RSSTHE ROLE OF THE STOMACH IN THE CONTROL OF APPETITE AND THE SECRETION OF SATIATION PEPTIDES.
Source
1University Hospital Basel.
Abstract
It is widely accepted that gastric parameters such as gastric distention provide a direct negative feedback signal to inhibit eating; moreover, gastric and intestinal signals have been reported to synergize to promote satiation. There are, however, only few human data exploring the potential interaction effects of gastric and intestinal signals in the short-term control of appetite and the secretion of satiation peptides. We performed experiments in healthy subjects receiving either a rapid intragastric load or a continuous intraduodenal infusion of glucose or a mixed liquid meal. Intraduodenal infusions (3 kcal/min) were at rates comparable to the duodenal delivery of these nutrients under physiological conditions. Intraduodenal infusions of glucose elicited only weak effects on appetite and the secretion of glucagon-likepeptide-1 (GLP-1) and peptide YY (PYY). In contrast, identical amounts of glucose delivered intragastrically markedly suppressed appetite (P < 0.05) paralleled by greatly increased plasma levels of GLP-1 and PYY (up to 3-fold, P < 0.05). Administration of the mixed liquid meal showed a comparable phenomenon. In contrast to GLP-1 and PYY, plasma ghrelin was suppressed to a similar degree both with intragastric and intraduodenal nutrients. Our data confirm that the stomach is an important element in the short-term control of appetite and suggest that gastric and intestinal signals interact to mediate early fullness and satiation, potentially by increased GLP-1 and PYY secretions.
- PMID:
- 22215654
- [PubMed - as supplied by publisher]
Postprandial plasma PYY concentrations are associated with increased regional gray matter volume and rCBF declines in caudate nuclei - A combined MRI and H(2)(15)O PET study.
Source
Obesity and Diabetes Clinical Research Section, NIDDK-NIH, DHHS, Phoenix, AZ, USA.
Abstract
The anorexigenic gastrointestinal hormone Peptide YY plays an important role in the communication between the gastrointestinal tract and the central nervous system. PYY has been shown to modulate brain activity in regions implicated in reward and food related behavior. Its effects on brain structure however, remain unknown. Voxel-based morphometry was used to investigate the relationship between fasting and postprandial plasma PYY concentrations and regional gray matter volume (GMV). For this analysis twenty adult, non diabetic Caucasians were included (18F/2M, age 31±9y, percentage of body fat [PFAT] 32±8%) who had volumetric brain magnetic resonance images and underwent H(2)(15)O positron emission tomographic (PET) measurements of regional cerebral blood flow (rCBF), a marker of local neuronal activity, and measurements of plasma total PYY, prior to (fasting) and following a satiating liquid meal. Voxel-wise analysis revealed a regional positive association between postprandial PYY and gray matter volume bilaterally in the caudate nuclei. These associations remained significant (p<0.05) after small volume correction for multiple comparisons. Based on these findings we investigated whether postprandial PYY is associated with PET measured rCBF of the caudate nucleus. We found a significant negative association between average postprandial caudate rCBF and postprandial plasma PYY concentrations (r=-0.60, p<0.02, age, sex and PFAT adjusted). Average postprandial caudate rCBF was also negatively associated with rCBF in the right medial orbitofrontal cortex and the right hippocampal formation (p<0.05, corrected for multiple comparisons). Total PYY is positively associated with gray matter but negatively with postprandial activity in the caudate nuclei while caudate activity is negatively associated with rCBF in prefrontal and paralimbic regions implicated in reward behavior. Thus, PYY may act centrally to modulate eating behavior via striatal networks.
Copyright © 2011. Published by Elsevier Inc.
FASTING PLASMA PEPTIDE YY (PYY) CONCENTRATIONS ARE INCREASED IN PATIENTS WITH MAJOR DEPRESSION WHO ASSOCIATE WEIGHT LOSS.
Source
Diabetes, Endocrinology and Nutrition Department, Sabadell Hospital, Corporació Sanitària Universitària Parc Taulí, Institut Universitàri Parc Taulí Sabadell (UAB), Sabadell (Barcelona) Spain.
Abstract
Background: Many patients with major depression refer a decreased appetite and weight loss among their symptoms.Peptide YY (PYY) and ghrelin belong to the family of peptides of the gut-brain axis implicated in the regulation of appetite and energy metabolism. PYY stimulates a powerful central satiety response and ghrelin increases food intake and weight gain. Brain derived neurothrophic factor (BDNF) also contributes to the central control of food intake as an anorexigenic factor. Aim: To study fasting plasma total and acylated ghrelin, plasma PYY and serum BDNF levels in patients with major depression with weight loss as one of their symptoms and compare them with matched healthy controls. Subjects and Methods: Fifteen adult patients, 9 male and 6 female, with recent diagnosis of major depression, and sixteen healthy adult subjects, matched by age and anthropometric parameters were studied. All depressed patients referred weight loss and were not under antidepressant therapy. Fasting total PYY, total ghrelin and acylated ghrelin and BDNF were determined. Results: Fasting total PYY was higher in patients than controls (2.01±0.09 pmol/L vs. 1.29±0.16 pmol/L). There were no differences in fasting total ghrelin, acylated ghrelin or BDNF levels. Conclusions: Major depressed patients, with weight loss at diagnosis, showed higher fasting plasma PYY levels that could contribute to their reduced appetite.
Dietary Fiber, Gut Peptides, and Adipocytokines.
Source
1 Department of Pharmacology, Faculty of Medicine, Complutense University , Madrid, Spain .
Abstract
Abstract The consumption of dietary fiber (DF) has increased since it was related to the prevention of a range of illnesses and pathological conditions. DF can modify some gut hormones that regulate satiety and energy intake, thus also affecting lipid metabolism and energy expenditure. Among these gut hormones are ghrelin, glucagon-like peptide 1,peptide YY, and cholecystokinin. Adipose tissue is known to express and secrete a variety of products known as "adipocytokines," which are also affected by DF. Some of the most relevant adipocytokines include adiponectin, leptin, tumor necrosis factor-α, and interleukin-6. The release of adipocytokines, by either adipocytes or macrophage-infiltrated adipose tissue, leads to a chronic subinflammatory state that could play a central role in the development of insulin resistance and type 2 diabetes, therefore increasing the risk of cardiovascular disease associated with obesity. DF modulation of these molecules could also have positive effects on obesity, insulin resistance, and hyperlipidemia. This review is focused on the effects of DF on the above-mentioned gut peptides and adipocytokines.
Influence of bariatric surgery on remission of type 2 diabetes.
Source
Zakład Regulacji Metabolizmu, Instytut Biochemii, Wydział Biologii, Uniwersytet Warszawski.
Abstract
The plague of obesity afflicts an increasing group of people. Moreover type 2 diabetes, which is the most serious illness accompanying excessive weight, is becoming more and more common. Traditional methods of obesity treatment, such as diet and physical exercise, fail. This applies especially to people with class III obesity. The only successful way of treating obesity in their case is bariatric surgery. There are three types of bariatric surgery: restrictive procedures (reducing stomach volume), malabsorptive procedures, and mixed procedures, which combine both methods. In spite of the risk connected with the surgery and complications after it, bariatric procedures are advised to patients with class III obesity and class II with an accompanying illness which increases the probability of death. It has been proved that bariatric surgery not only eliminates obesity but also very frequently (in 90% of cases) leads to the remission of type 2 diabetes. Moreover, the remission occurs very fast - it takes place a long time before the patients reduce their weight, even within a few days after surgery. Detailed studies have shown that the remission of diabetes is caused mostly by the change of the gastro-intestinal hormones' profile, resulting from the surgery. These hormones include GLP-1, GIP,peptide YY, ghrelin and oxyntomodulin. Additionally, the change of the amount of adipose tissue after the surgery influences the level of adipokines, i.e. the hormones of the adipose tissue, among which the most important are leptin, adiponectin and resistin. Thus, bariatric surgery not only changes the shape of the gastrointestinal tract but it also modulates the hormonal activity. Bariatric surgery is considered as therapy not only for the obese but also for diabetic patients.
Expression of genes involved in energy homeostasis in the duodenum and liver of Holstein-Friesian and Jersey cows and their F1 hybrid.
Source
University College Dublin, Dublin 4, Ireland.
Abstract
Differences in feed intake and production efficiency in lactating Holstein-Friesian (HF), Jersey (JE) and JE × HF (F(1)) dairy cows have been reported. The liver-gut axis is important in the regulation of energy homeostasis, appetite behaviour and production efficiency. The objectives of this study were to determine: i) the effect of dairy cow genotype on the expression profiles of genes involved in energy homeostasis in duodenal and hepatic tissue, and ii) the association between the expression of these genes across both tissues and with economically important production efficiency traits. The expression of 27 candidate genes involved in energy homeostasis, feed intake and energy storage was measured by qPCR. Duodenal expression of the pro-opiomelanocortin (POMC), glucagon-like peptide 1 receptor (GLP1R) and insulin-like growth factor 1 (IGF1) genes were highest in HF. In contrast, hepatic expression of the leptin receptor (LEPR), insulin-like growth factor 1 receptor (IGF1R), protein kinase, AMP-activated, beta 1 (AMPKB1) and POMC genes were highest in the F(1) cross. In the duodenum, positive correlations were observed between mRNA expression of anorectic peptides (POMC and GLP1R), whereas a negative correlation was detected between orexigenic (ghrelin (GHRL)) and anorectic (peptide YY (PYY)) gene expression. A negative correlation was observed between duodenal POMC gene expression and both residual feed intake and milk production efficiency traits while GLP1R gene expression was negatively correlated with milk production efficiency traits. A heterotic effect was observed in hepatic expression of AMKPB1, IGF1R, LEPR, POMC in the F(1) genotype, possibly mediating improved feed efficiency in cross-bred cows. In conclusion, key genes involved in energy homeostasis and appetite behaviour are differentially expressed due to cow genotype in a tissue dependent fashion. POMC and GLP1R are potential candidate genes for the identification of SNPs regulating energetic efficiency in the dairy cow, which may be incorporated into future breeding programmes.
The influence of rest and exercise at a simulated altitude of 4000 m on appetite, energy intake and plasma concentrations of acylated ghrelin and peptide YY.
Source
1Loughborough University.
Abstract
The reason for high altitude anorexia is unclear but could involve alterations in the appetite hormones ghrelin and peptide YY (PYY). This study examined the effect of resting and exercising in hypoxia (12.7% O(2); approximately 4000 m) on appetite, energy intake and plasma concentrations of acylated ghrelin and PYY. Ten healthy males completed four, 7 h trials in an environmental chamber in a random order. The four trials were: control-normoxia, control-hypoxia, exercise-normoxia, exercise-hypoxia. During exercise trials, participants ran for 60 minutes at 70% of altitude specific VO(2) max and then rested. Participants rested throughout control trials. A standardised meal was consumed at 2 h and an ad libitum buffet meal at 5.5 h. Area under the curve values for hunger (assessed using visual analogue scales) tended to be lower during hypoxic trials than normoxic trials (repeated measures ANOVA, P = 0.07). Ad libitum energy intake was lower (P = 0.001) in hypoxia (5291 ± 2189 kJ) than normoxia (7718 ± 2356 kJ) (mean ± SD). Mean plasma acylated ghrelin concentrations were lower in hypoxia than normoxia (82 ± 66 versus 100 ± 69 pg(.)mL(-1); P = 0.005) whilst PYY concentrations tended to be higher in normoxia (32 ± 4 versus 30 ± 3 pmol(.)L(-1); P = 0.059). Exercise suppressed hunger and acylated ghrelin and increased PYY but did not influence ad libitum energy intake. These findings confirm that hypoxia suppresses hunger and food intake. Further research is required to determine if decreased concentrations of acylated ghrelin orchestrate this suppression.
Rosiglitazone decreases fasting plasma peptide YY(3-36) in type 2 diabetic women: a possible role in weight gain?
Source
Department of Endocrinology and Metabolism, Turkiye Yuksek Ihtisas Education and Research Hospital, Kızılay sokak, 06100, Sihhiye, Ankara, Turkey, zehraberberoglu@gmail.com.
Abstract
Rosiglitazone often results in weight gain. We hypothesized that rosiglitazone may modulate circulating levels of ghrelin and peptide YY(3-36) and this modulation may be related to weight-gaining effect of this agent. This study was designed as an open-label, randomized, controlled trial of 3-month duration. Women with newly diagnosed type 2 diabetes were studied. Twenty-eight of the 55 eligible participants were randomly assigned to receive rosiglitazone (4 mg/d). Twenty-seven patients with diabetes matched for age and body mass index served as controls on diet alone. We evaluated the effects of 3 months of rosiglitazone treatment on fasting peptide YY(3-36) and ghrelin levels, and anthropometric measurements. The 3-month administration of rosiglitazone reduced fasting plasma peptide YY(3-36) levels by 25%, the between-group difference was statistically significant. No effect of this thiazolidinedione compound on fasting ghrelin concentrations was observed at the end of study. The ghrelin/body mass index ratio also did not change significantly after treatment. Seventy-five percent of the women with diabetes complained of increased hunger at the end of study. Nevertheless, all subjects exhibited a decrease in fasting PYY levels after 3 months of rosiglitazone therapy, irrespective of the levels of hunger. There was no significant correlation between changes in peptide YY(3-36) and those in anthropometric parameters and insulin sensitivity at the end of the study. Rosiglitazone-induced decrease in fastingpeptide YY(3-36) levels may in part contribute to orexigenic and weight-gaining effect of this thiazolidinedione derivative.
Low Densities of Serotonin and Peptide YY Cells in the Colon of Patients with Irritable Bowel Syndrome.
Source
Section for Gastroenterology, Department of Medicine, Stord Helse-Fonna Hospital, Box 4000, 54 09, Stord, Norway, magdy.el-salhy@helse-fonna.no.
Abstract
BACKGROUND:
The gut hormones are important in regulating gastrointestinal motility. Disturbances in gastrointestinal motility have been reported in patients with irritable bowel syndrome (IBS). Reduced endocrine cell density, as revealed by chromogranin A, has been reported in the colon of IBS patients.
AIMS:
To investigate a possible abnormality in the colonic endocrine cells of IBS patients.
METHODS:
A total of 41 patients with IBS according to Rome Criteria III and 20 controls were included in the study. Biopsies from the right and left colon were obtained from both patients and controls during colonoscopy. The biopsies were immunostained for serotonin, peptide YY (PYY), pancreatic polypeptide (PP), entroglucagon, and somatostatin cells. Cell densities were quantified by computerized image analysis.
RESULTS:
Serotonin and PYY cell densities were reduced in the colon of IBS patients. PP, entroglucagon, and somatostatin-immunoreactive cells were too few to enable reliable quantification.
CONCLUSION:
The cause of these observations could be primary genetic defect(s), secondary to altered serotonin and/or PYY signaling systems and/or subclinical inflammation. Serotonin activates the submucosal sensory branch of the enteric nervous system and controls gastrointestinal motility and chloride secretion via interneurons and motor neurons. PYY stimulates absorption of water and electrolytes, and inhibits prostaglandin (PG) E2, and vasoactive intestinal peptide, which stimulates intestinal fluid secretion and is a major regulator of the "ileal brake". Although the cause and effect relationship of these findings is difficult to elucidate, the abnormalities reported here might contribute to the symptoms associated with IBS.
Physiology of weight loss surgery.
Source
Duke Endosurgery, Department of Surgery, Duke University, DUMC 3351, Duke University Medical Center, Durham, NC 27713, USA.
Abstract
The clinical outcomes achieved by bariatric surgery have been impressive. However, the physiologic mechanisms and complex metabolic effects of bariatric surgery are only now beginning to be understood. Ongoing research has contributed a large amount of data and shed new light on the science behind obesity and its treatment, and this article reviews the current understanding of metabolic and bariatric surgery physiology.
Copyright © 2011 Elsevier Inc. All rights reserved.
Gastric bypass surgery restores meal stimulation of the anorexigenic gut hormones glucagon-like peptide-1 and peptide YY independently of caloric restriction.
Source
Department of Surgery, DUMC 3351, Duke University Medical Center, Durham, NC, 27713, USA.
Abstract
BACKGROUND:
The effects of gastric bypass surgery on the secretion of the anorexigenic gut-derived hormones glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), independent of caloric restriction and due to different dietary macronutrients, is not well characterized. This study examines the effects of a mixed-nutrient or high-fat liquid meal on the postprandial stimulation of GLP-1 and PYY following gastric bypass or equivalent hypocaloric diet.
METHODS:
Total PYY and active GLP-1 were measured fasting and at multiple points after standardized mixed-nutrient and high-fat liquid meals in two matched groups of obese subjects. The meal stimulation tests were performed before and 14.6 ± 3.3 days after gastric bypass (GBP, n = 10) and before and after a 7-day hypocaloric liquid diet matching the post-GBP diet (control, n = 10).
RESULTS:
Mixed-nutrient and high-fat postprandial GLP-1 levels increased following GBP (mixed-nutrient peak: 85.0 ± 28.6-323 ± 51 pg/ml, P < 0.01; high-fat peak: 81.8 ± 9.6-278 ± 49 pg/ml, P < 0.01), but not after diet (mixed-nutrient peak: 104.4 ± 9.4-114.9 ± 15.8 pg/ml, P = NS; high-fat peak: 118.1 ± 16.4-104.4 ± 10.8 pg/ml, P = NS). The postprandial PYY response also increased after GBP but not diet, though the increase in peak PYY did not reach statistical significance (GBP mixed-nutrient peak: 134.8 ± 26.0-220.7 ± 52.9 pg/ml, P = 0.09; GBP high-fat peak: 142.1 ± 34.6-197.9 ± 12.7 pg/ml, P = 0.07; diet mixed-nutrient peak: 99.8 ± 8.0-101.1 ± 13.3 pg/ml, P = NS; diet high-fat peak: 105.0 ± 8.8-103.1 ± 11.8 pg/ml, P = NS). The postprandial GLP-1 response was not affected by the macronutrient content of the meal. However, following GBP the mixed-nutrient PYY total area under the curve (AUC(0-120)) was significantly greater than the high-fat PYY AUC(0-120) (22,081 ± 5,662 pg/ml min vs. 18,711 ± 1,811 pg/ml min, P = 0.04).
CONCLUSIONS:
Following GBP there is an increase in the postprandial stimulation of PYY and GLP-1 that is independent of caloric restriction. The phenomenon of "bariatric surgery-induced anorexia" may be linked to the increased levels after GBP.
Long-term persistence of hormonal adaptations to weight loss.
Source
Department of Medicine (Austin and Northern Health), University of Melbourne, Melbourne, VIC, Australia.
Abstract
BACKGROUND:
After weight loss, changes in the circulating levels of several peripheral hormones involved in the homeostatic regulation of body weight occur. Whether these changes are transient or persist over time may be important for an understanding of the reasons behind the high rate of weight regain after diet-induced weight loss.
METHODS:
We enrolled 50 overweight or obese patients without diabetes in a 10-week weight-loss program for which a very-low-energy diet was prescribed. At baseline (before weight loss), at 10 weeks (after program completion), and at 62 weeks, we examined circulating levels of leptin, ghrelin, peptide YY, gastric inhibitory polypeptide, glucagon-like peptide1, amylin, pancreatic polypeptide, cholecystokinin, and insulin and subjective ratings of appetite.
RESULTS:
Weight loss (mean [±SE], 13.5±0.5 kg) led to significant reductions in levels of leptin, peptide YY, cholecystokinin, insulin (P<0.001 for all comparisons), and amylin (P=0.002) and to increases in levels of ghrelin (P<0.001), gastric inhibitory polypeptide (P=0.004), and pancreatic polypeptide (P=0.008). There was also a significant increase in subjective appetite (P<0.001). One year after the initial weight loss, there were still significant differences from baseline in the mean levels of leptin (P<0.001), peptide YY (P<0.001), cholecystokinin (P=0.04), insulin (P=0.01), ghrelin (P<0.001), gastric inhibitory polypeptide (P<0.001), and pancreatic polypeptide (P=0.002), as well as hunger (P<0.001).
CONCLUSIONS:
One year after initial weight reduction, levels of the circulating mediators of appetite that encourage weight regain after diet-induced weight loss do not revert to the levels recorded before weight loss. Long-term strategies to counteract this change may be needed to prevent obesity relapse. (Funded by the National Health and Medical Research Council and others; ClinicalTrials.gov number, NCT00870259.).
Axon-like basal processes in enteroendocrine cells: characteristics and potential targets.
Source
Department of Medicine, Duke University and Veterans Affairs Medical Center, Durham, North Carolina, USA.
Abstract
Enteroendocrine cells (EECs) play a key role in nutrient digestion and absorption, and are essential for normal life. Recently, EEC function has received considerable attention because several gastrointestinal hormones modulate insulin secretion and food intake; and, gut hormone-based therapies have been developed to treat diabetes mellitus. Despite these advances, the regulation of EECs remains poorly understood. The development of transgenic mouse models that express green fluorescent proteins (GFP) under specific hormone promoters (e.g., peptide YY-GFP) is shedding light onto previously overlooked features of EECs. These cells have prominent cytoplasmic processes that extend underneath enterocytes, and in some EECs, such as the L cell of the distal ileum, the basal process can be over 50 μm long. These basal cytoplasmic processes resemble axons and end in synaptic-like bouton. The location and anatomy of these processes suggest two functions: (1) to monitor absorbed nutrients at the base of enterocytes; and (2) to convey electrochemical information through cell-cell connections with subepithelial myofibroblasts and/or nerves located directly beneath in the lamina propria. Understanding how EECs communicate with cells in the lamina propria may provide novel ways to treat metabolic disorders such as obesity and diabetes.
© 2011 Wiley Periodicals, Inc.
Salivary PYY: a putative bypass to satiety.
Source
Pediatrics, University of Florida, Gainesville, Florida, United States of America.
Abstract
Peptide YY(3-36) is a satiation hormone released postprandially into the bloodstream from L-endocrine cells in the gut epithelia. In the current report, we demonstrate PYY(3-36) is also present in murine as well as in human saliva. In mice, salivary PYY(3-36) derives from plasma and is also synthesized in the taste cells in taste buds of the tongue. Moreover, the cognate receptor Y2R is abundantly expressed in the basal layer of the progenitor cells of the tongue epithelia and von Ebner's gland. The acute augmentation of salivary PYY(3-36) induced stronger satiation as demonstrated in feeding behavioral studies. The effect is mediated through the activation of the specific Y2 receptor expressed in the lingual epithelial cells. In a long-term study involving diet-induced obese (DIO) mice, a sustained increase in PYY(3-36) was achieved using viral vector-mediated gene delivery targeting salivary glands. The chronic increase in salivary PYY(3-36) resulted in a significant long-term reduction in food intake (FI) and body weight (BW). Thus this study provides evidence for new functions of the previously characterized gut peptide PYY(3-36) suggesting a potential simple and efficient alternative therapeutic approach for the treatment of obesity.
Mechanisms responsible for excess weight loss after bariatric surgery.
Source
Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA. viorica.ionut@cshs.org
Abstract
Obesity has increased alarmingly in the United States and is increasing in many countries of the world. Because obesity is an important risk factor for type 2 diabetes and other chronic diseases, it is important to develop approaches to counter the rapid increase in adiposity. One approach is bariatric surgery, the most successful clinical intervention known for treating obesity. Surgery can result in impressive weight loss and improvement of obesity-related comorbidities. Yet the mechanisms responsible for this remarkable effect of surgery remain controversial. It is now clear that caloric restriction, per se, does not explain all the reduction in stored fat mass after surgery. A number of gastrointestinal hormones, including glucagon-like peptide (GLP)-1, peptide YY, oxyntomodulin, GLP-2, glucose-dependent insulinotropic polypeptide, ghrelin, and others, can play roles in energy homeostasis and could be involved in bariatric-surgery-related weight loss and weight loss maintenance. Vagal innervation may play a role. In addition, there may be other yet-uncharacterized factors that could participate. This review discusses the possible roles of these hormonal mechanisms in various types of bariatric surgery to help elucidate some of the potential mechanisms at play in short-term and long-term post-bariatric surgery weight loss. Understanding such mechanisms could lead to new and efficacious means to control or even reduce the epidemic of obesity.
© 2011 Diabetes Technology Society.
The gut hormones PYY 3-36 and GLP-1 7-36 amide reduce food intake and modulate brain activity in appetite centers in humans.
Source
Section of Investigative Medicine, Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, UK.
Abstract
Obesity is a major public health issue worldwide. Understanding how the brain controls appetite offers promising inroads toward new therapies for obesity. Peptide YY (PYY) and glucagon-like peptide 1 (GLP-1) are coreleased postprandially and reduce appetite and inhibit food intake when administered to humans. However, the effects of GLP-1 and the ways in which PYY and GLP-1 act together to modulate brain activity in humans are unknown. Here, we have used functional MRI to determine these effects in healthy, normal-weight human subjects and compared them to those seen physiologically following a meal. We provide a demonstration that the combined administration of PYY(3-36) and GLP-1(7-36 amide) to fasted human subjects leads to similar reductions in subsequent energy intake and brain activity, as observed physiologically following feeding.
Copyright © 2011 Elsevier Inc. All rights reserved.
Assessment of a fully active class A G protein-coupled receptor isolated from in vitro folding.
Source
Institute of Medical Physics and Biophysics, University of Leipzig, Härtelstr. 16-18, D-04107 Leipzig, Germany.
Abstract
We provide a protocol for the preparation of fully active Y2 G protein-coupled receptors (GPCRs). Although a valuable target for pharmaceutical research, information about the structure and dynamics of these molecules remains limited due to the difficulty in obtaining sufficient amounts of homogeneous and fully active receptors for in vitro studies. Recombinant expression of GPCRs as inclusion bodies provides the highest protein yields at lowest costs. But this strategy can only successfully be applied if the subsequent in vitro folding results in a high yield of active receptors and if this fraction can be isolated from the nonactive receptors in a homogeneous form. Here, we followed that strategy to provide large quantities of the human neuropeptide Y receptor type 2 and determined the folding yield before and after ligand affinity chromatography using a radioligand binding assay. Directly after folding, we achieved a proportion of ~25% active receptor. This value could be increased to ~96% using ligand affinity chromatography. Thus, a very homogeneous sample of the Y2 receptor could be prepared that exhibited a K(D) value of 0.1 ± 0.05 nM for the binding of polypeptide Y, which represents one of the natural ligands of the Y2 receptor.
Pharmacokinetics, pharmacodynamics, safety, and tolerability of JNJ-38431055, a novel GPR119 receptor agonist and potential antidiabetes agent, in healthy male subjects.
Source
Johnson & Johnson Pharmaceutical Research & Development, L.L.C., Spring House, Pennsylvania, USA. LKatz3@its.jnj.com
Abstract
The incidence of type 2 diabetes mellitus is increasing worldwide. Several G-protein-coupled receptor agonists are being studied for their efficacy as antidiabetes agents. JNJ-38431055 is a novel, potent, and orally available selective agonist of the glucose-dependent insulinotropic (GPR119) receptor. Double-blind, randomized, placebo-controlled studies were conducted to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of single oral doses of JNJ-38431055 (2.5-800 mg) in healthy male volunteers. The systemic exposure of JNJ-38431055 in plasma increased in proportion to the dose and was not influenced by coadministration of food. The terminal elimination half-life was ~13 h when administered as an oral suspension formulation. JNJ-38431055 was well tolerated and was not associated with hypoglycemia. As compared with placebo, single-dose oral JNJ-38431055 increased postmeal plasma glucagon-likepeptide 1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and peptide YY (PYY) concentrations but did not significantly decrease glucose excursion or increase insulin secretion. However, in a graded glucose infusion study, JNJ-38431055 was shown to induce a higher insulin secretion rate (ISR) relative to placebo at elevated plasma glucose levels. These studies provide evidence for the potential efficacy of JNJ-38431055 as an antidiabetes agent in humans.
A role for metalloendopeptidases in the breakdown of the gut hormone, PYY 3-36.
Source
Section of Investigative Medicine, Imperial College London, Commonwealth Building, Du Cane Road, London W12 0NN, United Kingdom.
Abstract
Peptide YY(3-36) (PYY(3-36)) is a gut hormone that acts on Y2 receptors to reduce appetite. Obese humans are sensitive to the anorectic effects of PYY(3-36) and display a blunted postprandial rise in PYY(3-36). Bariatric surgery results in increased circulating PYY-immunoreactivity, which appears to play a role in postoperative weight loss. The utility of PYY(3-36) as an antiobesity treatment is limited by its short circulating half-life. Insight into the mechanisms by which PYY(3-36) is degraded may aid design of long-acting PYY(3-36) analogues or enzyme inhibitor therapies. We aimed to investigate the role of metalloendopeptidases in PYY(3-36) degradation and determine whether modulation of these enzymes enhanced PYY(3-36) plasma levels and bioactivity in vivo. Degradation and resultant cleavage products of PYY(3-36) were characterized after incubation with neprilysin and meprin β and with a kidney brush border preparation in vitro. Specific metalloendopeptidase inhibitors were coadministered with PYY(3-36) to mice and subsequent PYY(3-36) plasma levels and bioactivity determined. Meprin β cleaves PYY(3-36) at multiple conserved acidic sites. Blocking the actions of meprin β prevents the degradative effect of kidney brush borders on PYY(3-36). In mice, pretreatment with actinonin significantly prolonged the anorectic effect of PYY(3-36) and maintained higher PYY(3-36) plasma levels than treatment with PYY(3-36) alone. These studies suggest that inhibiting the degradation of PYY(3-36) using specific inhibitor therapies and/or the design of analogues resistant to cleavage by meprins may be useful to antiobesity therapeutics.
The gut hormones in appetite regulation.
Source
Section of Investigative Medicine, Imperial College London, London W12 0NN, UK.
Abstract
Obesity has received much attention worldwide in association with an increased risk of cardiovascular diseases, diabetes, and cancer. At present, bariatric surgery is the only effective treatment for obesity in which long-term weight loss is achieved in patients. By contrast, pharmacological interventions for obesity are usually followed by weight regain. Although the exact mechanisms of long-term weight loss following bariatric surgery are yet to be fully elucidated, several gut hormones have been implicated. Gut hormones play a critical role in relaying signals of nutritional and energy status from the gut to the central nervous system, in order to regulate food intake. Cholecystokinin, peptide YY, pancreatic polypeptide, glucagon-like peptide-1, and oxyntomodulin act through distinct yet synergistic mechanisms to suppress appetite, whereas ghrelin stimulates food intake. Here, we discuss the role of gut hormones in the regulation of food intake and body weight.
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