-36) causes only a transient reduction in food intake, thus potentially limiting its therapeutic efficacy. We hypothesized that a fall in leptin levels associated with reduced food intake could contribute to the transient anorectic effects of continuous PYY(3-36) infusion and thus that leptin replacement might prolong the anorectic effects of PYY(3-36). Seven-day administration of 100 microg x kg body wt(-1) x day(-1) PYY(3-36) using osmotic minipumps caused a significant reduction in food intake of ad libitum-fed rats, but only for the first 2 days postimplantation. Circulating levels of leptin were reduced 1 day following continuous infusion of PYY(3-36), and combined leptin infusion at a dose of leptin that had no anorectic effects on its own (100 microg x kg body wt(-1) x day(-1)) prolonged the anorectic actions of PYY(3-36) in ad libitum-fed rats for up to 6 days postimplantation and yielded reduced weight gain compared with either peptide alone. The inhibitory effects of 100 microg x kg body wt(-1) x day(-1) PYY(3-36) on food intake were absent in rats refed after a 24-h fast and substantially reduced at a dose of 1,000 microg x kg body wt(-1) x day(-1) PYY(3-36). Leptin replacement was unable to recover the anorectic effects of PYY(3-36) in fasted rats. Our results suggest that an acute fall in leptin levels is not solely responsible for limiting duration of action of chronic PYY(3-36) infusion, yet chronic coadministration of a subanorectic dose of leptin can extend the anorectic effects of PYY(3-36).

Topics: Absorbable Implants; Animals; Anorexia; Appetite Depressants; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Synergism; Leptin; Male; Peptide Fragments; Peptide YY; Rats; Rats, Inbred F344; Time Factors

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 PYY(1-36) and the pharmacologically active PYY(3-36) is indicated to determine the potential role in energy balance regulation.. 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.. Total plasma PYY levels (PYY(1-36) + PYY(3-36)) 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 PYY(3-36) levels were measured in 17 lean and 15 obese individuals.. 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. In obese patients, weight loss of 5.4% was associated with a 30% decrease in fasting total PYY plasma levels. In anorectic patients, weight gain had no effect on fasting PYY. PYY(3-36) levels did not differ between lean (96.2 +/- 8.6 pg/ml) and obese (91.5 +/- 6.9 pg/ml) subjects.. Our findings do not support a role for abnormal circulating PYY in human obesity. We conclude that circulating PYY levels in humans are significantly elevated in anorexia nervosa and, given the controversially discussed anorectic effect of PYY, could theoretically contribute to that syndrome.

Topics: Adult; Anorexia; Body Weight; Energy Intake; Fasting; Female; Humans; Leptin; Obesity, Morbid; Peptide Fragments; Peptide YY; Receptors, Cell Surface; Receptors, Leptin; Satiety Response; Weight Gain; Weight Loss