18,730 research outputs found
Inhibition of food intake in obese subjects by peptide YY3-36
Background: The gut hormone fragment peptide YY3-36 (PYY) reduces appetite and food intake when infused into subjects of normal weight. In common with the adipocyte hormone leptin, PYY reduces food intake by modulating appetite circuits in the hypothalamus. However, in obesity there is a marked resistance to the action of leptin, which greatly limits its therapeutic effectiveness. We investigated whether obese subjects were also resistant to the anorectic effects of PYY.Methods: We compared the effects of PYY infusion on appetite and food intake in 12 obese and 12 lean subjects in a double-blind, placebo-controlled, crossover study. The plasma levels of PYY, ghrelin, leptin, and insulin were also determined.Results: Caloric intake during a buffet lunch offered two hours after the infusion of PYY was decreased by 30 percent in the obese subjects (P<0.001) and 31 percent in the lean subjects (P<0.001). PYY infusion also caused a significant decrease in the cumulative 24-hour caloric intake in both obese and lean subjects. PYY infusion reduced plasma levels of the appetite-stimulatory hormone ghrelin. Endogenous fasting and postprandial levels of PYY were significantly lower in obese subjects (the mean [+/-SE] fasting PYY levels were 10.2+/-0.7 pmol per liter in the obese group and 16.9+/-0.8 pmol per liter in the lean group, P<0.001). Furthermore, the fasting PYY levels correlated negatively with the body-mass index (r=-0.84, P<0.001).Conclusions: We found that obese subjects were not resistant to the anorectic effects of PYY. Endogenous PYY levels were low in the obese subjects, suggesting that PYY deficiency may contribute to the pathogenesis of obesity
Liquid meal composition, postprandial satiety hormones, and perceived appetite and satiety in obese women during acute caloric restriction
OBJECTIVE:
The purpose of this study was to compare postprandial satiety regulating hormone responses (pancreatic polypeptide (PP) and peptide tyrosine tyrosine (PYY)) and visual analog scale- (VAS) assessed perceived appetite and satiety between liquid high-protein (HP) and high-carbohydrate (HC) meals in obese women during acute (24-h) caloric restriction.
DESIGN:
Eleven obese premenopausal women completed two conditions in random order in which they consumed 1500 calories as six 250-calorie HP meals or six 250-calorie HC meals over a 12-h period. Blood samples were taken at baseline and every 20 min thereafter and analyzed for PP and PYY concentrations. At these same points, perceived hunger and fullness were assessed with a VAS. The incremental area under the curve (iAUC) was used to compare postprandial responses.
RESULTS:
THE 12-H PP AND PYY IAUC WERE GREATER (P0.05) DURING THE HP CONDITION (PP: 4727±1306 pg/ml×12 h, PYY: 1373±357 pg/ml×12 h) compared with the HC condition (PP: 2300±528 pg/ml×12 h, PYY: 754±246 pg/ml×12 h). Perceived hunger and fullness were not different between conditions (P>0.05). The greatest changes in PYY and perceived fullness occurred after the morning meals during both conditions.
CONCLUSIONS:
These data suggest that in obese women during acute caloric restriction before weight loss, i) liquid HP meals, compared with HC meals, result in greater postprandial PP and PYY concentrations, an effect not associated with differential appetite or satiety responses, and ii) meal-induced changes in PYY and satiety are greatest during the morning period, regardless of dietary macronutrient composition
L-Arginine promotes gut hormone release and reduces food intake in rodents
Aims: To investigate the anorectic effect of L‐arginine (L‐Arg) in rodents.
Methods: We investigated the effects of L‐Arg on food intake, and the role of the anorectic gut hormones glucagon‐like peptide‐1 (GLP‐1) and peptide YY (PYY), the G‐protein‐coupled receptor family C group 6 member A (GPRC6A) and the vagus nerve in mediating these effects in rodents.
Results: Oral gavage of L‐Arg reduced food intake in rodents, and chronically reduced cumulative food intake in diet‐induced obese mice. Lack of the GPRC6A in mice and subdiaphragmatic vagal deafferentation in rats did not influence these anorectic effects. L‐Arg stimulated GLP‐1 and PYY release in vitro and in vivo. Pharmacological blockade of GLP‐1 and PYY receptors did not influence the anorectic effect of L‐Arg. L‐Arg‐mediated PYY release modulated net ion transport across the gut mucosa. Intracerebroventricular (i.c.v.) and intraperitoneal (i.p.) administration of L‐Arg suppressed food intake in rats.
Conclusions: L‐Arg reduced food intake and stimulated gut hormone release in rodents. The anorectic effect of L‐Arg is unlikely to be mediated by GLP‐1 and PYY, does not require GPRC6A signalling and is not mediated via the vagus. I.c.v. and i.p. administration of L‐Arg suppressed food intake in rats, suggesting that L‐Arg may act on the brain to influence food intake. Further work is required to determine the mechanisms by which L‐Arg suppresses food intake and its utility in the treatment of obesity
Investigating the physiological role of PYY-expressing cells in the gut and pancreas
Peptide YY (PYY) is a hormone produced by the enteroendocrine L cells in the gut. It is also expressed in the pancreatic islets and brainstem. PYY is secreted from the L cells in proportion to caloric intake and is involved in the regulation of satiety and energy homeostasis. The physiological role of PYY in the pancreatic islets and brainstem is not clear. In order to investigate the physiological role of PYY-expressing cells, I used a transgenic mouse model in which diphtheria toxin receptor (DTR) is expressed downstream of the PYY promoter. This enabled ablation of the PYY-expressing cells following administration of diphtheria toxin (DT) in adult mice. Intraperitoneal administration of DT at a dose of 40ng/g resulted in a significant loss of colonic, pancreatic and brainstem PYY (> 95%). Interestingly, ablation of PYY-expressing cells resulted in a significant loss of pancreatic insulin and hence severe hyperglycaemia in adult mice. In vitro administration of DT in cultured islets resulted in a significant dose-dependent loss of insulin, PYY and glucagon content. Immunohistochemical distribution of DTR was shown to be limited to the periphery of the islet, where PYY is also expressed. These experiments suggest that a product of the PYY-expressing cells may provide a paracrine factor essential for beta cell viability. Replacement of PYY using twice-daily subcutaneous injection of a long-acting PYY analogue (X-PYY) prevented the development of diabetes and reduced the loss of pancreatic insulin content. Administration of the analogue also reduced insulin loss in streptozotocin-treated mice. These studies suggest that PYY may be an important signal for beta cell maintenance. These findings have important implications for identifying novel therapies for prevention of beta cell loss in diabetes mellitus
SCFAs strongly stimulate PYY production in human enteroendocrine cells.
Peptide-YY (PYY) and Glucagon-Like Peptide-1 (GLP-1) play important roles in the regulation of food intake and insulin secretion, and are of translational interest in the field of obesity and diabetes. PYY production is highest in enteroendocrine cells located in the distal intestine, mirroring the sites where high concentrations of short chain fatty acids (SCFAs) are produced by gut microbiota. We show here that propionate and butyrate strongly increased expression of PYY but not GCG in human cell line and intestinal primary culture models. The effect was predominantly attributable to the histone deacetylase inhibitory activity of SCFA and minor, but significant contributions of FFA2 (GPR43). Consistent with the SCFA-dependent elevation of PYY gene expression, we also observed increased basal and stimulated PYY hormone secretion. Interestingly, the transcriptional stimulation of PYY was specific to human-derived cell models and not reproduced in murine primary cultures. This is likely due to substantial differences in PYY gene structure between mouse and human. In summary, this study revealed a strong regulation of PYY production by SCFA that was evident in humans but not mice, and suggests that high fibre diets elevate plasma concentrations of the anorexigenic hormone PYY, both by targeting gene expression and hormone secretion
Diet and Gastrointestinal Bypass–Induced Weight Loss: The Roles of Ghrelin and Peptide YY
OBJECTIVE-Bariatric surgery causes durable weight loss. Gut hormones are implicated in obesity pathogenesis, dietary failure, and mediating gastrointestinal bypass (GIBP) surgery weight loss. In mice, we determined the effects of diet-induced obesity (DIO), subsequent dieting, and GIBP surgery on ghrelin, peptide YY (PYY), and glucagon-like peptide-1 (GLP-1). To evaluate PYY's role in mediating weight loss post-GIBP, we undertook GIBP surgery in PyyKO mice.RESEARCH DESIGN AND METHODS-Male C57BL/6 mice randomized to a high-fat diet or control diet were killed at 4-week intervals. DIO mice underwent switch to ad libitum low-fat diet (DIO-switch) or caloric restriction (CR) for 4 weeks before being killed. PyyKO mice and their DIO wild-type (WT) littermates underwent GIBP or sham surgery and were culled 10 days post-operatively. Fasting acyl-ghrelin, total PYY, active GLP-1 concentrations, stomach ghrelin expression, and colonic Pyy and glucagon expression were determined. Fasting and postprandial PYY and GLP-1 concentrations were assessed 30 days postsurgery in GIBP and sham pair-fed (sham.PF) groups.RESULTS-DIO progressively reduced circulating fasting acyl-ghrelin, PYY, and GLP-1 levels. CR and DIO-switch caused weight loss but failed to restore circulating PYY to weight-appropriate levels. After GIBP, WT mice lost weight and exhibited increased circulating fasting PYY and colonic Pyy and glucagon expression. In contrast, the acute effects of GIBP on body weight were lost in PyyKO mice. Fasting PYY and postprandial PYY and GLP-1 levels were increased in GIBP mice compared with sham.PF mice.CONCLUSIONS-PYY plays a key role in mediating the early weight loss observed post-GIBP, whereas relative PYY deficiency during dieting may compromise weight-loss attempts. Diabetes 60:810-818, 201
Sitagliptin and Roux-en-Y gastric bypass modulate insulin secretion via regulation of intra-islet PYY.
The gut hormone peptide tyrosine tyrosine (PYY) is critical for maintaining islet integrity and restoring islet function following Roux-en-Y gastric bypass (RYGB). The expression of PYY and its receptors (NPYRs) in islets has been documented but not fully characterized. Modulation of islet PYY by the proteolytic enzyme dipeptidyl peptidase IV (DPP-IV) has not been investigated and the impact of DPP-IV inhibition on islet PYY function remains unexplored. Here we have addressed these gaps and their effects on glucose-stimulated insulin secretion (GSIS). We have also investigated changes in pancreatic PYY in diabetes and following RYGB.
Immunohistochemistry and gene expression analysis were used to assess PYY, NPYRs and DPP-IV expression in rodent and human islets. DPP-IV activity inhibition was achieved by sitagliptin. Secretion studies were used to test PYY and the effects of sitagliptin on insulin release, and the involvement of GLP-1. Radioimmunoassays were used to measure hormone content in islets.
PYY and DPP-IV localized in different cell types in islets while NPYR expression was confined to the beta-cells. Chronic PYY application enhanced GSIS in rodent and diabetic human islets. DPP-IV inhibition by sitagliptin potentiated GSIS; this was mediated by locally-produced PYY, and not GLP-1. Pancreatic PYY was markedly reduced in diabetes. RYGB strongly increased islet PYY content, but did not lead to full restoration of pancreatic GLP-1 levels.
Local regulation of pancreatic PYY, rather than GLP-1, by DPP-IV inhibition or RYGB can directly modulate the insulin secretory response to glucose, indicating a novel role of pancreatic PYY in diabetes and weight-loss surgery
Peptide YY ablation in mice leads to the development of hyperinsulinaemia and obesity
Aims/hypothesis. Obese people exhibit reduced circulating peptide YY (PYY) levels, but it is unclear whether this is a consequence or cause of obesity. We therefore investigated the effect of Pyy ablation on energy homeostasis.
Methods. Body composition, i.p. glucose tolerance, food intake and hypothalamic neuropeptide expression were determined in Pyy knock-out and wild-type mice on a normal or high-fat diet. Results. Pyy knock-out significantly increased bodyweight and increased fat mass by 50% in aged females on a normal diet. Male chow-fed Pyy −/− mice were resistant to obesity but became significantly fatter and glucose-intolerant compared with wild-types when fed a high-fat diet. Pyy knock-out animals exhibited significantly elevated fasting or glucose-stimulated serum insulin concentrations vs wild-types, with no increase in basal or fasting-induced food intake. Pyy knock-out decreased or had no effect on neuropeptide Y expression in the arcuate nucleus of the hypothalamus, and significantly increased proopiomelanocortin expression in this region. Male but not female knock-outs exhibited significantly increased growth hormone-releasing hormone expression in the ventromedial hypothalamus and significantly elevated serum IGF-I and testosterone levels. This sex difference in activation of the hypothalamo–pituitary somatotrophic axis by Pyy ablation may contribute to the resistance of chow-fed male knock-outs to late-onset obesity.
Conclusions/interpretation. PYY signalling is important in the regulation of energy balance and glucose homeostasis, possibly via regulation of insulin release. Therefore reduced PYY levels may predispose to the development of obesity, particularly with ageing or under conditions of high-fat feeding
Characterization of basal pseudopod-like processes in ileal and colonic PYY cells.
The peptide tyrosine tyrosine (PYY) is produced and secreted from L cells of the gastrointestinal mucosa. To study the anatomy and function of PYY-secreting L cells, we developed a transgenic PYY-green fluorescent protein mouse model. PYY-containing cells exhibited green fluorescence under UV light and were immunoreactive to antibodies against PYY and GLP-1 (glucagon-like peptide-1, an incretin hormone also secreted by L cells). PYY-GFP cells from 15 μm thick sections were imaged using confocal laser scanning microscopy and three-dimensionally (3D) reconstructed. Results revealed unique details of the anatomical differences between ileal and colonic PYY-GFP cells. In ileal villi, the apical portion of PYY cells makes minimal contact with the lumen of the gut. Long pseudopod-like basal processes extend from these cells and form an interface between the mucosal epithelium and the lamina propria. Some basal processes are up to 50 μm in length. Multiple processes can be seen protruding from one cell and these often have a terminus resembling a synapse that appears to interact with neighboring cells. In colonic crypts, PYY-GFP cells adopt a spindle-like shape and weave in between epithelial cells, while maintaining contact with the lumen and lamina propria. In both tissues, cytoplasmic granules containing the hormones PYY and GLP-1 are confined to the base of the cell, often filling the basal process. The anatomical arrangement of these structures suggests a dual function as a dock for receptors to survey absorbed nutrients and as a launching platform for hormone secretion in a paracrine fashion
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