peptide-yy and Obesity

The aim of this study was to perform a comprehensive literature review regarding the relevant hormonal and histologic changes observed after Roux-en-Y gastric bypass (RYGB). We aimed to describe the relevant hormonal (glucagon-like peptides 1 and 2 [GLP-1 and GLP-2], peptide YY [PYY], oxyntomodulin [OXM], bile acids [BA], cholecystokinin [CCK], ghrelin, glucagon, gastric inhibitory polypeptide [GIP], and amylin) profiles, as well as the histologic (mucosal cellular) adaptations happening after patients undergo RYGB. Our review compiles the current evidence and furthers the understanding of the rationale behind the food intake regulatory adaptations occurring after RYGB surgery. We identify gaps in the literature where the potential for future investigations and therapeutics may lie. We performed a comprehensive database search without language restrictions looking for RYGB bariatric surgery outcomes in patients with pre- and postoperative blood work hormonal profiling and/or gut mucosal biopsies. We gathered the relevant study results and describe them in this review. Where human findings were lacking, we included animal model studies. The amalgamation of physiologic, metabolic, and cellular adaptations following RYGB is yet to be fully characterized. This constitutes a fundamental aspiration for enhancing and individualizing obesity therapy.

Topics: Animals; Blood Glucose; Cholecystokinin; Gastric Bypass; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Obesity; Peptide YY

Determining if gastrointestinal (GI) hormone response to food intake differs between individuals with, and without, obesity may improve our understanding of obesity pathophysiology. A systematic review and meta-analysis of studies assessing the concentrations of GI hormones, as well as appetite ratings, following a test meal, in individuals with and without obesity was undertaken. Systematic searches were conducted in the databases MEDLINE, Embase, Cochrane Library, PsycINFO, Web of Science, and ClinicalTrials.gov. A total of 7514 unique articles were retrieved, 115 included in the systematic review, and 70 in the meta-analysis. The meta-analysis compared estimated standardized mean difference in GI hormones' concentration, as well as appetite ratings, between individuals with and without obesity. Basal and postprandial total ghrelin concentrations were lower in individuals with obesity compared with controls, and this was reflected by lower postprandial hunger ratings in the former. Individuals with obesity had a lower postprandial concentration of total peptide YY compared with controls, but no significant differences were found for glucagon-like peptide 1, cholecystokinin, or other appetite ratings. A large methodological and statistical heterogeneity among studies was found. More comprehensive studies are needed to understand if the differences observed are a cause or a consequence of obesity.

Topics: Appetite; Cholecystokinin; Gastrointestinal Hormones; Ghrelin; Humans; Obesity; Peptide YY; Postprandial Period

A systematic review and meta-analysis was performed to determine the effect of exercise training on fasting gastrointestinal appetite hormones in adults living with overweight and obesity. For eligibility, only randomised controlled trials (duration ≥ four weeks) examining the effect of exercise training interventions were considered. This review was registered in the International Prospective Register of Systematic Reviews (CRD42020218976). The searches were performed on five databases: MEDLINE, EMBASE, Cochrane Library, Web of Science, and Scopus. The initial search identified 13204 records. Nine studies, which include sixteen exercise interventions, met the criteria for inclusion. Meta-analysis was calculated as the standardised mean difference (Cohen's d). Exercise training had no effect on fasting concentrations of total ghrelin (d: 1.06, 95% CI -0.38 to 2.50, P = 0.15), acylated ghrelin (d: 0.08, 95% CI: -0.31 to 0.47, P = 0.68) and peptide YY (PYY) (d = -0.16, 95% CI: -0.62 to 0.31, P = 0.51) compared to the control group. Analysis of body mass index (BMI) (d: -0.31, 95% CI: -0.50 to -0.12, P < 0.01) and body mass (d: -0.22, 95% CI: -0.42 to -0.03, P = 0.03) found a significant reduction after exercise compared to controls. Overall, exercise interventions did not modify fasting concentrations of total ghrelin, acylated ghrelin, and PYY in individuals with overweight or obesity, although they reduced body mass and BMI. Thus, any upregulation of appetite and energy intake in individuals with overweight and obesity participating in exercise programmes is unlikely to be related to fasting concentrations of gastrointestinal appetite hormones.

Topics: Adult; Appetite; Exercise; Fasting; Gastrointestinal Hormones; Ghrelin; Humans; Obesity; Overweight; Peptide YY

Peptide YY (PYY) is a gastrointestinal hormone consisting of 36 amino acids, that is predominantly secreted by intestinal l-cells. Originally extracted from pig intestines, it belongs to the pancreatic polypeptide (PP) family, but has functions distinct from those of PP and neuropeptide Y (NPY). PYY is a potential treatment for type 2 diabetes mellitus (T2DM) because of its ability to delay gastric emptying, reduce appetite, decrease weight, and lower blood glucose. However, the clinical use of PYY is limited because it is rapidly cleared by the kidneys and degraded by enzymes. In recent years, researchers have conducted various structural modifications, including amino acid substitution, PEGylation, lipidation, and fusion of PYY with other proteins to prolong its half-life and enhance its biological activity. This study presents an overview of the recent progress on PYY, including its physiological functions, metabolites and structure-activity relationships.

Topics: Amino Acid Substitution; Amino Acids; Animals; Diabetes Mellitus, Type 2; Obesity; Peptide YY; Swine

Obesity is one of the major global threats to human health and risk factors for cardiometabolic diseases and certain cancers. Glucagon-like peptide-1 (GLP-1) plays a major role in appetite and glucose homeostasis and recently the USFDA approved GLP-1 agonists for the treatment of obesity and type 2 diabetes. GLP-1 is secreted from enteroendocrine L-cells in the distal part of the gastrointestinal (GI) tract in response to nutrient ingestion. Endogenously released GLP-1 has a very short half-life of <2 min and most of the nutrients are absorbed before reaching the distal GI tract and colon, which hinders the use of nutritional compounds for appetite regulation. The review article focuses on nutrients that endogenously stimulate GLP-1 and peptide YY (PYY) secretion via their receptors in order to decrease appetite as preventive action. In addition, various delivery technologies such as pH-sensitive, mucoadhesive, time-dependent, and enzyme-sensitive systems for colonic targeting of nutrients delivery are described. Sustained colonic delivery of nutritional compounds could be one of the most promising approaches to prevent obesity and associated metabolic diseases by, e.g., sustained GLP-1 release.

Topics: Appetite; Colon; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucose; Humans; Nutrients; Obesity; Peptide YY

Obesity is one of the major pandemics of the 21st century. Due to its multifactorial etiology, its treatment requires several actions, including dietary intervention and physical exercise. Excessive fat accumulation leads to several health problems involving alteration in the gut-microbiota-brain axis. This axis is characterized by multiple biological systems generating a network that allows bidirectional communication between intestinal bacteria and brain. This mutual communication maintains the homeostasis of the gastrointestinal, central nervous and microbial systems of animals. Moreover, this axis involves inflammatory, neural, and endocrine mechanisms, contributes to obesity pathogenesis. The axis also acts in appetite and satiety control and synthesizing hormones that participate in gastrointestinal functions. Exercise is a nonpharmacologic agent commonly used to prevent and treat obesity and other chronic degenerative diseases. Besides increasing energy expenditure, exercise induces the synthesis and liberation of several muscle-derived myokines and neuroendocrine peptides such as neuropeptide Y, peptide YY, ghrelin, and leptin, which act directly on the gut-microbiota-brain axis. Thus, exercise may serve as a rebalancing agent of the gut-microbiota-brain axis under the stimulus of chronic low-grade inflammation induced by obesity. So far, there is little evidence of modification of the gut-brain axis as a whole, and this narrative review aims to address the molecular pathways through which exercise may act in the context of disorders of the gut-brain axis due to obesity.

Topics: Animals; Brain-Gut Axis; Exercise; Microbiota; Obesity; Peptide YY

The antiobesity effects of activation of hypothalamic neuropeptide Y2 receptors (NPYR2) by the gut-derived hormone, peptide YY (PYY), are established. However, more recent insight into the biology of PYY has demonstrated remarkable benefits of sustained activation of pancreatic beta-cell NPYR1, that promises to open a new therapeutic avenue in diabetes.. The therapeutic applicability of NPYR2 agonists for obesity has been considered for many years. An alternative pathway for the clinical realisation of PYY-based drugs could be related to the development of NPYR1 agonists for treatment of diabetes. Thus, although stimulation of NPYR1 on pancreatic beta-cells has immediate insulinostatic effects, prolonged activation of these receptors leads to well defined beta-cell protective effects, with obvious positive implications for the treatment of diabetes. In this regard, NPYR1-specific, long-acting enzyme resistant PYY analogues, have been recently developed with encouraging preclinical effects observed on pancreatic islet architecture in diabetes. In agreement, the benefits of certain types of bariatric surgeries on beta-cell function and responsiveness have also been linked to elevated PYY secretion and NPY1 receptor activation.. Enzymatically stable forms of PYY, that selectively activate NPYR1, may have significant potential for preservation of beta-cell mass and the treatment of diabetes.

Topics: Diabetes Mellitus; Humans; Insulin-Secreting Cells; Islets of Langerhans; Obesity; Peptide YY

In this review, authors have selected from literature the most recent and suggestive studies on therapy of nonalcoholic fatty liver disease (NAFLD). The selected interventions regulate the action of gastrointestinal peptides, such as gastric inhibitory polypeptide (GIP), nesfatin, peptide YY, cholecystokinin, and glucagon-like peptide 1 (GLP-1). These hormones have been found frequently modified in obesity and/or type 2 diabetes mellitus, morbidities mostly associated with NAFLD. This disease has a very high prevalence worldwide and could evolve in a more severe form, that is, nonalcoholic steatohepatitis, characterized by inflammation and fibrosis. The findings shown by this article describe the metabolic effects of new drugs, mainly but not only, as well of some old substances.. Recent approaches, in animal models or in humans, use synthetic GLP-1 receptor agonists, a centrally administered antibody neutralizing GIP receptor, curcumin, compound being active on nesfatin, resveratrol (antiinflammatory agent), and Ginseg, both of them acting on nesfatin, a cholecystokinin receptor analogue, and finally coffee functioning on YY peptide.. The implications of the presented findings, if they are confirmed in larger clinical trials, likely open the door to future application in clinical practice. In fact, nowadays, patients have only diet and article (incl abstract and keywords) exercise as well accepted recommendations. Thus, there are unmet needs to find substances that could really improve the progression of nonalcoholic steatohepatitis toward liver cirrhosis and hepatocellular carcinoma.

Topics: Animals; Diabetes Mellitus, Type 2; Drugs, Investigational; Gastric Inhibitory Polypeptide; Gastrointestinal Tract; Glucagon-Like Peptide 1; Humans; Liver; Non-alcoholic Fatty Liver Disease; Obesity; Peptide Hormones; Peptide YY; Phytochemicals; Phytotherapy

Obesity represents an important public health challenge for the twenty-first century: globalised, highly prevalent and increasingly common with time, this condition is likely to reverse some of the hard-won gains in mortality accomplished in previous centuries. In the search for safe and effective therapies for obesity and its companion, type 2 diabetes mellitus (T2D), the gut hormone glucagon-like peptide-1 (GLP-1) has emerged as a forerunner and analogues thereof are now widely used in treatment of obesity and T2D, bringing proven benefits in improving glycaemia and weight loss and, notably, cardiovascular outcomes. However, GLP-1 alone is subject to limitations in terms of efficacy, and as a result, investigators are evaluating other gut hormones such as glucose-dependent insulinotropic peptide (GIP), glucagon and peptide YY (PYY) as possible partner hormones that may complement and enhance GLP-1's therapeutic effects. Such combination gut hormone therapies are in pharmaceutical development at present and are likely to make it to market within the next few years. This review examines the physiological basis for combination gut hormone therapy and presents the latest clinical results that underpin the excitement around these treatments. We also pose, however, some hard questions for the field which need to be answered before the full benefit of such treatments can be realised.

Topics: Animals; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Gastrointestinal Microbiome; Glucagon; Glucagon-Like Peptide 1; Humans; Obesity; Peptide YY

Obesity is one of the main challenges of public health in the 21st century. Obesity can induce a series of chronic metabolic diseases, such as diabetes, dyslipidemia, hypertension and nonalcoholic fatty liver, which seriously affect human health. Gut-brain axis, the two-direction pathway formed between enteric nervous system and central nervous system, plays a vital role in the occurrence and development of obesity. Gastrointestinal signals are projected through the gut-brain axis to nervous system, and respond to various gastrointestinal stimulation. The central nervous system regulates visceral activity through the gut-brain axis. Brain-gut peptides have important regulatory roles in the gut-brain axis. The brain-gut peptides of the gastrointestinal system and the nervous system regulate the gastrointestinal movement, feeling, secretion, absorption and other complex functions through endocrine, neurosecretion and paracrine to secrete peptides. Both neuropeptide Y and peptide YY belong to the pancreatic polypeptide family and are important brain-gut peptides. Neuropeptide Y and peptide YY have functions that are closely related to appetite regulation and obesity formation. This review describes the role of the gutbrain axis in regulating appetite and maintaining energy balance, and the functions of brain-gut peptides neuropeptide Y and peptide YY in obesity. The relationship between NPY and PYY and the interaction between the NPY-PYY signaling with the gut microbiota are also described in this review.

Topics: Animals; Brain; Gastrointestinal Tract; Homeostasis; Humans; Neuropeptide Y; Obesity; Peptide YY

The vast majority of research to date on the gut hormone Peptide YY (PYY) has focused on appetite suppression and body weight regulation effects. These biological actions are believed to occur through interaction of PYY with hypothalamic Y

Topics: Appetite Regulation; Diabetes Mellitus; Humans; Hypothalamus; Obesity; Peptide Fragments; Peptide YY; Receptors, Neuropeptide Y

A new strategy under development for the treatment of type 2 diabetes and obesity is to mimic some of the effects of bariatric surgery by delivering food-related stimuli to the distal gastrointestinal tract where they should enhance the release of gut hormones such as glucagon-like peptide-1 (GLP-1) and peptideYY (PYY). Methods include inhibition of food digestion and absorption in the upper GI tract, or oral delivery of stimuli in capsules or pelleted form to protect them against gastric degradation. A variety of agents have been tested in humans using capsules, microcapsules or pellets, delivering nutrients, bile acids, fatty acids and bitter compounds. This review examines the outcomes of these different approaches and supporting evidence from intestinal perfusion studies.

Topics: Bariatric Surgery; Diabetes Mellitus, Type 2; Food-Drug Interactions; Gastrointestinal Tract; Glucagon-Like Peptide 1; Humans; Incretins; Obesity; Peptide YY; Secretagogues

Obesity is a multifactorial, chronic disease that has proven difficult to treat. An increased understanding of aetiological mechanisms is critical to the development of more effective obesity prevention and treatment strategies. A growing body of empirical evidence has demonstrated parallels between obesity, overeating and substance abuse, including shared behavioural, psychological and neurophysiological factors implicated in the excessive intake of both food and substances of abuse. Several different lines of research have recently emerged that hold the potential to shed light on the connection between obesity, food reward and addiction, with studies examining changes in alcohol use/misuse after weight loss surgery providing a particularly interesting perspective on these interrelationships. However, these lines of investigation have proceeded in relative isolation, and relevant research findings have yet to be integrated in a synthesized, comprehensive manner. To provide an opportunity to achieve such a synthesis, a scientific symposium was convened at the Radcliffe Institute in Cambridge, Massachusetts. Invited participants were researchers working in diverse domains related to the intersection between obesity and addiction. Extensive discussion was generated suggesting novel research directions. In this article, we summarize and synthesize the symposium participants' ongoing research in this area, incorporating additional relevant research holding potential clues regarding the connections between obesity, weight loss surgery and addiction.

Topics: Alcohol Drinking; Alcoholism; Animals; Bariatric Surgery; Behavior, Addictive; Ethanol; Gastric Bypass; Glucagon-Like Peptide 1; Humans; Hyperphagia; Obesity; Peptide YY; Reward; Weight Loss

Gut hormones have long been understood to regulate food intake and metabolism. Bariatric surgery significantly elevates circulating gut hormone levels and is proven to affect acute remission of type 2 diabetes before any weight loss is observed. Subsequent weight loss is accrued over weeks to months but is sustained into the long term. Hence, there exists great enthusiasm to recapitulate these changes in gut hormones in the form of novel combination drugs for type 2 diabetes and obesity.

Topics: Animals; Cholecystokinin; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Gastrointestinal Tract; Glucagon-Like Peptide 1; Humans; Obesity; Oxyntomodulin; Peptide YY

In moderately or morbidly obese patients, bariatric surgery has been proven to be an effective therapeutic approach to control body weight and comorbidities. Surgery-mediated modulation of brain function via modified postoperative secretion of gut peptides and vagal nerve stimulation was identified as an underlying mechanism in weight loss and improvement of weight-related diseases. Increased basal and postprandial plasma levels of gastrointestinal hormones like glucagon-like peptide 1 and peptide YY that act on specific areas of the hypothalamus to reduce food intake, either directly or mediated by the vagus nerve, are observed after surgery while suppression of meal-induced ghrelin release is increased. Hormones released from the adipose tissue like leptin and adiponectin are also affected and leptin plasma levels are reduced in treated patients. Besides homeostatic control of body weight, surgery also changes hedonistic behavior in regard to food intake and cognitive performance involving the limbic system and prefrontal areas.

Topics: Adiponectin; Bariatric Surgery; Brain; Cognition; Eating; Energy Metabolism; Feeding Behavior; Ghrelin; Glucagon-Like Peptide 1; Homeostasis; Humans; Hypothalamus; Leptin; Limbic System; Obesity; Peptide YY; Prefrontal Cortex; Vagus Nerve

The efficacy of Roux-en-Y gastric-bypass (RYGB) and other bariatric surgeries in the management of obesity and type 2 diabetes mellitus and novel developments in gastrointestinal (GI) endocrinology have renewed interest in the roles of GI hormones in the control of eating, meal-related glycemia, and obesity. Here we review the nutrient-sensing mechanisms that control the secretion of four of these hormones, ghrelin, cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1), and peptide tyrosine tyrosine [PYY(3-36)], and their contributions to the controls of GI motor function, food intake, and meal-related increases in glycemia in healthy-weight and obese persons, as well as in RYGB patients. Their physiological roles as classical endocrine and as locally acting signals are discussed. Gastric emptying, the detection of specific digestive products by small intestinal enteroendocrine cells, and synergistic interactions among different GI loci all contribute to the secretion of ghrelin, CCK, GLP-1, and PYY(3-36). While CCK has been fully established as an endogenous endocrine control of eating in healthy-weight persons, the roles of all four hormones in eating in obese persons and following RYGB are uncertain. Similarly, only GLP-1 clearly contributes to the endocrine control of meal-related glycemia. It is likely that local signaling is involved in these hormones' actions, but methods to determine the physiological status of local signaling effects are lacking. Further research and fresh approaches are required to better understand ghrelin, CCK, GLP-1, and PYY(3-36) physiology; their roles in obesity and bariatric surgery; and their therapeutic potentials.

Topics: Blood Glucose; Cholecystokinin; Eating; Gastric Bypass; Ghrelin; Glucagon-Like Peptide 1; Humans; Obesity; Peptide Fragments; Peptide YY

The aims of this article were to review the discrepancy between numbers of people requiring weight loss treatment and results and to assess the potential effects of pharmacologic treatments (recently approved for obesity) and endoscopically deployed devices on quantitative GI traits in development for obesity treatment.. We conducted a review of relevant literature to achieve our objectives.. The 2013 guidelines increased the number of adults recommended for weight loss treatment by 20.9% (116.0 million to 140.2 million). There is an imbalance between efficacy and costs of commercial weight loss programs and drug therapy (average weight loss about 5 kg). The number of bariatric procedures performed in the United States has doubled in the past decade. The efficacy of bariatric surgery is attributed to reduction in the volume of the stomach, nutrient malabsorption with some types of surgery, increased postprandial incretin responses, and activation of farnesoid X receptor mechanisms. These GI and behavioral traits identify sub-phenotypes of obesity, based on recent research.. The mechanisms or traits targeted by drug and device treatments include centrally mediated alterations of appetite or satiation, diversion of nutrients, and alteration of stomach capacity, gastric emptying, or incretin hormones. Future treatment may be individualized based on quantitative GI and behavioral traits measured in obese patients.

Topics: Anti-Obesity Agents; Bariatric Surgery; Combined Modality Therapy; Depression; Endoscopy, Gastrointestinal; Equipment and Supplies; Feeding Behavior; Gastric Balloon; Gastric Bypass; Gastric Emptying; Gastroplasty; Glucagon-Like Peptide 1; Humans; Hypothalamus; Obesity; Organ Size; Peptide YY; Precision Medicine; Principal Component Analysis; Satiation; Stomach; Treatment Outcome; Weight Loss

Despite significant progress in understanding the homeostatic regulation of energy balance, successful therapeutic options for curbing obesity remain elusive. One potential target for the treatment of obesity is via manipulation of the gut-brain axis, a complex bidirectional communication system that is crucial in maintaining energy homeostasis. Indeed, ingested nutrients induce secretion of gut peptides that act either via paracrine signaling through vagal and non-vagal neuronal relays, or in an endocrine fashion via entry into circulation, to ultimately signal to the central nervous system where appropriate responses are generated. We review here the current hypotheses of nutrient sensing mechanisms of enteroendocrine cells, including the release of gut peptides, mainly cholecystokinin, glucagon-like peptide-1, and peptide YY, and subsequent gut-to-brain signaling pathways promoting a reduction of food intake and an increase in energy expenditure. Furthermore, this review highlights recent research suggesting this energy regulating gut-brain axis can be influenced by gut microbiota, potentially contributing to the development of obesity.

Topics: Animals; Appetite Regulation; Brain; Cholecystokinin; Energy Metabolism; Gastrointestinal Microbiome; Gastrointestinal Tract; Glucagon-Like Peptide 1; Humans; Obesity; Peptide YY; Signal Transduction

Pandemic obesity is the most pressing health issue of this century. The most successful treatment so far is bariatric surgery, but for various reasons, surgery cannot be applied to all patients who require treatment. Gastrointestinal hormones are likely to play a key role in the success of bariatric surgery. This article examines in detail three of these gut hormones: peptide YY, oxyntomodulin and pancreatic polypeptide, and reviews how recent developments may offer new targets for therapy.. Both the free fatty acid 2 and the melanocortin 4 receptors have been discovered to regulate peptide YY and glucagon-like peptide-1 secretion, and drugs targeting these may represent new antiobesity therapies. Dual agonism of glucagon-like peptide-1 and glucagon receptors, for example with oxyntomodulin, has synergistic effects in reducing appetite and increasing energy expenditure. Plasma pancreatic polypeptide concentration correlates with visceral adiposity, and may serve as a biomarker for metabolic syndrome.. Gut hormones continue to show promise on an individual basis as anti-obesity treatments, but combination therapies are needed to achieve beneficial effects comparable to bariatric surgery. Innovative pathways for stimulating native gut hormone secretion may well provide an alternative method for weight loss without necessitating the administration of gut hormone analogues via injection.

Topics: Biomarkers; Humans; Obesity; Oxyntomodulin; Pancreatic Polypeptide; Peptide YY

Obesity develops when energy intake exceeds energy expenditure over time. Numerous neurotransmitters, hormones, and factors have been implicated to coordinately control energy homeostasis, centrally and peripherally. However, the neuropeptide Y (NPY) system has emerged as the one with the most critical functions in this process. While NPY centrally promotes feeding and reduces energy expenditure, peptide YY (PYY) and pancreatic polypeptide (PP), the other family members, mediate satiety. Importantly, recent research has uncovered additional functions for these peptides that go beyond the simple feeding/satiety circuits and indicate a more extensive function in controlling energy homeostasis. In this review, we will discuss the actions of the NPY system in the regulation of energy balance, with a particular focus on energy expenditure.

Topics: Energy Intake; Energy Metabolism; Homeostasis; Humans; Hypothalamus; Neuropeptide Y; Obesity; Peptide YY

Although the role of peptide YY (PYY) as a regulator of energy homeostasis was first highlighted only in 2002, our understanding of the physiological role of PYY has since rapidly advanced. In recent years, insights from mechanistic studies in patients undergoing bariatric surgery, from pancreatic islet research, from functional neuroimaging studies, and from exercise research have greatly added to the field, and these areas provide the focus of discussion for this narrative review. We critically discuss recent findings relating to the role of PYY in mediating the beneficial effects of bariatric surgery, the role of PYY in glucose homeostasis, the role of hepatoportal PYY in mediating its central physiological effects, the specific modulation of brain regions by PYY, and the exercise-induced PYY response.

Topics: Adult; Animals; Bariatric Surgery; Energy Metabolism; Exercise; Female; Glucose; Homeostasis; Humans; Male; Obesity; Peptide YY; Weight Loss

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

The hormone PYY is released from the distal gut in response to nutrient ingestion. Numerous studies have shown that PYY3-36, the most abundant circulating isoform of PYY, reduces food intake when given to obese rodents and humans. Its infusion to mimic postprandial levels in fasting subjects inhibits appetite, suggesting a physiological role in postprandial satiety. However, the mechanisms underlying this effect remain unclear. Neuronal activity within several brain areas appears to be modified following peripheral administration of PYY3-36 and a direct effect on the central nervous system is possible. Several studies suggest that PYY3-36 levels are reduced in obesity and are elevated following gastric bypass surgery, possibly contributing to the increased feelings of satiety following this procedure. Whether PYY has a role in the regulation of energy expenditure is currently unclear. However, due to the clear appetite-inhibitory effect of PYY, this hormone continues to be investigated as a potential therapeutic agent in the treatment of obesity.

Topics: Animals; Appetite Regulation; Brain; Energy Intake; Energy Metabolism; Humans; Obesity; Peptide YY; Satiation

As obesity continues to be a global epidemic, research into the mechanisms of hunger and satiety and how those signals act to regulate energy homeostasis persists. Peptide YY (PYY) is an acute satiety signal released upon nutrient ingestion and has been shown to decrease food intake when administered exogenously. More recently, investigators have studied how different factors influence PYY release and circulating levels in humans. Some of these factors include exercise, macronutrient composition of the diet, body-weight status, adiposity levels, sex, race and ageing. The present article provides a succinct and comprehensive review of the recent literature published on the different factors that influence PYY release and circulating levels in humans. Where human data are insufficient, evidence in animal or cell models is summarised. Additionally, the present review explores the recent findings on PYY responses to different dietary fatty acids and how this new line of research will make an impact on future studies on PYY. Human demographics, such as sex and age, do not appear to influence PYY levels. Conversely, adiposity or BMI, race and acute exercise all influence circulating PYY levels. Both dietary fat and protein strongly stimulate PYY release. Furthermore, MUFA appear to result in a smaller PYY response compared with SFA and PUFA. PYY levels appear to be affected by acute exercise, macronutrient composition, adiposity, race and the composition of fatty acids from dietary fat.

Topics: Adipose Tissue; Adiposity; Animals; Body Mass Index; Diet; Dietary Fats; Dietary Proteins; Eating; Exercise; Fatty Acids; Humans; Obesity; Peptide YY; Racial Groups

Obesity continues to be a major public health problem in the United States and worldwide. While recent statistics have demonstrated that obesity rates have begun to plateau, more severe classes of obesity are accelerating at a faster pace with important implications in regards to treatment. Bariatric surgery has a profound and durable effect on weight loss, being to date one of the most successful interventions for obesity.. To provide updates to the possible role of gut hormones in post bariatric surgery weight loss and weight loss maintenance.. The current review examines the changes in gastro-intestinal hormones with bariatric surgery and the potential mechanisms by which these changes could result in decreased weight and adiposity.. The mechanism by which bariatric surgery results in body weight changes is incompletely elucidated, but it clearly goes beyond caloric restriction and malabsorption.. Changes in gastro-intestinal hormones, including increases in GLP-1, PYY, and oxyntomodulin, decreases in GIP and ghrelin, or the combined action of all these hormones might play a role in induction and long-term maintenance of weight loss.

Topics: Bariatric Surgery; Bile Acids and Salts; Caloric Restriction; Diabetes Mellitus, Type 2; Gastrointestinal Hormones; Ghrelin; Glucagon-Like Peptide 1; Humans; Obesity; Oxyntomodulin; Peptide YY; Postoperative Period; United States; Weight Loss

peripheral nervous system. Considering the structure and evolutionary origin, neuropeptide Y (NPY) is a peptide of the same family as peptide YY (PYY) and pancreatic polypeptide (PP). These proteins were discovered relatively recently, however, knowledge about them is deepened. They are 36-amino acid peptide acting through G-protein coupled receptors, Y1, Y2, Y3, Y4, Y5 and Y6. The diverse structure C-terminus of the peptide and protein binding to receptors affect the biological activity and the physiological effects on the digestive system, blood vessels, and the center of hunger and satiety in the hypothalamus. Peptides have anorexic properties, they regulate appetite and food intake mainly through the intestinal cerebrospinal axis and the hypothalamus. These substances represent an important potential target of new drugs in the long-term treatment and prevention of obesity. Furthermore, neuropeptide Y affects many processes depending on the central nervous system modifies ethanol consumption, affect circadian rhythms, memory processes, anxiety behavior. Peripherally NPY affects smooth muscle contraction of the blood vessels, blood pressure, and atherogenic processes. Conducted more thorough research trying to define the role and participation of various neuropeptides in the development of diseases of the pancreas and the gastrointestinal tract, cardiovascular system and use it for diagnosis.

Topics: Animals; Anxiety; Appetite; Circadian Rhythm; Eating; Gastrointestinal Tract; Humans; Hypothalamus; Neuropeptide Y; Obesity; Pancreatic Polypeptide; Peptide YY; Receptors, Neuropeptide Y

The gastrointestinal (GI) tract is a specialized sensory system that detects and responds to constant changes in nutrient- and bacterial-derived intestinal signals, thus contributing to controls of food intake. Chronic exposure to dietary fat causes morphological, physiological and metabolic changes leading to disruptions in the regulatory feeding pathways promoting more efficient fat absorption and utilization, blunted satiation signals and excess adiposity. Accumulating evidence demonstrates that impaired gastrointestinal signals following long-term high fat consumption are, at least partially, responsible for increased caloric intake. This review focuses on the role of dietary fat in modulating oral and post-oral chemosensory signaling elements responsible for lipid detection and responses, including changes in sensitivity to satiation signals, such as GLP-1, PYY and CCK and their impact on food intake and weight gain. Furthermore, the influence of the gut microbiota on mechanisms controlling energy regulation in the face of excessive fat exposure will be explored. The profound influence of dietary fats on altering complex regulatory feeding pathways can result in dysregulation of body weight and development of obesity, while restoration or manipulation of satiation signaling may prove an effective tool in prevention and treatment of obesity.

Topics: Adiposity; Animals; CD36 Antigens; Cholecystokinin; Dietary Fats; Energy Intake; Gastrointestinal Tract; Ghrelin; Glucagon-Like Peptide 1; Humans; Intestinal Absorption; Microbiota; Obesity; Peptide YY; Receptors, G-Protein-Coupled; Satiation; Signal Transduction; Taste; Weight Gain

Consumption of milk and dairy products has been associated with reduced risk of metabolic disorders and cardiovascular disease. Milk contains two primary sources of protein, casein (80%) and whey (20%). Recently, the beneficial physiological effects of whey protein on the control of food intake and glucose metabolism have been reported. Studies have shown an insulinotropic and glucose-lowering properties of whey protein in healthy and Type 2 diabetes subjects. Whey protein seems to induce these effects via bioactive peptides and amino acids generated during its gastrointestinal digestion. These amino acids and peptides stimulate the release of several gut hormones, such as cholecystokinin, peptide YY and the incretins gastric inhibitory peptide and glucagon-like peptide 1 that potentiate insulin secretion from β-cells and are associated with regulation of food intake. The bioactive peptides generated from whey protein may also serve as endogenous inhibitors of dipeptidyl peptidase-4 (DPP-4) in the proximal gut, preventing incretin degradation. Indeed, recently, DPP-4 inhibitors were identified in whey protein hydrolysates. This review will focus on the emerging properties of whey protein and its potential clinical application for obesity and Type 2 diabetes.

Topics: Appetite; Cholecystokinin; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Ghrelin; Glucagon-Like Peptide 1; Glucose; Humans; Incretins; Milk Proteins; Obesity; Peptide YY; Thermogenesis; Whey Proteins

Polyphenols are natural substances and are enriched in vegetables, fruits, grains, bark, tea, and wine. Some polyphenols have insulin-potentiating and anti-inflammatory effects, both of which are important in obesity. Dietary supplementation with polyphenolic compounds is associated with reduced diet-induced obesity and/or metabolic syndrome in animal and human studies. Insights into mechanisms that regulate food intake and satiety have led to an increased understanding of obesity but the pathogenesis underlying obesity is lacking. Food intake is subject to a complex regulation by the hypothalamus and other brain centers including the brain stem and the hippocampus. An intricate network of interacting feedback mechanisms that involve the aforementioned neural centers along with the stomach, gut, liver, thyroid, and adipose tissue in the periphery, influence the eventual outcome of food intake and satiety. Key peripheral signals, such as leptin, insulin, and ghrelin, have been linked to hypothalamic neuropeptide systems in energy regulation. This review will examine the neural centers important in food intake, the role of various neuropeptides, and the neurohormonal influence on food intake. The potential role of polyphenols in influencing the neuroregulatory factors, the neural signaling pathways and/or the peripheral feedback mechanisms that modulate food intake will also be examined.

Topics: Agouti-Related Protein; Animals; Dietary Supplements; Energy Intake; Gastric Mucosa; Ghrelin; Glucagon-Like Peptide 1; Humans; Hypothalamic Hormones; Hypothalamus; Insulin; Islet Amyloid Polypeptide; Leptin; Liver; Melanins; Melanocortins; Neuropeptide Y; Neurotransmitter Agents; Obesity; Peptide YY; Pituitary Hormones; Polyphenols; Satiation; Signal Transduction; Stomach; Thyroid Gland

Central nervous system (CNS) receives peripheral relevant information that are able to regulate individual's energy balance through metabolic, neural, and endocrine signals. Ingested nutrients come into contact with multiple sites in the gastrointestinal tract that have the potential to alter peptide and neural signaling. There is a strong relationship between CNS and those peripheral signals (as gastrointestinal hormones) in the control of food intake. The purpose of this review is to give updated information about the role of gut hormones as mediators of feeding behavior and of different nutrients in modulating gut hormones production. The role of gut hormones in the pathogenesis of emerging diseases as obesity and non-alcoholic fatty liver disease (NAFLD) is also discussed together with the possible role of these peripheral signals as targets of future therapeutic options.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Brain Stem; Cholecystokinin; Eating; Energy Intake; Energy Metabolism; Fatty Liver; Feeding Behavior; Gastrointestinal Hormones; Ghrelin; Glucagon-Like Peptide 1; Humans; Hunger; Hyperphagia; Non-alcoholic Fatty Liver Disease; Obesity; Peptide YY; Satiation

Nonalcoholic steatohepatitis (NASH) is a stage of nonalcoholic fatty liver disease (NAFLD), and in most patients, is associated with obesity and the metabolic syndrome. The current best treatment of NAFLD and NASH is weight reduction with the current options being life style modifications, with or without pharmaceuticals, and bariatric surgery. Bariatric surgery is an effective treatment option for individuals who are severely obese (body mass index ≥ 35 kg/m(2)), and provides for long-term weight loss and resolution of obesity-associated diseases in most patients. Regression and/or histologic improvement of NASH have been documented after bariatric surgery. We review the available literature reporting on the impact of the various bariatric surgery techniques on NASH.

Topics: Bariatric Surgery; Fatty Liver; Ghrelin; Glucagon-Like Peptide 1; Humans; Non-alcoholic Fatty Liver Disease; Obesity; Peptide YY; Weight Loss

Peptide YY has been found to reduce food intake via the vagal-brainstem-hypothalamic pathway. There is some indication that PYY levels may differ in early childhood in comparison with adult studies. Studies of PYY in children have yet to be synthesized.. This review synthesized 21 articles including studies with infants/newborns, primary school age children and populations with special health needs.. Some important differences emerge between studies of PYY in children in comparison to those with adults. In those studies with infants and newborns, there is a high level of PYY in preterm and full-term neonates in comparison with school age children and adults. As children get older the relationship between PYY levels and body composition and obesity is more similar to that of adults. Fasting PYY levels may be lower in obese children in comparison with adults and weight loss may restore a higher postprandial level of PYY in contrast with adults whose levels remain low.. Additional studies are needed to better understand the role of higher PYY in infancy and to assess the effectiveness of different diets on children throughout time-points in growth and development as well as those with different racial/ethnic background.

Topics: Adult; Child; Diet; Humans; Obesity; Peptide YY

Dysregulation of nutrient homeostasis is implicated in the current epidemics of obesity and type 2 diabetes mellitus. The maintenance of homeostasis in the setting of repeated cycles of feeding and fasting occurs through complex interactions between metabolic, hormonal and neural factors. Although pancreatic islets, the liver, muscle, adipocytes and the central nervous system are all key players in this network, the gastrointestinal tract is the first tissue exposed to ingested nutrients and thus has an important role. This Review focuses on several of the endocrine hormones released by the gastrointestinal tract prior to or during nutrient ingestion that have key roles in maintaining energy balance. These hormones include the gastric orexigenic hormone, ghrelin, and the distal L cell anorexigenic and metabolic hormones, glucagon-like peptide (GLP)-1, GLP-2, oxyntomodulin and peptide YY. Each of these hormones exerts a distinct set of biological actions to maintain nutrient homeostasis, the properties of which are currently, or might soon be, exploited in the clinic for the treatment of obesity and type 2 diabetes mellitus.

Topics: Diabetes Mellitus, Type 2; Digestive System; Energy Metabolism; Food; Ghrelin; Glucagon-Like Peptides; Homeostasis; Humans; Obesity; Oxyntomodulin; Peptide YY

Ghrelin and peptide YY (PYY) are brain-gut peptides that have a variety of physiological functions and are involved in energy regulation. Thus far, abnormalities in the expression and secretion of ghrelin and PYY are known to occur in lifestyle-related diseases, including obesity, and the improvement of these abnormalities has become an important challenge. Exercise has recently been reported to influence ghrelin and PYY concentrations. Exercise increases the PYY secretion. The effects of exercise on ghrelin levels vary with the study subject, timing of exercise, and duration of exercise. Here, we review the findings of recent studies on the association of PYY and ghrelin with obesity, particularly, on the influence of exercise on PYY and ghrelin levels.

Topics: Energy Metabolism; Exercise; Ghrelin; Humans; Obesity; Peptide YY

NPY, PYY and PP constitute the so-called NPY hormone family, which exert its biological functions in humans through YRs (Y₁, Y₂, Y₄ and Y₅). Systematic modulation of YR function became important as this multireceptor/multiligand system is known to mediate various essential physiological key functions and is involved in a variety of major human diseases such as epilepsy, obesity and cancer. As several YRs have been found to be overexpressed on different types of malignant tumors they emerge as promising target in modern drug development. Here, we summarize the current understanding of YRs function and the molecular mechanisms of ligand binding and trafficking. We further address recent advances in YR-based drug design, the development of promising future drug candidates and novel approaches in YR-targeted tumor diagnostics and therapy opportunities.

Topics: Drug Design; Humans; Ligands; Molecular Structure; Neoplasms; Neuropeptide Y; Obesity; Pancreatic Polypeptide; Peptide YY; Protein Isoforms; Receptors, Neuropeptide Y

The intestine is an important metabolic organ that has gained attention in recent years for the newly identified role that it plays in the pathophysiology of various metabolic diseases including obesity, insulin resistance and diabetes. Recent insights regarding the role of enteroendocrine hormones, such as GIP, GLP-1, and PYY in metabolic diseases, as well as the emerging role of the gut microbial community and gastric bypass bariatric surgeries in modulating metabolic function and dysfunction have sparked a wave of interest in understanding the mechanisms involved, in an effort to identify new therapeutics and novel regulators of metabolism. This review summarizes the current evidence that the gastrointestinal tract has a key role in the development of obesity, inflammation, insulin resistance and diabetes and discusses the possible players that can be targeted for therapeutic intervention.

Topics: Animals; Bariatric Surgery; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Gastrointestinal Hormones; Gastrointestinal Tract; Glucagon-Like Peptide 1; Humans; Inflammation; Insulin Resistance; Metabolic Diseases; Metagenome; Obesity; Peptide YY

Ghrelin is a peptide hormone secreted into circulation from the stomach. It has been postulated to act as a signal of hunger. Ghrelin administration acutely increases energy intake in lean and obese humans and chronically induces weight gain and adiposity in rodents. Circulating ghrelin levels are elevated by fasting and suppressed following a meal. Inhibiting ghrelin signaling therefore appears an attractive target for anti-obesity therapies. A number of different approaches to inhibiting the ghrelin system to treat obesity have been explored. Despite this, over a decade after its discovery, no ghrelin based anti-obesity therapies are close to reaching the market. This article discusses the role of ghrelin in appetite control in humans, examines different approaches to inhibiting the ghrelin system and assesses their potential as anti-obesity therapies.

Topics: Acyltransferases; Adipose Tissue; Adiposity; Animals; Antibodies, Neutralizing; Appetite; Appetite Regulation; Eating; Fasting; Ghrelin; Humans; Hunger; Mice; Obesity; Peptide Hormones; Peptide YY; Peptides; Rats; Receptors, Ghrelin; Satiety Response; Substance P; Weight Gain

The obesity epidemic has a direct impact on every aspect of health. Current strategies to treat obesity are limited and there is a need to pioneer novel solutions. Anorectic gut hormones, physiologically secreted post-prandially to mediate satiety, have recently emerged as potential therapeutic targets in obesity. Peptide tyrosine tyrosine (PYY) is one such anorectic gut hormone, secreted from entero-endocrine L cells, which acts on neuropeptide Y (NPY) receptors within the central appetite circuit. Since the first intravenous administration of PYY to man nearly a decade ago, a number of translational studies and clinical trials have ensued with a view to developing this peptide as a treatment for obesity. This review reports on the current state of play of this on-going research.

Topics: Animals; Anti-Obesity Agents; Appetite Depressants; Gastrointestinal Agents; Humans; Molecular Targeted Therapy; Obesity; Peptide YY; Receptors, Gastrointestinal Hormone; Receptors, Neuropeptide Y; Signal Transduction; Translational Research, Biomedical

Obesity is one of the greatest public health challenges of the 21st century with 1.6 billion adults currently classified as being overweight and 400 million as obese. Obesity is causally associated with type 2 diabetes, hypertension, cardiovascular disease, obstructive sleep apnoea and certain forms of cancer and is now one of the leading causes of mortality and morbidity worldwide. The gastrointestinal tract is the largest endocrine organ in the body producing hormones that have important sensing and signaling roles in regulating body weight and energy expenditure. The last decade has witnessed a marked increase in our understanding of the role of gut hormones in energy homeostasis. Consequently, strategies aimed at modulating circulating gut hormone concentrations or targeting their receptors are being developed as potential pharmacotherapies for obesity. This review summarizes the current knowledge regarding the mechanisms, sites of action and effects of the anorectic gut hormones peptide tyrosine-tyrosine (PYY), pancreatic polypeptide (PP), oxyntomodulin, and amylin and of the unique orexigenic hormone, ghrelin.

Topics: Amyloid; Animals; Body Weight; Energy Metabolism; Gastrointestinal Hormones; Gastrointestinal Tract; Ghrelin; Homeostasis; Humans; Islet Amyloid Polypeptide; Obesity; Oxyntomodulin; Pancreatic Polypeptide; Peptide YY

A great deal of research interest is directed toward understanding the control of appetite and regulation of metabolism. It seems as if an epidemic of obesity is sweeping the world, and type II diabetes (T2DM) is following in its wake. The regulation of energy homeostasis is an area that straddles neurobiology, classical endocrinology and metabolism. It is currently one of the most exciting and rapidly advancing topics in medical research, and is also one of the most frustrating areas. The availability of highly palatable, calorie-dense food, together with the low requirement for physical activity in our modern environment, are major factors contributing to the obesity epidemic. If energy intake exceeds energy use, the excess calories are stored as body fat. Knowledge of the homeostatic system that controls body weight has increased dramatically over the last years and has revealed new potential targets for the treatment of obesity. One therapeutic approach is the development of agents based on the gastrointestinal hormones that control food intake and appetite. This review discusses several gut hormones and ligands for their receptors as potential anti-obesity treatments.

Topics: Amyloid; Gastrointestinal Hormones; Ghrelin; Glucagon-Like Peptide 1; Humans; Islet Amyloid Polypeptide; Obesity; Peptide YY

Bariatric surgery is the most effective treatment modality for obesity, resulting in durable weight loss and amelioration of obesity-associated comorbidities, particularly type 2 diabetes mellitus (T2DM). Moreover, the metabolic benefits of bariatric surgery occur independently of weight loss. There is increasing evidence that surgically induced alterations in circulating gut hormones mediate these beneficial effects of bariatric surgery. Here, we summarise current knowledge on the effects of different bariatric procedures on circulating gut hormone levels. We also discuss the theories that have been put forward to explain the weight loss and T2DM resolution following bariatric surgery. Understanding the mechanisms mediating these beneficial outcomes of bariatric surgery could result in new non-surgical treatment strategies for obesity and T2DM.

Topics: Bariatric Surgery; Caloric Restriction; Diabetes Mellitus, Type 2; Energy Metabolism; Ghrelin; Glucagon-Like Peptide 1; Humans; Obesity; Peptide YY; Weight Loss

The gastrointestinal tract is the largest endocrine organ in the body. It secretes more than 20 different peptide hormones, which serve both a local regulatory function and provide a means by which the gut can regulate appetite and satiety. As the worldwide prevalence of obesity reaches epidemic proportions, the importance of delineating the mechanisms which regulate food intake becomes even more urgent. There is now a substantial body of work in both rodent and human models demonstrating the effects of these peptides on appetite and work is underway to therapeutically manipulate the gut-brain axis for the treatment of obesity. In addition, it may also be possible to use our understanding of the entero-endocrine system to treat calorie-deficient states.

Topics: Animals; Appetite Regulation; Cholecystokinin; Eating; Gastrointestinal Hormones; Ghrelin; Glucagon-Like Peptide 1; Humans; Models, Animal; Obesity; Oxyntomodulin; Pancreatic Polypeptide; Peptide YY; Satiety Response

Amylin is a pancreatic B-cell hormone that plays an important role in the control of nutrient fluxes because it reduces food intake, slows gastric emptying, and reduces postprandial glucagon secretion. These actions seem to depend on a direct effect on the area postrema (AP). Subsequent to area AP activation, the amylin signal is conveyed to the forebrain via distinct relay stations. Within the lateral hypothalamic area, amylin diminishes the expression of orexigenic neuropeptides. Recent studies suggest that amylin may also play a role as a long term, adiposity signal. Similar to leptin or insulin, an infusion of amylin into the brain resulted in lower body weight gain than in controls, irrespective of the starting body weight. Interestingly, preliminary data also suggest that rats fed an energy-dense diet develop resistance to central amylin. In addition to amylin's action to control meal termination and to act as a potential adiposity signal, amylin and its agonist salmon calcitonin have recently been shown to increase energy expenditure under certain conditions. In summary, amylin may be an interesting target as a body weight lowering drug. In fact, recent studies provide evidence that amylin, especially when combined with other anorectic hormones (for example, peptide YY and leptin) has beneficial long-term effects on body weight.

Topics: Adiposity; Amyloid; Animals; Appetite Depressants; Appetite Regulation; Area Postrema; Dose-Response Relationship, Drug; Energy Metabolism; Feeding Behavior; Humans; Islet Amyloid Polypeptide; Leptin; Obesity; Peptide YY; Proto-Oncogene Proteins c-fos; Rats; Satiety Response; Weight Gain

Gut peptides play multiple roles in the controls of gastrointestinal function and in the initiation and termination of meals. Plasma levels of these peptides are differentially affected by the presence of nutrients in the digestive tract, and the patterns of peptide release are consistent with both their feeding stimulatory and inhibitory actions. A number of these peptide systems have been investigated as potential targets for antiobesity drug development. Progress has been made in developing long-acting peptide analogs and, in some cases, nonpeptide agonists and antagonists. Whether any individual approach will have significant long-term efficacy remains to be demonstrated. Approaches that target multiple systems may hold the most promise.

Topics: Anti-Obesity Agents; Cholecystokinin; Eating; Gastrointestinal Hormones; Glucagon-Like Peptide 1; Humans; Obesity; Peptide YY

The function of the stomach and the gut hormonal responses to food ingestion constitute highly integrated homeostatic responses that maintain euglycemia and normal digestion. This intrinsic feedback involves vagal and hormonal mechanisms. Important signals such as GLP-1 and PYY that arise peripherally induce satiation and also delay gastric emptying or increase insulin secretion. Novel therapies are being developed to mimic or enhance these feedback mechanisms and to control appetite as a means to treat obesity.

Topics: Animals; Anti-Obesity Agents; Appetite; Gastrointestinal Motility; Glucagon-Like Peptide 1; Humans; Incretins; Obesity; Peptide YY; Satiation

Bariatric surgery is the only effective treatment for patients with morbid obesity. This is no solution to the present obesity pandemic however. Currently licensed non-surgical pharmaceuticals are of limited efficacy and alternatives are needed. Harnessing the body's own appetite-regulating signals is a desirable pharmacological strategy. The gastrointestinal tract has a prime role in sensing and signalling food intake to the brain. Gut hormones are key mediators of this information, including: peptide YY (PYY), pancreatic polypeptide (PP), glucagon-like peptide 1 (GLP-1), oxyntomodulin (OXM), ghrelin, amylin and cholecystokinin (CCK). This review summarises the latest knowledge regarding the physiological and pathophysiological role of gut hormones in regulating our food intake and how this knowledge could guide, or has guided, the development of weight-loss drugs. Up-to-date outcomes of clinical trials are evaluated and directions for the future suggested.

Topics: Amyloid; Animals; Cholecystokinin; Gastrointestinal Hormones; Ghrelin; Glucagon-Like Peptide 1; Humans; Islet Amyloid Polypeptide; Obesity; Oxyntomodulin; Pancreatic Polypeptide; Peptide YY

Our knowledge of the complex mechanisms underlying energy homeostasis has expanded enormously in recent years. Food intake and body weight are tightly regulated by the hypothalamus, brainstem and reward circuits, on the basis both of cognitive inputs and of diverse humoral and neuronal signals of nutritional status. Several gut hormones, including cholecystokinin, glucagon-like peptide-1, peptide YY, oxyntomodulin, amylin, pancreatic polypeptide and ghrelin, have been shown to play an important role in regulating short-term food intake. These hormones therefore represent potential targets in the development of novel anti-obesity drugs. This review focuses on the role of gut hormones in short- and long-term regulation of food intake, and on the current state of development of gut hormone-based obesity therapies.

Topics: Amyloid; Anti-Obesity Agents; Appetite Depressants; Appetite Regulation; Cholecystokinin; Eating; Energy Metabolism; Gastrointestinal Agents; Ghrelin; Humans; Islet Amyloid Polypeptide; Obesity; Oxyntomodulin; Pancreatic Polypeptide; Peptide YY

This review discusses the physiology of the hormones leptin, adiponectin, resistin, peptide YY, and ghrelin and how each of these contributes to energy homoeostasis, weight regulation, and the pathogenesis of obesity. The relationship these hormones have with insulin and insulin resistance is also discussed, and the potential therapeutic use of each of these hormones is also considered.

Topics: Adipokines; Adipose Tissue; Energy Metabolism; Ghrelin; Homeostasis; Humans; Obesity; Peptide YY

The increasing prevalence of obesity and the associated morbidity and mortality has resulted in a major research effort to identify mechanisms that regulate appetite. It is well established that the hypothalamus and brain stem are major sites in the central nervous system (CNS) that regulate appetite. Until recently the missing element has been how information regarding food intake and energy stores is communicated to the CNS. Gut hormones have recently been found to be an important element in this regulation, communicating information regarding food intake to the CNS. Several gut hormones have been found to exert anorectic effects. These include members of the Pancreatic Polypeptide (PP)-fold family, namely PP itself and also peptide tyrosine-tyrosine (PYY), the first gut hormone shown to have appetite-inhibiting properties. The other main class of anorectic gut hormones are those derived by proteolytic processing from proglucagon, most importantly glucagon-like peptide-1 (GLP-1) and oxyntomodulin. All of these are currently being investigated as the basis of treatments to prevent the development of obesity. So far the only gastrointestinal hormone demonstrated to stimulate appetite is ghrelin. Potential sites and mechanisms of action and therapeutic use of these gastrointestinal hormones are discussed.

Topics: Animals; Appetite; Appetite Regulation; Body Weight; Gastrointestinal Hormones; Ghrelin; Glucagon-Like Peptide 1; Humans; Obesity; Oxyntomodulin; Pancreatic Polypeptide; Peptide YY; Proglucagon; Signal Transduction

Appetite is regulated by a complex system of central and peripheral signals which interact in order to modulate the individual response to nutrient ingestion. Peripheral regulation includes satiety signals and adiposity signals, while central control is accomplished by several effectors, including the neuropeptidergic, monoaminergic and endocannabinoid systems. Satiety signals, including cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), originate from the gastrointestinal (GI) tract during a meal and, through the vagus nerve, reach the nucleus tractus solitarius (NTS) in the caudal brainstem. From NTS afferents fibers project to the arcuate nucleus (ARC), where satiety signals are integrated with adiposity signals, namely leptin and insulin, and with several hypothalamic and supra-hypothalamic inputs, thus creating a complex network of neural circuits which finally elaborate the individual response to a meal. As for the neuropeptidergic system, ARC neurons secrete orexigenic substances, such as neuropeptide Y (NPY) and agouti-related peptide (AGRP), and anorexigenic peptides such as pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART). Other brain areas involved in the control of food intake are located downstream the ARC: among these, the paraventricular nucleus (PVN), which produces anorexigenic peptides such as thyrotropin releasing hormone (TRH), corticotrophin releasing hormone (CRH) and oxytocin, the lateral hypothalamus (LHA) and perifornical area (PFA), secreting the orexigenic substances orexin-A (OXA) and melanin concentrating hormone (MCH). A great interest in endocannabinoids, important players in the regulation of food intake, has recently developed. In conclusion, the present work reviews the most recent insights into the complex and redundant molecular mechanisms regulating food intake, focusing on the most encouraging perspectives for the treatment of obesity.

Topics: Adiposity; Animals; Anti-Obesity Agents; Appetite Regulation; Arcuate Nucleus of Hypothalamus; Biogenic Monoamines; Cannabinoid Receptor Modulators; Cholecystokinin; Feeding Behavior; Ghrelin; Glucagon-Like Peptide 1; Humans; Insulin; Leptin; Neuropeptides; Neurosecretory Systems; Obesity; Peptide YY; Pituitary Hormone-Releasing Hormones; Satiety Response; Signal Transduction

This review discusses recent studies examining the effects of peptide YY on energy homeostasis, highlights the emerging hedonic effects of peptide YY and evaluates the therapeutic potential of the peptide YY system.. A role for exogenous PYY3-36 as an anorectic agent in obese humans and rodents has been established and weight loss effects demonstrated in obese rodents. New lines of evidence support a role for endogenous peptide YY in regulating energy homeostasis. The NPY-Y2 receptor mediates the anorectic actions of PYY3-36 with rodent studies implicating the hypothalamus, vagus and brainstem as key target sites. Functional imaging in humans has confirmed that PYY3-36 activates brainstem and hypothalamic regions. The greatest effects, however, were observed within the orbitofrontal cortex, a brain region involved in reward processing. Further evidence for a hedonic role for PYY3-36 is supported by rodent studies showing that PYY3-36 decreases the motivation to seek high-fat food. Rodent studies using selective Y2 agonists and strategies combining PYY3-36/Y2 agonists with other anorectic agents have revealed increased anorectic and weight-reducing effects.. Peptide YY plays a role in the integrative regulation of metabolism. The emerging hedonic effects of peptide YY together with the weight-reducing effects observed in obese rodents suggest that targeting the peptide YY system may offer a therapeutic strategy for obesity.

Topics: Animals; Energy Metabolism; Feeding Behavior; Homeostasis; Humans; Mice; Mice, Transgenic; Models, Biological; Obesity; Peptide Fragments; Peptide YY; Reward

Following the discovery of secretin in 1902, a host of further peptide hormones that are synthesised and released from the gastrointestinal tract have been identified. While their roles in the regulation of gastrointestinal function have been known for some time, it is now evident that many of these hormones also physiologically regulate energy balance. Our understanding of how gut hormones signal to the brain has advanced significantly in recent years. Several hormones, including peptide YY, pancreatic polypeptide, oxyntomodulin, glucagon-like peptide 1 and cholecystokinin function as satiety signals. In contrast, only ghrelin, produced by the stomach, has emerged as a putative hunger signal, appearing to act both as a meal initiator and a long-term body weight regulator. Recent research suggests that gut hormones can be manipulated to regulate energy balance in man and that obese subjects retain sensitivity to the actions of gut hormones. The worldwide obesity pandemic continues unabated, despite public health initiatives and current best therapy. Future gut hormone-based therapies may provide an effective and well-tolerated treatment for obesity.

Topics: Animals; Area Postrema; Cholecystokinin; Diet Therapy; Energy Metabolism; Feedback, Physiological; Gastrointestinal Hormones; Ghrelin; Glucagon-Like Peptide 1; Homeostasis; Humans; Hunger; Hypothalamus; Neuropeptide Y; Obesity; Oxyntomodulin; Pancreatic Polypeptide; Peptide YY; Receptors, Ghrelin; Satiety Response; Solitary Nucleus

The relentless rise in the prevalence of obesity predicts an exponential increase in the incidence of obesity-related complications. Medical and surgical treatments are necessary to prevent and treat obese co-morbidities, thereby avoiding disability and premature death. Interventions for obesity should be evaluated not by weight loss alone but against the new incidence in obesity-related co-morbidities, their remission or improvement. In combination with lifestyle measures, currently available pharmacological therapies -- rimonabant, orlistat and sibutramine -- achieve 5-10% weight loss, although a return to baseline is the norm after cessation of medication. All these agents demonstrate approximately 0.5% reduction in HbA1c in diabetic subjects; orlistat also reduces the new incidence of type 2 diabetes. Modest improvement in lipid profiles and reduced calculated cardiovascular risk is observed, but data on improvement of other co-morbidities are sparse. In contrast, surgical procedures that restrict food ingestion and/or curtail the absorptive surface area of the gut consistently achieve substantial weight loss, typically 20-35%, effect resolution of co-morbid conditions and improve quality of life. Although mortality is low, complications and hospitalisation are not uncommon after bariatric surgery. Intriguingly, surgical patients experience a reduction in appetite and report changes in food preference. Accentuation of the normal gastrointestinal hormonal response to food intake and possible changes in vagal afferent signalling are proposed to induce satiety. Increased understanding of body weight homeostasis and appetite regulation has provided an impressive list of potential targets for drug development, with the promise that single or combination therapy may ultimately challenge the supremacy of bariatric surgery.

Topics: Adipose Tissue; Amyloid; Anticonvulsants; Antidepressive Agents; Anxiety; Appetite Regulation; Bariatric Surgery; Body Mass Index; Bupropion; Cholecystokinin; Ciliary Neurotrophic Factor; Clinical Trials as Topic; Cyclobutanes; Depression; Diabetes Mellitus, Type 2; Female; Fluoxetine; Fructose; Ghrelin; Humans; Intra-Abdominal Fat; Islet Amyloid Polypeptide; Isoxazoles; Lactones; Leptin; Metabolic Syndrome; Metformin; Obesity; Obesity, Morbid; Orlistat; Oxyntomodulin; Peptide YY; Piperidines; Polycystic Ovary Syndrome; Pyrazoles; Rimonabant; Sertraline; Sleep Apnea, Obstructive; Surgical Procedures, Operative; Topiramate; Zonisamide

Most of the drugs that have entered the market for treating obesity were originally developed to treat psychiatric diseases. During the past decade, understanding of the neural circuits that underlie food intake has increased considerably. Different aspects of ingestive behavior such as meal termination, meal initiation and overconsumption of highly rewarding and palatable foods are modulated by different neuroanatomical structures. Integration of the action of many signaling molecules (e.g. hormones, neurotransmitters and neuropeptides) in these structures results in a response that, ultimately, modulates food intake. Thus, the type of drug required by an obese patient might depend on the individual cause of obesity. In this article, we summarize the neural circuits that regulate food intake and we provide a framework for understanding how obesity drugs function. Several potential drug targets are expressed in different neural circuits, implying that current and future obesity drugs act on partially overlapping systems that control food intake.

Topics: Animals; Anti-Obesity Agents; Arcuate Nucleus of Hypothalamus; Brain; Humans; Norepinephrine; Nucleus Accumbens; Obesity; Peptide YY; Pro-Opiomelanocortin; Satiation; Serotonin

The obesity epidemic is fast becoming one of the leading causes of mortality and morbidity worldwide. Over the past 30 years, gastrointestinal hormones have been increasingly understood to have an important role as regulators of appetite and energy balance in obese individuals. The levels of these hormones are modulated by bariatric surgery, and understanding how they are affected by such procedures can contribute to our comprehension of the underlying mechanisms by which these hormones affect obesity and its treatment. In this Review, we consider several gastrointestinal hormones that can contribute to obesity by modulating the activity of the gut-brain axis, and examine their specific effects on appetite, hunger and energy balance. Better understanding of the mechanisms by which these peptides exert their effects may enable the development of improved weight-loss medications and new treatments for obesity.

Topics: Appetite; Bariatric Surgery; Cholecystokinin; Gastric Inhibitory Polypeptide; Gastrointestinal Hormones; Ghrelin; Glucagon-Like Peptide 1; Humans; Obesity; Oxyntomodulin; Pancreatic Polypeptide; Peptide Hormones; Peptide YY

Obesity is a major cause of premature death in the UK, and may contribute to as many as 30 000 deaths a year in the UK. Although effective treatment for obesity is still awaited, many developments have occurred to improve our understanding of neuroendocrine regulation of food intake and weight gain, especially regarding the role of gut hormones. One such gut hormone is peptide tyrosine-tyrosine also known as PYY where Y depicts the abbreviation for tyrosine. PYY is a 36 amino acid hormone, first isolated from porcine intestine. PYY, along with few other gut hormones, has been suggested as a potential therapeutic agent for obesity. This review examines the relationship of PYY to appetite regulation, energy homeostasis and the relevant neuroendocrine feedback mechanism.

Topics: Animals; Anti-Obesity Agents; Appetite Regulation; Bariatric Surgery; Feeding and Eating Disorders; Genetic Predisposition to Disease; Humans; Obesity; Peptide Fragments; Peptide YY; Satiation

By itself, glucagon-like peptide-1(GLP-1) appears to be an excellent drug for appetite control and the treatment of obesity. Unfortunately, few enzymes, such as IV dipeptidyl peptidase and renal excretin, degrade and render GLP-1 inactive within minutes. A receptor agonist, exendin-4, with a longer biological half-life than GLP-1, has been tried. Subcutaneous injection of exendin-4 or continuous IV injection of GLP-1 warrants further research and investigation.

Topics: Animals; Appetite; Gastric Bypass; Ghrelin; Glucagon-Like Peptide 1; Humans; Obesity; Oxidative Stress; Oxyntomodulin; Peptide Hormones; Peptide YY

Obesity is an increasing global epidemic. Several central and peripheral hormones and neurotransmitters are involved in appetite control. Peptide YY (PYY) - one of the major anorexigenic (satiation-causing) gastrointestinal peptides - when administered peripherally, leads to decreased food intake and hunger scores.. The vagus nerve, brainstem, and hypothalamus play an important role in PYY-mediated appetite control. In some studies, fasting and postprandial PYY levels are decreased in obese subjects. In others, levels are no different between obese and nonobese subjects. One study showed that obese subjects must consume more calories to increase PYY to levels seen in nonobese subjects. Surgical weight-loss procedures lead to increased fasting and postprandial PYY levels that are thought to contribute to weight loss achieved with these procedures.. These findings lend some support for the association between PYY and obesity that could lead to possible new therapeutic options in obesity. PYY exerts anorexigenic effects; it is possible that surgical weight-loss procedures work synergistically with PYY to promote weight loss. Further investigation is needed to clarify whether PYY actually causes reduced calorie intake or whether the rate of food delivery to the ileo-colonic segment influences PYY levels, thus affecting satiation.

Topics: Animals; Eating; Humans; Hunger; Intestines; Obesity; Peptide YY; Satiety Response

Obesity is a rapidly increasing, worldwide epidemic. Despite recent scientific advances, no currently recommended dietary program or medication results in long-term weight loss of more than 10% of body weight for the vast majority of people who attempt these interventions. Hence, surgical intervention is recommended for patients with a BMI > or =40 kg/m2. Although surgery is an effective, sustainable treatment of obesity, it can be associated with potentially significant perioperative risks and long-term complications. Current research is focused on developing a medical therapy, which produces more effective and sustainable weight loss, yet avoids the risks inherent in major surgery. With a reduced risk profile, such therapy could also be appropriately offered to those who are less obese and, in theory, help those who have BMIs as low as 27 kg/m2. Toward that end, numerous scientists are working to both unravel the pathophysiology of obesity and to determine why surgical intervention is so effective. This review briefly examines the current status of obesity pathophysiology and management, the reasons for failure of conventional medical treatments, and the success of surgical intervention. Finally, future areas of research are discussed.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Bariatric Surgery; Gastric Bypass; Ghrelin; Humans; Hypothalamus; Obesity; Obesity, Morbid; Peptide Fragments; Peptide YY; Satiety Response; Signal Transduction; Weight Loss

The first hormone discovered in the gastrointestinal tract was secretin, isolated from duodenal mucosa. Some years later, two additional gastrointestinal hormones, gastrin and cholecystokinin (CCK), were discovered, but it was not until the 1970s that gastrointestinal endocrinology studies became more prevalent, resulting in the discovery of many more hormones. Here, we examine the role of gut hormones in energy balance regulation and their possible use as pharmaceutical targets for obesity.

Topics: Animals; Anti-Obesity Agents; Appetite Regulation; Body Weight; Energy Metabolism; Ghrelin; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Homeostasis; Humans; Obesity; Oxyntomodulin; Peptide Hormones; Peptide YY

A number of anti-obesity drugs are currently undergoing clinical development. These include: (i) centrally-acting drugs, such as the noradrenergic and dopaminergic reuptake inhibitor radafaxine, the endocannabinoid antagonist rimonabant, the selective serotonin 5-HT2c agonist APD-356, and oleoyl-estrone; (ii) drugs that target peripheral episodic satiety signals, such as glucagon-like peptide-1 (exenatide, exenatide-LAR and liraglutide), peptide YY (intranasal PYY3-36 and AC-162325) and amylin (pramlintide); (iii) drugs that block fat absorption, such as the novel lipase inhibitors cetilistat and GT-389255; and (iv) a human growth hormone fragment (AOD-9604) that increases adipose tissue breakdown. Of these, only rimonabant has got as far as completing phase III clinical trials. This review will provide an overview of the most prominent drugs currently undergoing clinical development as potential anti-obesity therapies.

Topics: Amyloid; Animals; Anti-Obesity Agents; Appetite Depressants; Energy Metabolism; Glucagon-Like Peptide 1; Humans; Islet Amyloid Polypeptide; Obesity; Peptide Fragments; Peptide YY; Receptor, Cannabinoid, CB1; Selective Serotonin Reuptake Inhibitors; Somatostatin

There is a growing worldwide epidemic of obesity. Obese people have a higher incidence of type 2 diabetes and cardiovascular disease, and hence present increasing social, financial and health burdens. Weight loss is always difficult to achieve through lifestyle changes alone, and currently licensed anti-obesity drug treatments, such as orlistat and sibutramine, if tolerated, only achieve modest weight loss. Therefore, there is a need to identify more potent pharmacological targets. In the last 10 years, discoveries of new hormones such as leptin and ghrelin, together with greater understanding of previously described hormones such as cholecystokinin (CCK), pancreatic polypeptide (PP), peptide YY (PYY) and glucagon-like peptide 1 (GLP-1), have led to a rapid increase in our knowledge of the regulation of energy balance. Among the most important factors, controlling appetite and satiety are peptide hormones released from the gut. In this paper, we provide a full up-to-date overview of the current state of knowledge of this field, together with the potential of these peptides as drugs, or as other therapeutic targets, in the treatment of obesity. Finally, we propose an integrated model to describe the complex interplay of these hormones in the broader physiology of energy balance.

Topics: Appetite Regulation; Cholecystokinin; Energy Metabolism; Gastrointestinal Hormones; Ghrelin; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Humans; Leptin; Obesity; Oxyntomodulin; Peptide Hormones; Peptide YY; Satiation

Peptide YY (PYY) is secreted as a 36 amino acid, straight chain polypeptide, and is found in greatest concentrations in the terminal ileum, colon and rectum. After secretion, dipeptidyl peptidase IV (DPP-IV) cleaves the N-terminal Tyrosine-Proline residues from PYY(1-36), producing PYY(3-36). PYY(1-36) acts at all four human Y receptors, Y1, Y2, Y4 and Y5, while PYY(336) is a specific Y2 receptor agonist. PYY participates in the regulation of appetite and weight balance through hypothalamic-based mechanisms. PYY(1-36) stimulates appetite and weight gain through Y1 and Y5 receptors. PYY(3-36) suppresses appetite and stimulates weight loss through Y2 receptors. GI diseases that cause malabsorption increase both basal and meal-stimulated PYY levels. In contrast, obesity decreases both basal and meal-stimulated PYY levels. Mutations in the human PYY and Y2 receptor genes may contribute to the development of obesity. Small bowel resection elevates PYY levels in humans. Colon resections increase PYY levels in animal models but not in man. PYY changes following bariatric operations are incompletely studied. Vertical banded gastroplasty, open Roux-en-Y gastric bypass and jejunoileal bypass significantly elevate basal and meal-stimulated PYY levels. In dogs with Pavlov pouches, Roux-en-Y duodenojejunostomy (duodenal switch) increases PYY levels compared to Roux-en-Y gastrojejunostomy. DPP-IV activity is increased in obese individuals and remains increased after biliopancreatic diversion. Thus, diseases or operations which cause malabsorption, elevate basal and meal-stimulated PYY levels. Bariatric operations also increase basal and meal-stimulated PYY levels. This suggests that the combination of increased PYY levels and elevated levels of DPP-IV observed after bariatric operations may generate increased circulating levels of PYY(3-36), leading to hypothalamic-mediated suppression of appetite and promotion of weight loss through Y2 receptor mediated mechanisms.

Topics: Animals; Appetite; Bariatric Surgery; Biliopancreatic Diversion; Colonic Pouches; Digestive System Surgical Procedures; Dipeptidyl Peptidase 4; Gastric Bypass; Gastrointestinal Diseases; Gastroplasty; Gastrostomy; Humans; Jejunoileal Bypass; Jejunostomy; Obesity; Obesity, Morbid; Peptide Fragments; Peptide YY; Polymorphism, Genetic; Postoperative Period; Proctocolectomy, Restorative

Oxyntomodulin and peptide tyrosine-tyrosine (PYY) are released from intestinal enteroendocrine cells in response to a meal. These circulating hormones are considered to be satiety signals, as they have been found to decrease food intake, body weight and adiposity in rodents. Their effect on energy homeostasis is mediated by the hypothalamus and brainstem, and several studies have demonstrated alterations in neuropeptide signaling within the arcuate nucleus. The weight loss that has been observed in animal models after repeated administration of oxyntomodulin and PYY has led to interest in developing these peptides as antiobesity therapies in humans. Indeed, preliminary studies have found that oxyntomodulin or PYY administration reduces food intake and body weight effectively in overweight human volunteers. This research suggests that modulation of these gut hormones could prove to be effective long-term therapies in the quest to combat the obesity epidemic.

Topics: Animals; Appetite Regulation; Brain; Gastrointestinal Tract; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Models, Biological; Obesity; Oxyntomodulin; Peptide YY; Receptors, Glucagon; Satiety Response

Recent progress in the field of energy homeostasis was triggered by the discovery of adipocyte hormone leptin and revealed a complex regulatory neuroendocrine network, which precisely regulates appetite. Discovery of ghrelin, a novel hormone derived from the stomach, has illustrated the relationship of the stomach and hypothalamus which is a crucial missing link in the regulation of energy balance, growth and coordinated gastrointestinal function. The discovery of ghrelin opens new perspectives of research with potential therapeutic relevance in patients with gastrointestinal, metabolic, endocrine and other diseases.

Topics: Animals; Appetite Regulation; Energy Metabolism; Gastrointestinal Hormones; Ghrelin; Human Growth Hormone; Humans; Hypothalamus; Leptin; Obesity; Peptide Hormones; Peptide YY; Stomach

Obesity is strongly associated with hypertension and cardiovascular disease. Several central and peripheral abnormalities that can explain the development or maintenance of high arterial pressure in obesity have been identified. These include activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system. Obesity is also associated with endothelial dysfunction and renal functional abnormalities that may play a role in the development of hypertension. The continuing discovery of mechanisms regulating appetite and metabolism is likely to lead to new therapies for obesity-induced hypertension. Better understanding of leptin signaling in the hypothalamus and the mechanisms of leptin resistance should facilitate therapeutic approaches to reverse the phenomenon of selective leptin resistance. Other hunger and satiety signals such as ghrelin and peptide YY are potentially attractive therapeutic strategies for treatment of obesity and its complications. These recent discoveries should lead to novel strategies for treatment of obesity and hypertension.

Topics: Adiponectin; Aldosterone; Animals; Appetite; Endothelium, Vascular; Energy Metabolism; Ghrelin; Humans; Hyperinsulinism; Hypertension; Intercellular Signaling Peptides and Proteins; Kidney; Leptin; Mice; Mice, Mutant Strains; Mineralocorticoid Receptor Antagonists; Obesity; Peptide Hormones; Peptide YY; Receptors, Cell Surface; Receptors, Leptin; Renin-Angiotensin System; Repressor Proteins; Satiation; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Sympathetic Nervous System; Transcription Factors

Obesity now represents a modern epidemic in western society with major health and economic consequences. Unfortunately, previous pharmacological approaches to the treatment of obesity have been associated with life-threatening side effects and limited efficacy. Over recent years there has been a marked increase in our understanding of the physiological mechanisms that regulate body weight and how these are perturbed in obesity. One therapeutic strategy is to develop drugs which both mimic and enhance the body's own satiety signals. The gut hormone peptide tyrosine tyrosine (PYY), which is released postprandially from the gastrointestinal tract, has recently been shown to be a physiological regulator of food intake. Peripheral administration of PYY reduces feeding in rodents via a mechanism which requires the Y2 receptor and is thought to primarily involve modulation of the hypothalamic arcuate nucleus (ARC) circuitry. In humans a single 90-minute infusion of PYY has been shown to markedly reduce subsequent 24-hour caloric intake in lean, normal-weight and obese subjects. Moreover, obese subjects have been found to have low levels of fasting and postprandial PYY suggesting a role for this hormone in the pathogenesis of obesity. Although studies examining the effects of chronic peripheral administration of PYY to humans are awaited, the results from continuous infusion studies in a number of obese rodent models are encouraging with reductions in food intake, body weight and adiposity observed. Potential therapeutic manipulations based on the PYY system include development of Y2 agonists, exogenously administration of PYY or increased endogenous release from the gastrointestinal tract.

Topics: Amino Acid Sequence; Animals; Appetite; Eating; Humans; Molecular Sequence Data; Obesity; Peptide YY; Receptors, Gastrointestinal Hormone; Stomach

Topics: Appetite; Cachexia; Energy Intake; Ghrelin; Humans; Hypothalamus; Obesity; Peptide Hormones; Peptide YY; Vagus Nerve

Energy balance is largely regulated by the central nervous system (CNS), which senses metabolic status from a wide range of humoral and neural signals, and controls energy intake. Accumulating evidence supports the model that stimulation of leptin- and ghrelin-responsive pathways, including the central melanocortin system, in the hypothalamus, contributes to the maintenance of body weight. Ghrelin is the brain-gut peptide with growth hormone-releasing and appetite-inducing activities. It is mainly secreted from the stomach and acts as an afferent signal to the hypothalamus and hindbrain. Leptin, the adipocyte hormone, is believed to tonically act as an afferent signal from adipose tissue to the brain, in particular hypothalamus, as a part of negative feedback loop regulating the size of energy stores and energy balance. Dysregulation of these pathways is a marker of changes in energy balance. Ghrelin is negatively correlated with weight and obese subjects have lower ghrelin levels than lean subjects, consistent with a compensatory rather than causal role for ghrelin in obesity. On the contrary, circulating leptin levels correlate in proportion to adiposity being high in obesity suggesting that human obesity is associated with insensitivity to leptin. The leptin resistance in diet-induced obesity emphasizes that environmental factors can modulate leptin sensitivity. It is speculated that through hypothalamic/pituitary axis ghrelin and leptin operate as a metabolic switch. Ghrelin actually transfers information from the stomach to the hypothalamus in cooperation with leptin and provides calories that growth hormone (GH) needs for growth and repair. Pharmacological manipulations of circulating hormone levels may work well in "cheating" the brain regarding information from the periphery. It might also be necessary to combine two or three agents to fight obesity. A combination of drugs that decrease preprandial appetite (ghrelin antagonist) and increase post-prandial satiety (gut hormone fragment peptide YY 3-36) might have a chance of achieving sustained weight loss. The administration of exogenous satiety hormone peptide YY 3-36 (PYY) may prevent the action of appetite-stimulating hypothalamic circuits on the anorexigenic melanocortin pathways.

Topics: Adipose Tissue; Animals; Appetite; Body Weight; Brain; Energy Metabolism; Ghrelin; Humans; Hypothalamus; Leptin; Obesity; Peptide Fragments; Peptide Hormones; Peptide YY; Pituitary Gland; Satiation; Signal Transduction

Many peptides are synthesised and released from the gastrointestinal tract. Although their roles in the regulation of gastrointestinal function have been known for some time, it has become increasingly evident that they also influence eating behaviour. Peptide YY (PYY) is released postprandially from gastrointestinal L-cells with glucagon-like peptide 1 (GLP-1) and oxyntomodulin. Following peripheral administration of PYY3-36, the circulating form of PYY, to mouse, rat or human there is marked inhibition of food intake. Obese subjects have lower basal fasting PYY levels and have a smaller postprandial rise. However, obesity does not appear to be associated with resistance to PYY (as it is with leptin) and exogenous infusion of PYY3-36 results in a reduction in food intake by 30% in an obese group and 31% in a lean group at a buffet meal. Overall PYY significantly reduced 24-h caloric intake in both obese (16.5%) and lean groups (23.5%). Obesity is the current major cause of premature death in the UK, killing almost 1000 people a week. Worldwide its prevalence is accelerating. The administration of the naturally occurring gut hormone may offer a long-term therapeutic approach to weight control. Here, the therapeutic potential of PYY is considered.

Topics: Animals; Anti-Obesity Agents; Gastrointestinal Hormones; Humans; Obesity; Peptide Fragments; Peptide Hormones; Peptide YY

Obesity is taking on pandemic proportions. The laws of thermodynamics, however, remain unchanged, as energy will be stored if less energy is expended than consumed; the storage is usually in the form of adipose tissue. Several neural, humeral and psychological factors control the complex process known as appetite. Recently, a close evolutionary relationship between the gut and brain has become apparent. The gut hormones regulate important gastrointestinal functions such as motility, secretion, absorption, provide feedback to the central nervous system on availability of nutrients and may play a part in regulating food intake. Peptide YY (PYY) is a thirty-six amino acid peptide related to neuropeptide Y (NPY) and is co-secreted with glucagon-like peptide 1. Produced by the intestinal L-cells, the highest tissue concentrations of PYY are found in distal segments of the gastrointestinal tract, although it is present throughout the gut. Following food intake PYY is released into the circulation. PYY concentrations are proportional to meal energy content and peak plasma levels appear postprandially after 1 h. PYY3-36 is a major form of PYY in both the gut mucosal endocrine cells and the circulation. Peripheral administration of PYY3-36 inhibits food intake for several hours in both rodents and man. The binding of PYY3-36 to the Y2 receptor leads to an inhibition of the NPY neurones and a possible reciprocal stimulation of the pro-opiomelanocortin neurones. Thus, PYY3-36 appears to control food intake by providing a powerful feedback on the hypothalamic circuits. The effect on food intake has been demonstrated at physiological concentrations and, therefore, PYY3-36 may be important in the everyday regulation of food intake.

Topics: Appetite; Appetite Regulation; Digestive System Physiological Phenomena; Energy Intake; Humans; Obesity; Peptide YY; Receptors, Neuropeptide Y

Recent advances in obesity research focused on neuroendocrine control of food intake, appetite and body weight balance. Gut hormones, which are sequentially released from different regions of the gut, send signals to the areas of appetite control in the central nervous system causing a release of counter-regulatory hormones also originating from the gastrointestinal system. Ghrelin, a peptide secreted from the gastric fundus is released just before meal intake and stimulates hunger and food intake. Recently, peptide YY has been suggested to counteract ghrelin by inducing satiety and reducing appetite and caloric intake. While the effects of PYY on various gastrointestinal functions are well described, its action on weight loss is less known. Controversial results on the effect of exogenous administration of PYY(3-36) opened the discussion on the respective roles of PYY and/or PYY(3-36) in body weight homeostasis in man.

Topics: Appetite Regulation; Brain; Humans; Obesity; Peptide YY; Weight Loss

New approaches for enhancing intranasal drug delivery based on recent discoveries on the molecular biology of tight junctions (TJ) are significantly improving the bioavailability of 'non-Lipinsky' small molecules, and peptide, protein and oligonucleotide drugs. As knowledge of the structure and function of the TJ has developed, so has the ability to identify mechanism-based TJ modulators using high-throughput molecular biology-based screening methods. The present review focuses on recent developments on the TJ protein complex as a lipid raft-like membrane microdomain, the emerging role of unique endocytic pathways in regulating TJ dynamics, and the utility of techniques such as RNA interference and phage display to study TJ components and identify novel peptides and related molecules that can modulate their function. Experimental and statistical methodologies used for the identification of new classes of TJ modulators are described, which are capable of reversibly opening TJ barriers with broad potential to significantly improve intranasal and, eventually, oral drug delivery. The development of an advanced intranasal formulation for the obesity therapeutic PYY(3-36), the endogenous Y2 receptor agonist is also reviewed.

Topics: Administration, Intranasal; Animals; Anti-Obesity Agents; Calcium Signaling; Cells, Cultured; Chemistry, Pharmaceutical; Clinical Trials as Topic; Drug Delivery Systems; Drug Evaluation, Preclinical; Epithelium; Gene Expression Profiling; Humans; Membrane Microdomains; Multiprotein Complexes; Nasal Mucosa; Nebulizers and Vaporizers; Obesity; Peptide Fragments; Peptide YY; Permeability; Tight Junctions

Topics: Abnormalities, Multiple; Child; Drug Resistance; Endocrine System Diseases; Energy Metabolism; Ghrelin; Homeostasis; Hormones; Humans; Hypothalamus, Middle; Insulin; Insulin Resistance; Leptin; Obesity; Peptide Fragments; Peptide Hormones; Peptide YY; Sympathetic Nervous System; Vagus Nerve

Health problems resulting from obesity could offset many of the recent health gains achieved by modern medicine, and obesity may replace tobacco as the number one health risk for developed societies. An estimated 300,000 deaths per year and significant morbidity are directly attributable to obesity, mainly due to heart disease, diabetes, cancer, asthma, sleep apnea, arthritis, reproductive complications and psychological disturbances. In parallel with the increasing prevalence of obesity, there has been a dramatic increase in the number of scientific and clinical studies on the control of energy homeostasis and the pathogenesis of obesity to further our understanding of energy balance. It is now recognized that there are many central and peripheral factors involved in energy homeostasis, and it is expected that the understanding of these mechanisms should lead to effective treatments for the control of obesity. This brief review discusses the potential role of several recently discovered molecular pathways involved in the control of energy homeostasis, obesity and eating disorders.

Topics: Adiponectin; Animals; Appetite; Child; Energy Metabolism; Feeding and Eating Disorders; Ghrelin; Homeostasis; Humans; Insulin; Intercellular Signaling Peptides and Proteins; Leptin; Obesity; Peptide Fragments; Peptide Hormones; Peptide YY; Proteins

Obesity is the main cause of premature death in the UK. Worldwide its prevalence is accelerating. It has been hypothesized that a gut nutriment sensor signals to appetite centres in the brain to reduce food intake after meals. Gut hormones have been identified as an important mechanism for this. Ghrelin stimulates, and glucagon like peptide-1, oxyntomodulin, peptide YY (PYY), cholecystokinin and pancreatic polypeptide inhibit, appetite. At physiological postprandial concentrations they can alter food intake markedly in humans and rodents. In addition, in obese humans fasting levels of PYY are suppressed and postprandial release is reduced. Administration of gut hormones might provide a novel and physiological approach in anti-obesity therapy. Here, we summarize some of the recent advances in this field.

Topics: Animals; Appetite Regulation; Cholecystokinin; Gastrointestinal Hormones; Ghrelin; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Humans; Leptin; Obesity; Oxyntomodulin; Pancreatic Polypeptide; Peptide Fragments; Peptide Hormones; Peptide YY; Protein Precursors

Peptide YY (PYY) is an important gut hormone synthesized and secreted by the gastrointestinal tract. Peripheral administration of PYY(3-36), one of the circulating forms of PYY, is known to inhibit food intake. This anorexigenic effect is masked by stress inhibition of appetite, and it is therefore important for animals to be thoroughly acclimatised for PYY(3-36) to be effective. Evidence suggests that PYY(3-36) acts via the hypothalamic Y(2) receptor. Levels of the anorexigenic hormone PYY(3-36) are low in overweight volunteers and could provide an important therapeutic avenue in the quest to combat the obesity epidemic.

Topics: Animals; Appetite Depressants; Appetite Regulation; Gastrointestinal Tract; Humans; Models, Biological; Obesity; Peptide Fragments; Peptide YY; Receptors, Neuropeptide Y; United Kingdom

Obesity is quickly becoming one of the most common and debilitating disorders of the developed world. More than 60% of American adults are now overweight or obese, predisposing them to a host of chronic diseases. To understand the etiology of obesity, and to discover new therapies for obesity, we must understand the components of energy balance. In simple terms, energy intake (feeding) must equal energy expenditure (physical activity, basal metabolism and adaptive thermogenesis) for body weight homeostasis. To maintain homeostasis, neurocircuitry must sense both immediate nutritional status and the amount of energy stored in adipose tissue, and must be able to provide appropriate output to balance energy intake and energy expenditure. The brain receives various signals that carry information about nutritional and metabolic status including neuropeptide PYY(3-36), ghrelin, cholecystokinin, leptin, glucose and insulin. Circulating satiety signals access the brain either by "leakage" across circumventricular organs or transport across the blood-brain barrier. Signals can also activate sensory vagal terminals that innervate the whole gastrointestinal tract.

Topics: Brain; Eating; Electrophysiology; Energy Intake; Energy Metabolism; Gastrointestinal Tract; Ghrelin; Homeostasis; Humans; Hypothalamic Hormones; Insulin; Intracellular Signaling Peptides and Proteins; Leptin; Melanins; Neuropeptides; Nutritional Status; Obesity; Orexins; Peptide Fragments; Peptide Hormones; Peptide YY; Pituitary Hormones

Many peptides are synthesised and released from the gastrointestinal tract. Whilst their roles in regulation of gastrointestinal function have been known for some time, it is now evident that they also influence eating behaviour and thus potential anti obesity targets. Peptide YY (PYY) is released post prandially from the gastrointestinal L-cells with glucagon-like peptide 1 (GLP-1) and oxyntomodulin. Following peripheral administration of PYY 3-36, the circulating form of PYY, to mouse, rat or human there is marked inhibition of food intake. PYY 3-36 is thought to mediate its actions through the NPY Y2 GPCR. Obese subjects have lower basal fasting PYY levels and have a smaller post prandial rise. However, obesity does not appear to be associated with resistance to PYY (as it is with leptin) and exogenous infusion of PYY 3-36 results in a reduction in food intake by 30% in an obese group and 31% in a lean group. GLP-1 or oxyntomodulin, products of the prepreglucagon gene, decrease food intake when administered either peripherally or directly into the CNS. In addition, both have been shown to decrease food intake in humans. These effects are thought to be mediated by the GLP-1 receptor. Ghrelin, a huger hormone produced by the stomach, increases in the circulation following a period of fasting. Administration of ghrelin either peripherally or directly into the CNS increases food intake and chronic administration leads to obesity. Further infusion into normal healthy volunteers increases both food intake and appetite. Ghrelin is thought to act through the growth hormone secretagogue receptor (GHS-R). Obesity is the current major cause of premature death in the UK, killing almost 1000 people a week. Worldwide its prevalence is accelerating. The administration of the naturally occurring gut hormone may offer a long-term therapeutic approach to weight control. Here we consider the therapeutic potential of some gut hormones, and the GPCR's through which they act, in the treatment of obesity.

Topics: Animals; Anti-Obesity Agents; Appetite Regulation; Drug Design; Gastrointestinal Hormones; Ghrelin; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Humans; Mice; Obesity; Oxyntomodulin; Pancreatic Polypeptide; Peptide Fragments; Peptide Hormones; Peptide YY; Protein Precursors; Rats; Receptors, G-Protein-Coupled

Obesity has reached epidemic levels in industrialized countries and is increasing worldwide. This trend has serious public health consequences, since obesity increases the risk of diabetes, hypertension, heart disease, sleep apnea, cancer, arthritis, cholelithiasis, fatty liver disease, and other complications. Obesity is the result of an imbalance between energy intake and expenditure; hence, an understanding of how gastrointestinal function is integrated with the hormonal regulation of energy balance is pertinent to the pathophysiology of obesity. Nutrients, peptides, and neural afferents from the gut influence the size and frequency of meals and satiety. The long-term regulation of energy stores is mediated primarily through the actions of adiposity hormones, such as leptin and insulin, in the hypothalamus and other neuronal circuits in the brain. Efforts are underway to determine how these peripheral and central pathways may be targeted for treatment of obesity and related diseases.

Topics: Animals; Appetite; Body Weight; Cholecystokinin; Energy Metabolism; Gastrointestinal Hormones; Ghrelin; Humans; Insulin; Leptin; Obesity; Peptide Hormones; Peptide YY; Peptides; Satiety Response; Stomach

To investigate whether the elevation in postprandial concentrations of the gut hormones glucagon-like peptide-1 (GLP-1), oxyntomodulin (OXM) and peptide YY (PYY) accounts for the beneficial changes in food preferences, sweet taste function and eating behaviour after Roux-en-Y gastric bypass (RYGB).. This was a secondary analysis of a randomized single-blind study in which we infused GLP-1, OXM, PYY (GOP) or 0.9% saline subcutaneously for 4 weeks in 24 subjects with obesity and prediabetes/diabetes, to replicate their peak postprandial concentrations, as measured at 1 month in a matched RYGB cohort (ClinicalTrials.gov NCT01945840). A 4-day food diary and validated eating behaviour questionnaires were completed. Sweet taste detection was measured using the method of constant stimuli. Correct sucrose identification (corrected hit rates) was recorded, and sweet taste detection thresholds (EC50s: half maximum effective concencration values) were derived from concentration curves. The intensity and consummatory reward value of sweet taste were assessed using the generalized Labelled Magnitude Scale.. Mean daily energy intake was reduced by 27% with GOP but no significant changes in food preferences were observed, whereas a reduction in fat and increase in protein intake were seen post-RYGB. There was no change in corrected hit rates or detection thresholds for sucrose detection following GOP infusion. Additionally, GOP did not alter the intensity or consummatory reward value of sweet taste. A significant reduction in restraint eating, comparable to the RYGB group was observed with GOP.. The elevation in plasma GOP concentrations after RYGB is unlikely to mediate changes in food preferences and sweet taste function after surgery but may promote restraint eating.

Topics: Food Preferences; Gastric Bypass; Gastrointestinal Hormones; Glucagon-Like Peptide 1; Humans; Obesity; Peptide YY; Prediabetic State; Single-Blind Method; Sucrose; Taste; Volunteers

Evidence is emerging that interdaily meal pattern variability potentially affects response such as thermic effect of food (TEF), macronutrient metabolism, and appetite.. To investigate the effect of irregular meal pattern on TEF, glucose, insulin, lipid profile, and appetite regulation in women who are overweight or with obesity and confirmed insulin resistance.. In a randomized crossover trial, 9 women [mean ± SD BMI (in kg/m2): 33.3 ± 3.1] with confirmed insulin resistance consumed a regular (14 d; 6 meals/d) and an irregular (14 d; 3-9 meals/d) meal pattern separated by a 14-d washout interval. Identical foods were provided during the interventions, and at the start and end of each meal pattern, participants attended the laboratory after an overnight fast. Energy expenditure, glucose, insulin, lipids, adiponectin, leptin, glucagon-like peptide 1 (GLP-1), peptide YY (PYY), and ghrelin were measured at baseline and for 3 h after consumption of a test drink, after which an ad libitum test meal was offered. Subjective appetite ratings were recorded before and after the test drink, after the ad libitum meal, and during the intervention. Continuous interstitial glucose monitoring was undertaken for 7 consecutive days during each intervention.. TEF (over 3 h) was significantly lower postirregular intervention compared with postregular (97.7 ± 19.2 kJ*3 h in postregular visit and 76.7 ± 35.2 kJ*3 h in postirregular visit, paired t test, P = 0.048). Differences in HOMA-IR between the 2 interventions (3.3 ± 1.7 and 3.6 ± 1.6 in postregular and postirregular meal pattern, respectively) were not significant. Net incremental AUC for GLP-1 concentrations (over 3 h) for the postregular meal pattern were higher (864.9 ± 456.1 pmol/L*3 h) than the postirregular meal pattern (487.6 ± 271.7 pmol/L*3 h, paired t test, P = 0.005).. Following a 14-d period of an irregular meal pattern, TEF was significantly less than following a regular meal pattern, potentially compromising weight management if sustained long term. This study was registered at www.clinicaltrials.gov as NCT02582606.

Topics: Adiponectin; Adolescent; Adult; Appetite; Blood Glucose; Blood Glucose Self-Monitoring; Energy Metabolism; Feeding Behavior; Female; Ghrelin; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Leptin; Lipids; Meals; Middle Aged; Obesity; Overweight; Peptide YY; Thermogenesis; Young Adult

Continuous exercise can increase postprandial gut hormone such as glucagon-like peptide 1 (GLP-1) and peptide YY (PYY) responses, but it is unknown whether interrupting prolonged sitting with intermittent walking elicits this effect.. Ten participants with central overweight/obesity (7 men and 3 postmenopausal women, 51 ± 5 yr; mean ± SD) completed a randomized crossover study in which they consumed breakfast and lunch in the laboratory while either sitting continuously for the entire 5.5-h period (SIT) or the prolonged sitting interrupted every 20 min by walking briskly (6.4 km·h-1) for 2 min (BREAKS). Blood samples were collected at regular intervals to examine postprandial plasma GLP-1, PYY, and glucose-dependent insulinotropic polypeptide concentrations. Adipose tissue samples were collected at baseline and at the end of the trials to examine changes in net dipeptidyl peptidase 4 secretion from primary explants.. Mean (95% confidence interval) postprandial GLP-1 and PYY incremental area under curve values were elevated by 26% and 31% in the BREAKS trial versus SIT (8.4 [0.7, 16.1] vs 6.7 [-0.8, 14.2], P = 0.001, and 26.9 [8.1, 45.6] vs 20.4 [5.1, 35.8] nmol·330 min·L-1, P = 0.024, respectively) but without any such effect on glucose-dependent insulinotropic polypeptide (P = 0.076) or net adipose tissue dipeptidyl peptidase 4 secretion (P > 0.05).. Interrupting prolonged sitting with regular short bouts of brisk walking increases postprandial GLP-1 and PYY concentrations in healthy middle-age men and women with central adiposity.

Topics: Blood Glucose; Cross-Over Studies; Dipeptidyl Peptidase 4; Female; Glucagon-Like Peptide 1; Humans; Insulin; Male; Middle Aged; Obesity; Obesity, Abdominal; Peptide YY; Postprandial Period; Walking

To assess the impact of the sodium-glucose co-transporter-2 (SGLT2) inhibitor empagliflozin (25 mg once-daily), dietary energy restriction, or both combined, on circulating appetite-regulatory peptides in people with type 2 diabetes (T2D) and overweight or obesity.. The mean weight loss in each group at 24 weeks was 0.44, 1.91, 2.22 and 5.74 kg, respectively. The change from baseline to 24 weeks in postprandial total PYY was similar between experimental groups and placebo only (mean difference [95% CI]: -8.6 [-28.6 to 11.4], 13.4 [-6.1 to 33.0] and 1.0 [-18.0 to 19.9] pg/ml in placebo-plus diet, empagliflozin-only and empagliflozin-plus-diet groups, respectively [all P ≥ .18]). Similarly, there was no consistent pattern of difference between groups for postprandial total GLP-1, acylated ghrelin and subjective appetite perceptions.. In people with T2D and overweight or obesity, changes in postprandial appetite-regulatory gut peptides may not underpin the less than predicted weight loss observed with empagliflozin therapy.. NCT02798744, www.. gov; 2015-001594-40, www.EudraCT.ema.europa.eu; ISRCTN82062639, www.ISRCTN.org.

Topics: Adult; Aged; Appetite; Benzhydryl Compounds; Diabetes Mellitus, Type 2; Double-Blind Method; Ghrelin; Glucagon-Like Peptide 1; Glucose; Glucosides; Humans; Hypoglycemic Agents; Middle Aged; Obesity; Overweight; Peptide YY; Sodium-Glucose Transporter 2 Inhibitors; Weight Loss

The aim of this study is to compare acute effects of consuming extra virgin coconut oil (EVCO) as a source of medium chain fatty acids and extra virgin olive oil (EVOO) as a source of long chain fatty acids in normal weight and obese subjects.. Randomised, crossover design.. Metabolically healthy twenty male subjects (10 normal weight; 10 obese) aged 19-40 years.. Subjects consumed breakfast meals containing skimmed milk, fat-free white cheese, bread and EVCO (25 g) or EVOO (25 g).. Visual analog scale evaluations, resting metabolic rate measurements and selected blood parameters analysis (glucose, triglyceride, insulin and plasma peptide YY) were performed before and after the test breakfast meals. In addition, energy intakes were evaluated by ad libitum lunch meal at 180 min.. Visual analogue scale values of hunger and desire to eat decreased significantly after EVCO consumption than EVOO consumption in normal weight subjects at 180 min. There was an increase trend in plasma PYY at 30 and 180 min after EVCO breakfast compared to EVOO breakfast. Ad libitum energy intakes after EVCO and EVOO consumption in normal weight subjects were 924 ± 302; 845 ± 158 kcal (p = 0.272), respectively whereas in obese subjects were 859 ± 238; 994 ± 265 kcal (p = 0.069) respectively.. The results of this study shows that consumption of EVCO compared to EVOO may have suppressive effect on hunger and desire to eat, may affect postprandial PYY levels differently and have no effect on postprandial energy expenditure.. Clinical Trials NCT04738929.

Topics: Adult; Appetite; Coconut Oil; Eating; Fatty Acids; Glucose; Humans; Insulin; Male; Obesity; Olive Oil; Peptide YY; Triglycerides; Young Adult

Fructose compared to glucose has adverse effects on metabolic function, but endocrine responses to oral sucrose vs glucose is not well understood.. We investigated how oral sucrose vs glucose affected appetite-regulating hormones, and how biological factors (body mass index [BMI], insulin sensitivity, sex) influence endocrine responses to these 2 types of sugar.. Sixty-nine adults (29 men; 23.22 ± 3.74 years; BMI 27.03 ± 4.96 kg/m2) completed the study. On 2 occasions, participants consumed 300-mL drinks containing 75 g of glucose or sucrose. Blood was sampled at baseline, 10, 35, and 120 minutes post drink for plasma glucose, insulin, glucagon-like peptide (GLP-1)(7-36), peptide YY (PYY)total, and acyl-ghrelin measures. Hormone levels were compared between conditions using a linear mixed model. Interaction models were performed, and results were stratified to assess how biological factors influence endocrine responses.. Sucrose vs glucose ingestion provoked a less robust rise in glucose (P < .001), insulin (P < .001), GLP-1 (P < .001), and PYY (P = .02), whereas acyl-ghrelin suppression was similar between the sugars. We found BMI status by sugar interactions for glucose (P = .01) and PYY (P = .03); obese individuals had smaller increases in glucose and PYY levels after consuming sucrose vs glucose. There were interactions between insulin sensitivity and sugar for glucose (P = .003) and insulin (P = .04), and a sex by sugar interaction for GLP-1 (P = .01); men demonstrated smaller increases in GLP-1 in response to oral sucrose vs glucose.. Sucrose is less efficient at signaling postprandial satiation than glucose, and biological factors influence differential hormone responses to sucrose vs glucose consumption.

Topics: Administration, Oral; Adolescent; Adult; Appetite; Appetite Regulation; Blood Glucose; Body Mass Index; Down-Regulation; Eating; Female; Ghrelin; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; Humans; Insulin Resistance; Male; Obesity; Peptide YY; Satiation; Sex Characteristics; South Carolina; Sucrose; Young Adult

To report the results from a Phase 1 trial of an extended-release peptide YY analogue, Y14, developed for the treatment of obesity.. Y14 was evaluated in overweight/obese volunteers in a Phase 1 randomized placebo-controlled trial, conducted in a clinical trial unit in the United Kingdom. Part A was a blinded single-ascending-dose study evaluating doses up to 36 mg. Part B was double-blinded and tested multiple ascending doses between 9 and 36 mg, given at 7- to 14-day intervals, over the course of 28 days, with up to five doses given per participant. The primary outcome was safety and tolerability; the secondary outcome was assessment of pharmacokinetic (PK) characteristics. Exploratory outcomes included food intake, body weight change and glucose tolerance after multiple doses.. Between April 11, 2017 and December 24, 2018, 53 participants were enrolled into Part A and 24 into Part B of the trial. The PK characteristics were compatible with administration every 7 to 14 days. The most common adverse events (AEs) were nausea, vomiting or administration site reactions, which were mild in most cases and settled with time. No serious AE occurred. Participants given multiple doses of Y14 lost between -2.87 and -3.58 kg body weight compared with placebo (P <0.0001) at 31 days from the first dose, with profound reductions in food intake of 38% to 55% (P <0.0001, compared to placebo) and there was no evidence of tachyphylaxis.. Our results support the continued development of Y14 as a novel treatment for obesity.

Topics: Double-Blind Method; Humans; Obesity; Overweight; Peptide YY; United Kingdom

Several nights of moderate (4-5 hr/night) sleep restriction increases appetite and energy intake, and may alter circulating concentrations of appetite regulating hormones. Whether more severe sleep restriction has similar effects is unclear. This study aimed to determine the effects of severe, short-term sleep restriction on appetite, ad libitum energy intake during a single meal, appetite regulating hormones, and food preferences.. Area under the curve (AUC) of postprandial hunger (-23%), desire to eat (-23%), and prospective consumption (-18%) ratings were all lower, and postprandial fullness AUC (25%) was higher after SR relative to after AS (p ≤ 0.02). Ad libitum energy intake at the lunch meal was 332 kcal [95% CI: -479, -185] (p<0.001) lower after SR relative to after AS, but relative macronutrient intakes and LFPQ scores did not differ. Postprandial glucose, insulin, PYY, GLP-1, and ghrelin AUCs did not differ between phases. However, mean concentrations of PYY (-11%) and GLP-1 (-4%) over the 4-hr testing period were lower, and glucose concentrations were 6% higher, after SR relative to after AS (p ≤ 0.01).. In contrast with reported effects of moderate sleep restriction, severe sleep restriction reduced appetite and energy intake, had no impact food preferences, and had little impact on appetite regulating hormones. Findings suggest that severe sleep restriction may suppress appetite and food intake, at least at a single meal, by a mechanism independent of changes in food preference or appetite regulating hormones.

Topics: Appetite; Cross-Over Studies; Energy Intake; Ghrelin; Glucagon-Like Peptide 1; Humans; Insulin; Male; Obesity; Peptide YY; Postprandial Period; Prospective Studies; Sleep

Altered meal-related gut hormone secretion seems important for weight loss and diabetes remission after Roux-en-Y gastric bypass (RYGB). Elucidating the responsible meal components and receptors could aid discovery of new treatments of obesity and diabetes. Enteroendocrine cells respond to digestion products of dietary triacylglycerol, especially long-chain fatty acids (LCFAs) and 2-oleoyl-glycerol (2-OG), but not medium-chain fatty acids (MCFAs).. We examined the impact of olive oil (20 mL) and its derivates, LCFAs and 2-OG, on enteroendocrine secretions [glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), cholecystokinin (CCK), peptide YY (PYY), and neurotensin (NT)] and on glucose, lipid, and bile acid metabolism in RYGB-operated and unoperated individuals.. In an exploratory randomized crossover design, 10 RYGB-operated patients and 10 matched controls ingested 3 equimolar triacylglycerol formulations on separate days: olive oil (digested to 2-OG + LCFAs), C8-dietary oil (2-OG + MCFAs), and tricaprylin (MCFAs; negative control). Hormone responses were calculated as area under the curve (AUC).. Independent of group status, olive oil had greater effects than C8-dietary oil on AUCs of plasma GLP-1 (+32%; 95% CI: 23%, 43%; P < 0.01), CCK (+53%, P < 0.01), and NT (+71%, P < 0.01), whereas the effect on GIP differed between groups (+90% in controls, P < 0.01; +24% in RYGB, P = 0.10). Independent of group status, C8-dietary oil had greater effects than tricaprylin on AUCs of plasma CCK (+40%, P < 0.01) and NT (+32%, P < 0.01), but not GLP-1 (+5%; 95% CI: -2.9%, 13%; P = 0.22), whereas the effect on GIP again differed between groups (+78% in controls, P < 0.01; +39% in RYGB, P = 0.01). Distal (GLP-1/PYY/NT), but not proximal (CCK/GIP), enteroendocrine responses were generally greater in RYGB patients than in controls.. The combination of LCFAs plus 2-OG was substantially more effective than 2-OG plus MCFAs in stimulating enteroendocrine secretion in RYGB-operated and matched control individuals. Distal lipid-induced gut hormone release was greater after RYGB.This trial was registered at clinicaltrials.gov as NCT03223389.

Topics: Adult; Cholecystokinin; Dietary Fats; Female; Gastric Bypass; Gastric Inhibitory Polypeptide; Gastrointestinal Hormones; Glucagon-Like Peptide 1; Glycerides; Humans; Intestinal Mucosa; Male; Obesity; Peptide YY; Triglycerides

Topics: Appetite; Caloric Restriction; Energy Intake; Exercise; Female; Ghrelin; Humans; Hunger; Obesity; Peptide YY

Acute exercise is associated with a transient suppression of appetite. The effects of regular exercise on appetite are not well understood. We aimed to determine the effects of active commuting and leisure-time exercise on appetite. One hundred thirty physically inactive women and men (20-45 yr) with overweight and obesity were randomized to 6 mo of habitual lifestyle (CON, n = 18), active commuting (BIKE, n = 35), or leisure-time exercise of moderate [MOD, 50% peak oxygen uptake (V̇o

Topics: Adult; Appetite; Appetite Regulation; Energy Intake; Energy Metabolism; Exercise; Female; Ghrelin; Glucagon-Like Peptide 1; Humans; Hunger; Leisure Activities; Male; Meals; Middle Aged; Obesity; Overweight; Oxygen Consumption; Peptide YY; Postprandial Period; Sedentary Behavior; Transportation; Young Adult

Proteins, particularly whey proteins, represent the most satiating macronutrient in animals and humans. A dietetic regimen based on proteins enriched preload before eating might be a strategy to counteract obesity.. Each drink significantly augmented satiety and reduced hunger, and the effects were more evident with whey proteins than maltodextrins. Similarly, there were significant increases in GLP-1 and PYY levels (but not PP) after the ingestion of each drink; these anorexigenic responses were higher with whey proteins than maltodextrins. While insulinemia identically increased after each drink, whey proteins induced a lower glycemic response than maltodextrins. No differences in satiety and hunger were found after the meal, which is presumably due to the late administration of the meal test, when the hypophagic effect of whey proteins was disappearing.. While whey proteins actually reduce appetite, stimulate anorexigenic gastrointestinal peptides, and improve glucometabolic homeostasis in young obese women, further additional studies are mandatory to demonstrate their hypophagic effects in obese subjects, when administered as preload before eating.

Topics: Adolescent; Adult; Appetite; Blood Glucose; Female; Glucagon-Like Peptide 1; Homeostasis; Humans; Insulin; Obesity; Pancreatic Polypeptide; Peptide YY; Polysaccharides; Satiation; Whey Proteins; Young Adult

Bariatric surgery is widely used to treat obesity and improves type 2 diabetes beyond expectations from the degree of weight loss. Elevated post-prandial concentrations of glucagon-like peptide 1 (GLP-1), peptide YY (PYY), and insulin are widely reported, but the importance of GLP-1 in post-bariatric physiology remains debated. Here, we show that GLP-1 is a major driver of insulin secretion after bariatric surgery, as demonstrated by blocking GLP-1 receptors (GLP1Rs) post-gastrectomy in lean humans using Exendin-9 or in mice using an anti-GLP1R antibody. Transcriptomics and peptidomics analyses revealed that human and mouse enteroendocrine cells were unaltered post-surgery; instead, we found that elevated plasma GLP-1 and PYY correlated with increased nutrient delivery to the distal gut in mice. We conclude that increased GLP-1 secretion after bariatric surgery arises from rapid nutrient delivery to the distal gut and is a key driver of enhanced insulin secretion.

Topics: Adult; Animals; Bariatric Surgery; Enteroendocrine Cells; Female; Glucagon-Like Peptide 1; Glucose; Homeostasis; Humans; Hypoglycemic Agents; Insulin Secretion; Intestinal Mucosa; Male; Mice; Mice, Inbred C57BL; Middle Aged; Obesity; Peptide Fragments; Peptide YY; Postoperative Period; Transcriptome

Potential mechanisms of abnormal food intake, such as dysregulation of meal-related appetite hormones, including acyl ghrelin (AG) and des-acyl ghrelin (DAG), were investigated among men and women with obesity, with and without binge eating (BE).. Participants (n = 42: 19 female, 23 male) were assigned to a liquid meal and water condition in counterbalanced order, and blood samples for measuring hormones were obtained before and after these conditions.. Participants with BE had significantly lower fasting and postingestive AG concentrations than participants without BE in both conditions. During the meal condition, postprandial decreases in AG concentrations were significantly smaller for the BE group than for the non-BE group. There were no significant differences in DAG by BE group. Leptin increased significantly less after meals for those with BE compared with those without BE. There were no differences in other hormones by BE group. Fasting and postmeal hunger ratings were significantly higher for those with BE than for those without BE.. In individuals with BE, lower fasting AG may be due to downregulation by habitual overeating, and a smaller postmeal decline in AG may contribute to overeating. Lower postmeal leptin concentrations may also contribute to overeating.

Topics: Adult; Appetite; Binge-Eating Disorder; Bulimia; Cholecystokinin; Eating; Female; Ghrelin; Glucagon-Like Peptide 1; Humans; Hyperphagia; Insulin; Leptin; Male; Meals; Middle Aged; Obesity; Peptide YY; Postprandial Period; Young Adult

Diet-induced weight loss (WL) is usually accompanied by increased appetite, a response that seems to be absent when ketogenic diets are used. It remains unknown if sex modulates the appetite suppressant effect of ketosis.. The aim of this study was to examine if sex modulates the impact of WL-induced changes in appetite and if ketosis alters these responses.. Ninety-five individuals (55 females) with obesity (BMI [kg/m 2]: 37  ± 4) underwent 8 wk of a very-low-energy diet, followed by 4 wk of refeeding and weight stabilization. Body composition, plasma concentration of β-hydroxybutyrate (β-HB) and appetite-related hormones (active ghrelin, active glucagon-like peptide 1 [GLP-1], total peptide YY [PYY], cholecystokinin and insulin), and subjective feelings of appetite were measured at baseline, week 9 in ketosis, and week 13 out of ketosis.. The mean WL at week 9 was 17% for males and 15% for females, which was maintained at week 13. Weight, fat, and fat-free mass loss were greater in males (P < 0.001 for all) and the increase in β-HB at week 9 higher in females (1.174 ± 0.096 compared with 0.783 ± 0.112 mmol/L, P = 0.029). Basal and postprandial GLP-1 and postprandial PYY (all P < 0.05) were significantly different for males and females. There were no significant sex × time interactions for any other appetite-related hormones or subjective feelings of appetite. At week 9, basal GLP-1 was decreased only in males (P < 0.001), whereas postprandial GLP-1 was increased only in females (P < 0.001). No significant changes in postprandial PYY were observed over time for either sex.. Ketosis appears to have a greater beneficial impact on GLP-1 in females. However, sex does not seem to modulate the changes in the secretion of other appetite-related hormones, or subjective feelings of appetite, seen with WL, regardless of the ketotic state. This trial was registered at clinicaltrials.gov as NCT01834859.

Topics: Adolescent; Adult; Aged; Appetite; Cholecystokinin; Female; Ghrelin; Glucagon-Like Peptide 1; Humans; Insulin; Ketosis; Male; Middle Aged; Obesity; Peptide YY; Sex Factors; Weight Loss; Young Adult

To assess the effects of walnuts on cardiometabolic outcomes in obese people and to explore the underlying mechanisms using novel methods including metabolomic, lipidomic, glycomic and microbiome analysis, integrated with lipid particle fractionation, appetite-regulating hormones and haemodynamic measurements.. A total of 10 obese individuals were enrolled in this cross-over, randomized, double-blind, placebo-controlled clinical trial. The participants had two 5-day inpatient stays, during which they consumed a smoothie containing 48 g walnuts or a macronutrient-matched placebo smoothie without nuts, with a 1-month washout period between the two visits.. Walnut consumption improved aspects of the lipid profile; it reduced fasting small and dense LDL particles (P < 0.02) and increased postprandial large HDL particles (P < 0.01). Lipoprotein insulin resistance score, glucose and the insulin area under the curve (AUC) decreased significantly after walnut consumption (P < 0.01, P < 0.02 and P < 0.04, respectively). Consuming walnuts significantly increased 10 N-glycans, with eight of them carrying a fucose core. Lipidomic analysis showed a robust reduction in harmful ceramides, hexosylceramides and sphingomyelins, which have been shown to mediate effects on cardiometabolic risk. The peptide YY AUC significantly increased after walnut consumption (P < 0.03). No major significant changes in haemodynamic or metabolomic analysis or in microbiome host health-promoting bacteria such as Faecalibacterium were found.. These data provide a more comprehensive mechanistic perspective of the effect of dietary walnut consumption on cardiometabolic variables. Lipidomic and lipid nuclear magnetic resonance spectroscopy analysis showed an early but significant reduction in ceramides and other atherogenic lipids with walnut consumption, which may explain the longer-term benefits of walnuts or other nuts on insulin resistance, cardiovascular risk and mortality.

Topics: Cardiovascular Diseases; Cross-Over Studies; Diet; Double-Blind Method; Eating; Fasting; Female; Humans; Inpatients; Insulin Resistance; Juglans; Lipids; Male; Middle Aged; Obesity; Peptide YY; Postprandial Period; Protective Factors

Roux-en-Y gastric bypass (RYGB) augments postprandial secretion of glucagon-like peptide 1 (GLP-1), oxyntomodulin (OXM), and peptide YY (PYY). Subcutaneous infusion of these hormones ("GOP"), mimicking postprandial levels, reduces energy intake. Our objective was to study the effects of GOP on glycemia and body weight when given for 4 weeks to patients with diabetes and obesity.. In this single-blinded mechanistic study, obese patients with prediabetes/diabetes were randomized to GOP (. GOP infusion improves glycemia and reduces body weight. It achieves superior glucose tolerance and reduced glucose variability compared with RYGB and VLCD. GOP is a viable alternative for the treatment of diabetes with favorable effects on body weight.

Topics: Adult; Blood Glucose; Blood Glucose Self-Monitoring; Body Weight; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Infusions, Subcutaneous; Insulin; Male; Meals; Middle Aged; Obesity; Oxyntomodulin; Peptide YY; Postprandial Period; Prediabetic State; Single-Blind Method; Weight Loss

Dietary management of phenylketonuria (PKU) requires the replacement of natural protein-containing foods with special low protein foods. The effect of a PKU type diet on factors contributing to energy balance requires investigation.. To investigate the impact of a PKU type meal on appetite ratings, gut appetite hormones, thermic effect of feeding (TEF) and fat oxidation.. Twenty-three healthy adults (mean ± SD age: 24.3 ± 5.1 years; BMI: 22.4 ± 2.5 kg/m. Responses of appetite ratings, plasma concentrations of GLP-1 and PYY (P > 0.05, trial effect, two-way ANOVA) and energy intake during ad libitum buffet dinner (P > 0.05, paired t-test) were not significantly different between the two trials. The TEF (PKU, 10.2 ± 1.5%; Control, 13.2 ± 1.0%) and the total amount of fat oxidized (PKU, 18.90 ± 1.10 g; Control, 22.10 ± 1.10 g) were significantly (P < 0.05, paired t-tests) lower in the PKU than in the Control trial. The differences in TEF and fat oxidation were significant (P < 0.05, paired t-tests) for the post-meal period.. Consumption of a meal composed of special low protein foods has no detrimental impact on appetite and appetite hormones but produces a lower TEF and postprandial fat oxidation than an ordinary meal. These metabolic alterations may contribute to the increased prevalence of obesity reported in patients with PKU on contemporary dietary management.. The trial has been registered in ClinicalTrials as NCT02440932.

Topics: Adult; Appetite; Blood Glucose; Body Mass Index; Cross-Over Studies; Diet, Protein-Restricted; Dietary Fats; Eating; Energy Intake; Energy Metabolism; Female; Glucagon-Like Peptide 1; Humans; Insulin; Male; Obesity; Oxidation-Reduction; Peptide YY; Phenylketonurias; Postprandial Period; Thermogenesis; Young Adult

Strong compensatory responses, with reduced resting metabolic rate (RMR), increased exercise efficiency (ExEff) and appetite, are activated when weight loss (WL) is achieved with continuous energy restriction (CER), which try to restore energy balance. Intermittent energy restriction (IER), where short spells of energy restriction are interspaced by periods of habitual energy intake, may offer some protection in minimizing those responses. We aimed to compare the effect of IER versus CER on body composition and the compensatory responses induced by WL.. Changes in body weight (≈12.5% WL) and composition were similar in both groups. Fasting RQ and ExEff at 10 W increased in both groups. Losing weight, either by IER or CER dieting, did not induce significant changes in subjective appetite ratings. RMR decreased and ExEff at 25 and 50 W increased (P < 0.001 for all) in IER group only. Basal and postprandial AG increased (P < 0.05) in IER group, whereas basal active GLP-1 decreased (P = 0.033) in CER group only. Postprandial CCK decreased in both groups (P = 0.0012 and P = 0.009 for IER and CER groups, respectively). No between group differences were apparent for any of the outcomes.. The technique used to achieve energy restriction, whether it is continuous or intermittent, does not appear to modulate the compensatory mechanisms activated by weight loss.. NCT02169778 (the study was registered in clinicaltrial.gov).

Topics: Adult; Basal Metabolism; Body Composition; Body Weight; Caloric Restriction; Cholecystokinin; Diet, Reducing; Eating; Energy Intake; Exercise; Ghrelin; Glucagon-Like Peptide 1; Humans; Hunger; Middle Aged; Norway; Obesity; Oxygen Consumption; Peptide YY; Weight Loss

It is known that the macronutrient content of a meal has different impacts on the postprandial satiety and appetite hormonal responses. Whether obesity interacts with such nutrient-dependent responses is not well characterized. We examined the postprandial appetite and satiety hormonal responses after a high-protein (HP), high-carbohydrate (HC), or high-fat (HF) mixed meal. This was a randomized cross-over study of 9 lean insulin-sensitive (mean±SEM HOMA-IR 0.83±0.10) and 9 obese insulin-resistant (HOMA-IR 4.34±0.41) young (age 21-40 years), normoglycaemic Chinese men. We measured fasting and postprandial plasma concentration of glucose, insulin, active glucagon-like peptide-1 (GLP-1), total peptide-YY (PYY), and acyl-ghrelin in response to HP, HF, or HC meals. Overall postprandial plasma insulin response was more robust in the lean compared to obese subjects. The postprandial GLP-1 response after HF or HP meal was higher than HC meal in both lean and obese subjects. In obese subjects, HF meal induced higher response in postprandial PYY compared to HC meal. HP and HF meals also suppressed ghrelin greater compared to HC meal in the obese than lean subjects. In conclusion, a high-protein or high-fat meal induces a more favorable postprandial satiety and appetite hormonal response than a high-carbohydrate meal in obese insulin-resistant subjects.

Topics: Adult; Asian People; Blood Glucose; Cross-Over Studies; Diet, High-Fat; Diet, High-Protein; Dietary Carbohydrates; Dietary Fats; Dietary Proteins; Ghrelin; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Male; Obesity; Peptide YY; Postprandial Period; Satiety Response; Singapore; Young Adult

Topics: Adolescent; Adult; Appetite; Basal Metabolism; Calorimetry, Indirect; Capsaicin; Capsicum; Energy Intake; Female; Ghrelin; Glucagon-Like Peptide 1; Humans; Hunger; Male; Meals; Obesity; Peptide YY; Plant Extracts; Postprandial Period; Satiety Response; Single-Blind Method; Young Adult

Gut hormones, such as PYY and ghrelin, are associated with appetite control and obesity. Protein is thought to be the most satiating nutrient and could affect the production of several gut hormones. The purpose of the current study was to find the effect of breakfast with different protein composition on PYY, ghrelin, and ad libitum intake 4 h after breakfast.. This clinical trial involves 22 obese women participants. Subjects were given three types of breakfast: low protein consumption (12.4% protein), medium protein (23.5% protein), and high protein (40.6% protein). PYY and ghrelin levels were measured at 0, 15, 60, 120, and 180 min after breakfast. Ad libitum meal was given 4 h after breakfast and measured after. This study found that there is no significant difference in PYY and ghrelin level at each measurement time between different type of breakfast. This study also found no significant difference of ad libitum energy intake between different type of breakfast. Trial registration ClinicalTrials.gov NCT03697486, 3 December 2018. Retrospectively registered.

Topics: Adult; Breakfast; Dietary Proteins; Double-Blind Method; Energy Intake; Female; Ghrelin; Humans; Indonesia; Obesity; Peptide YY; Young Adult

Studies on the effect of chronic interval training on appetite in the obese population are scarce. The aim of this study was to determine the effect of 12 wk of isocaloric programs of moderate-intensity continuous training (MICT), high-intensity interval training (HIIT), or short-duration HIIT on subjective feelings of appetite, appetite-related hormones, and reward value of food in sedentary obese individuals.. Forty-six sedentary obese individuals (30 women and 16 men), with a body mass index of 33.3 ± 2.9 kg·m and age of 34.4 ± 8.8 yr, were randomly assigned to one of the three training groups: MICT (n = 14), HIIT (n = 16), or short-duration HIIT (n = 16). Exercise was performed three times per week for 12 wk. Subjective feelings of appetite and plasma levels of acylated ghrelin, polypeptide YY3-36, and glucagon-like peptide 1 were measured before and after a standard breakfast (every 30 min up to 3 h), before and after the exercise intervention. Fat and sweet taste preferences and food reward were measured using the Leeds Food Preference Questionnaire.. A significant increase in fasting and postprandial feelings of hunger was observed with the exercise intervention (P = 0.01 and P = 0.048, respectively), but no effect of group and no interaction. No significant effect of exercise intervention, group, or interaction was found on fasting or postprandial subjective feelings of fullness, desire to eat, and prospective food consumption or plasma concentration of acylated ghrelin, polypeptide YY3-36, and glucagon-like peptide 1. No changes in food preference or reward over time, differences between groups, or interactions were found.. This study suggests that chronic HIIT has no independent effect on appetite or food reward when compared with an isocaloric program of MICT in obese individuals.

Topics: Adult; Appetite; Energy Intake; Fasting; Female; Food Preferences; Ghrelin; Glucagon-Like Peptide 1; High-Intensity Interval Training; Humans; Male; Obesity; Peptide Fragments; Peptide YY; Postprandial Period; Prospective Studies; Reward

Regular nut consumption is associated with lower adiposity and reduced weight gain in adulthood. Walnut feeding studies have observed minimal effect on body weight despite potential additional energy intake. Several mechanisms may explain why consuming nuts promotes weight control, including increased early phase satiety, possibly reflected in postprandial response of gastrointestinal and pancreatic peptides hypothesized to affect appetite. The purpose of this study was to compare postprandial insulin, glucagon and gastrointestinal peptide response and satiety following a meal with ∼54% of energy from walnuts or cream cheese, using a within-subject crossover study design in overweight/obese adults (N = 28). Sixty minutes after the walnut-containing meal, glucagon-like peptide-1 was lower than after the reference meal (p=0.0433), and peptide YY, cholecystokinin and ghrelin did not differ after the two meals. Sixty and 120 min after the walnut-containing meal, pancreatic polypeptide (p = 0.0014 and p = 0.0002) and glucose-dependent insulinotropic peptide (p < 0.0001 and p = 0.0079) were lower than after the reference meal, and 120 min after the walnut-containing meal, glucagon was higher (p=0.0069). Insulin and C-peptide increased at 60 min in response to both meals but were lower at 120 min after the walnut-containing meal (p=0.0349 and 0.0237, respectively). Satiety measures were similar after both meals. These findings fail to support the hypothesis that acute postprandial gastrointestinal peptide response to a walnut-containing meal contributes to increased satiety. However, inclusion of walnuts attenuated the postprandial insulin response, which may contribute to the more favorable lipid profile observed in association with regular walnut consumption.

Topics: Adult; Aged; Cholecystokinin; Cross-Over Studies; Diet; Energy Intake; Feeding Behavior; Female; Gastrointestinal Hormones; Glucagon; Glucagon-Like Peptide 1; Humans; Insulin; Juglans; Male; Meals; Middle Aged; Nuts; Obesity; Peptide YY; Peptides; Postprandial Period; Satiation

The impact of stress on circulating levels of appetite-regulating hormones remains largely unknown. The aim of this study was to analyze the effect of acute psychosocial stress on the gut hormone peptide YY (PYY) secretion in obese and normal weight women. Therefore, we compared pre- and post-prandial plasma PYY secretion of 42 obese and 43 normal weight women in a repeated measure randomized controlled laboratory experiment. PYY and cortisol concentrations were measured and ratings of stress and satiety were also recorded in response to a psychological stressor (Trier Social Stress Test, TSST). PYY samples were collected in the fasting state both before participating in the TSST and before a control session. Participants had a standardized meal after the TSST and control session, respectively. PYY was measured both 30 and 60 min after the TSST and control session, respectively. Stress inhibited PYY secretion as well as food intake in all women, but did not influence subjective satiety perception. The present data indicate that despite of lower PYY levels the subjects' requirement to overeat was not increased. From an evolutionary perspective this finding is adaptive. After stress the organism is prepared for fight or flight reaction, whereas not primarily necessary functions are inhibited. Therefore, increased food intake during stress would be dysfunctional.

Topics: Adolescent; Adult; Eating; Female; Humans; Hydrocortisone; Obesity; Peptide YY; Postprandial Period; Saliva; Satiation; Stress, Psychological; Young Adult

Limited research has examined the effects of habitual SSB consumption on hunger/fullness ratings and gut hormones. This study hypothesized that high versus low intakes of habitual SSBs would result in greater hunger, decreased fullness, and a blunted gut hormone response, however the high versus low fiber group would exhibit decreased hunger and increased fullness. This was a randomized crossover feeding trial with 47 African American and Hispanic adolescents. The experiment included three 24-hour recalls to assess habitual dietary intake. During the test meal phase, subjects were served breakfast and lunch. During the ad libitum meal phase, subjects were fed an ad libitum dinner. During the test meal phase, blood was drawn every 30 minutes for 3 hours. During the ad libitum meal phase, hunger and fullness visual analogue scales were completed. For this analysis, subjects were grouped into the following habitual SSB categories: low SSB (≤1 SSB serv/day), medium SSB (>1 - <2 serv/day), and high SSB (≥2 serv/day). Fiber categories were created based on quartiles of intake. Mixed modeling was used to explore how SSB and fiber categories predicted ghrelin/PYY values and hunger/fullness ratings across time within and between test meals. The following a priori covariates included: sex, ethnicity, age, and obesity status. The low SSB group had higher fullness ratings over the ad libitum meal compared to the high SSB group (β =-0.49, CI=(-0.89, -0.08), p=0.02) and higher ghrelin concentrations than the medium and high SSB group over the test meal phase (β =-1.86, CI=(-2.81, -0.92), p<0.01). Habitual SSB intake appears to play a key role in moderating fullness responses possibly via ghrelin.

Topics: Adolescent; Appetite; Beverages; Black or African American; Cross-Over Studies; Dietary Carbohydrates; Dietary Fiber; Energy Intake; Feeding Behavior; Female; Ghrelin; Hispanic or Latino; Humans; Male; Meals; Nutritive Sweeteners; Obesity; Peptide YY; Satiation

The relationship between dietary macronutrient composition and appetite is controversial. We examined the effects of a year-long low-carbohydrate diet compared to a low-fat diet on appetite-related hormones and self-reported change in appetite.. A total of 148 adults with a body mass index 30-45 kg/m(2), who were free of diabetes, cardiovascular disease and chronic kidney disease at baseline were randomly assigned to either a low-carbohydrate diet (carbohydrate [excluding dietary fiber]<40 g/day; N = 75) or a low-fat diet (<30% energy from fat, <7% from saturated fat; N = 73). Participants in both groups attended individual and group dietary counseling sessions where they were provided the same behavioral curriculum and advised to maintain baseline levels of physical activity. Appetite and appetite-related hormones were measured at 0, 3, 6 and 12 months of intervention. At 12 months, mean changes (95% CI) in peptide YY were -34.8 pg/mL (-41.0 to -28.6) and in the low-carbohydrate group and -44.2 pg/mL (-50.4 to -38.0) in the low-fat group (net change: 9.54 pg/mL [0.6 to 18.2]; p = 0.036). Approximately 99% of dietary effects on peptide YY are explained by differences in dietary macronutrient content. There was no difference in change in ghrelin or self-reported change in appetite between the groups.. A low-fat diet reduced peptide YY more than a low-carbohydrate diet. These findings suggest that satiety may be better preserved on a low-carbohydrate diet, as compared to a low fat diet.. clinicaltrials.gov Identifier: NCT00609271.

Topics: Adult; Aged; Appetite Regulation; Biomarkers; Counseling; Diet, Carbohydrate-Restricted; Diet, Fat-Restricted; Exercise; Female; Ghrelin; Humans; Male; Middle Aged; New Orleans; Obesity; Peptide YY; Satiation; Time Factors; Treatment Outcome; Weight Loss; Young Adult

Dietary mycoprotein decreases energy intake in lean individuals. The effects in overweight individuals are unclear, and the mechanisms remain to be elucidated. This study aimed to investigate the effect of mycoprotein on energy intake, appetite regulation, and the metabolic phenotype in overweight and obese volunteers. In two randomised-controlled trials, fifty-five volunteers (age: 31 (95 % CI 27, 35) years), BMI: 28·0 (95 % CI 27·3, 28·7) kg/m2) consumed a test meal containing low (44 g), medium (88 g) or high (132 g) mycoprotein or isoenergetic chicken meals. Visual analogue scales and blood samples were collected to measure appetite, glucose, insulin, peptide tyrosine-tyrosine (PYY) and glucagon-like peptide-1 (GLP-1). Ad libitum energy intake was assessed after 3 h in part A (n 36). Gastric emptying by the paracetamol method, resting energy expenditure and substrate oxidation were recorded in part B (n 14). Metabonomics was used to compare plasma and urine samples in response to the test meals. Mycoprotein reduced energy intake by 10 % (280 kJ (67 kcal)) compared with chicken at the high content (P=0·009). All mycoprotein meals reduced insulin concentrations compared with chicken (incremental AUClow (IAUClow): -8 %, IAUCmedium: -12 %, IAUChigh: -21 %, P=0·004). There was no significant difference in glucose, PYY, GLP-1, gastric emptying rate and energy expenditure. Following chicken intake, paracetamol-glucuronide was positively associated with fullness. After mycoprotein, creatinine and the deamination product of isoleucine, α-keto-β-methyl-N-valerate, were inversely related to fullness, whereas the ketone body, β-hydroxybutyrate, was positively associated. In conclusion, mycoprotein reduces energy intake and insulin release in overweight volunteers. The mechanism does not involve changes in PYY and GLP-1. The metabonomics analysis may bring new understanding to the appetite regulatory properties of food.

Topics: Adult; Animals; Appetite; Appetite Regulation; Dietary Proteins; Dipeptides; Eating; Energy Intake; Female; Fungal Proteins; Fusarium; Gastric Emptying; Gastrointestinal Hormones; Glucagon-Like Peptide 1; Humans; Insulin; Male; Middle Aged; Obesity; Peptide YY; Postprandial Period; Poultry; Satiation; Young Adult

There is considerable interest in the effect of foods containing high intensity sweeteners on satiation. However, less is known about low-calorie bulk sweeteners such as erythritol. In this randomized three-way crossover study, we studied 10 lean and 10 obese volunteers who consumed three test meals on separate occasions: (a) control sucrose meal; (b) isovolumic meal with partial replacement of sucrose by erythritol; (c) isocaloric meal which contained more erythritol but equivalent calories to the control meal. We measured gut hormone levels, hunger and satiety scores, ad libitum food intake, sucrose preference and intake after the manipulations. There was a greater post-prandial excursion in glucose and insulin levels after sucrose than after the erythritol meals. There was no difference in GLP-1/PYY levels or subsequent energy intake and sucrose preference between sucrose control and isovolumic erythritol meals. In lean (but not obese) participants, hunger decreased to a greater extent after the isocaloric erythritol meal compared to the control meal (p = 0.003) reflecting the larger volume of this meal. Replacing sucrose with erythritol leads to comparable hunger and satiety scores, GLP-1 and PYY levels, and subsequent sucrose preference and intake.

Topics: Adult; Cross-Over Studies; Erythritol; Female; Glucagon-Like Peptide 1; Humans; Hunger; Male; Meals; Middle Aged; Non-Nutritive Sweeteners; Obesity; Peptide YY; Postprandial Period; Satiation; Sucrose; Sweetening Agents

The effect of acute exercise, and exercise intensity, on appetite control in obese individuals requires further study. The aim of this study was to compare the effects of acute isocaloric bouts (250 kcal) of high-intensity intermittent cycling (HIIC) and moderate-intensity continuous cycling (MICC) or short-duration HIIC (S-HIIC) (125 kcal) and a resting control condition on the appetite hormone responses, subjective feelings of appetite, energy intake (EI), and food reward in overweight/obese individuals.. This study is a randomized crossover study on 12 overweight/obese volunteers. Participants were assigned to the control, MICC, HIIC, and S-HIIC conditions, 1 wk apart, in a counterbalanced order. Exercise was performed 1 h after a standard breakfast. An ad libitum test lunch was served 3 h after breakfast. Fasting/postprandial plasma samples of insulin, acylated ghrelin, polypeptide YY3-36, and glucagon-like peptide 1 and subjective feelings of appetite were measured every 30 min for 3 h. Nutrient and taste preferences were measured at the beginning and end of each condition using the Leeds Food Preference Questionnaire.. Insulin levels were significantly reduced, and glucagon-like peptide 1 levels significantly increased during all exercise bouts compared with those during rest. Acylated ghrelin plasma levels were lower in the MICC and HIIC, but not in S-HIIC, compared with those in control. There were no significant differences for polypeptide YY3-36 plasma levels, hunger or fullness ratings, EI, or food reward.. Our findings suggest that, in overweight/obese individuals, isocaloric bouts of moderate- or high-intensity exercise lead to a similar appetite response. This strengthens previous findings in normal-weight individuals that acute exercise, even at high intensity, does not induce any known physiological adaptation that would lead to increased EI.

Topics: Acylation; Adult; Appetite; Cross-Over Studies; Energy Intake; Exercise; Female; Food Preferences; Ghrelin; Glucagon-Like Peptide 1; Humans; Insulin; Male; Obesity; Peptide Fragments; Peptide YY; Physical Exertion; Reward; Taste; Young Adult

Weight loss after pharmacotherapy varies greatly. We aimed to examine associations of quantitative gastrointestinal and psychological traits with obesity, and to validate the ability of these traits to predict responses of obese individuals to pharmacotherapy.. In a prospective study, we measured gastric emptying of solids and liquids, fasting and postprandial gastric volume, satiation by nutrient drink test (volume to fullness and maximal tolerated volume), satiety after an ad libitum buffet meal, gastrointestinal hormones, and psychological traits in 328 normal-weight, overweight, or obese adults. We also analyzed data from 181 previously studied adults to assess associations betwecen a subset of traits with body mass index and waist circumference. Latent dimensions associated with overweight or obesity were appraised by principal component analyses. We performed a proof of concept, placebo-controlled trial of extended-release phentermine and topiramate in 24 patients to validate associations between quantitative traits and response to weight-loss therapy.. In the prospective study, obesity was associated with fasting gastric volume (P = .03), accelerated gastric emptying (P < .001 for solids and P = .011 for liquids), lower postprandial levels of peptide tyrosine tyrosine (P = .003), and higher postprandial levels of glucagon-like peptide 1 (P < .001). In a combined analysis of data from all studies, obesity was associated with higher volume to fullness (n = 509; P = .038) and satiety with abnormal waist circumference (n = 271; P = .016). Principal component analysis identified latent dimensions that accounted for approximately 81% of the variation among overweight and obese subjects, including satiety or satiation (21%), gastric motility (14%), psychological factors (13%), and gastric sensorimotor factors (11%). The combination of phentermine and topiramate caused significant weight loss, slowed gastric emptying, and decreased calorie intake; weight loss in response to phentermine and topiramate was significantly associated with calorie intake at the prior satiety test.. Quantitative traits are associated with high body mass index; they can distinguish obesity phenotypes and, in a proof of concept clinical trial, predicted response to pharmacotherapy for obesity. ClinicalTrials.gov Number: NCT01834404.

Topics: Adult; Aged; Anti-Obesity Agents; Anxiety; Body Image; Body Mass Index; Cholecystokinin; Cohort Studies; Delayed-Action Preparations; Depression; Dipeptides; Drug Combinations; Fasting; Female; Fructose; Gastric Emptying; Ghrelin; Glucagon-Like Peptide 1; Humans; Male; Middle Aged; Obesity; Organ Size; Overweight; Peptide YY; Phentermine; Postprandial Period; Principal Component Analysis; Prospective Studies; Satiation; Self Efficacy; Stomach; Topiramate; Treatment Outcome

It is unknown whether leptin and peptide YY (PYY) influence changes in resting energy expenditure (REE), independently of fat mass (FM) and fat-free mass (FFM) in addition to changes in other energy expenditure (EE) components during weight loss.. The objective of the study was to examine the relationships between leptin, PYY, and body composition with different EE components before and after weight loss and whether changes in leptin and PYY were associated with differences in predicted vs measured REE after the intervention.. This was a randomized controlled design.. The study was conducted in a laboratory.. Participants were ninety-three overweight/obese postmenopausal women (aged 58.1 ± 4.8 y; body mass index 32.1 ± 4.3 kg/m(2)).. Interventions included a 6-month caloric restriction diet alone or caloric restriction diet+resistance training.. Body composition (dual energy x-ray absorptiometry), REE (indirect calorimetry), total EE (TEE; doubly labeled water), and fasting leptin and total PYY before and after weight loss were measured.. Both interventions yielded significant decreases in weight, FFM, REE, and leptin, whereas a significant time × group interaction was noted for FM (greater decrease in FM in the diet+resistance training group) (P < .05 for all outcomes). No significant differences in TEE, physical activity EE, and PYY were noted between baseline and after the intervention. Age, FFM, leptin, and PYY were the best predictors of baseline REE (R(2) = 0.77; P = .0001), whereas age, FFM, and FM were associated with REE after the intervention (R(2) = 0.88; P = .0001). The same predictors, except for leptin, were significantly related to TEE at baseline (R(2) = 0.70; P = .0001) and after the intervention (R(2) = 0.29; P = .0001), whereas only PYY was a significant predictor of physical activity EE at baseline and after the intervention. Changes in FM and leptin accounted for 27% of the variance in ΔREE (P = .0001). Greater predicted vs measured REE was noted after the intervention (P = .02). However, Δ leptin and ΔPYY were not significant predictors of the differences between postintervention measurement and predicted REE.. Δ Leptin and ΔFM were strong contributors to changes in REE. However, Δ leptin and ΔPYY were not significant predictors of the differences between predicted and measured REE after the intervention.

Topics: Basal Metabolism; Caloric Restriction; Diet, Reducing; Down-Regulation; Energy Metabolism; Female; Humans; Leptin; Middle Aged; Obesity; Overweight; Peptide YY; Rest; Weight Loss

Dietary fibers are associated with enhanced satiety. However, the mechanism of different dietary fibers contributing to satiety-related gastrointestinal (GI) peptide release, especially in an obese population, is still poorly understood. Polydextrose (PDX), a water-soluble glucose polymer, has demonstrated its ability to reduce energy intake at a subsequent meal, but its mechanism of action requires further research. Also, there is limited evidence on its capacity to regulate subjective feelings of appetite. This study examines the effects of PDX on postprandial secretion of satiety-related GI peptides, short chain fatty acids (SCFAs), lactic acid, and subjective appetite ratings in obese participants.. 18 non-diabetic, obese participants (42.0 y, 33.6 kg/m2) consumed a high-fat meal (4293 kJ, 36% from fat) with or without PDX (15 g) in an acute, multicenter, randomized, double-blind, placebo-controlled and crossover trial. Postprandial plasma concentrations of satiety-related peptides, namely ghrelin, cholecystokinin (CCK), glucagon-like peptide 1 (GLP-1), and peptide YY (PYY), as well as SCFAs and lactic acid were assessed. GI peptide, SCFA and lactate concentrations were then modeled using a linear mixed-effects model.The subjective feelings of hunger, satisfaction, and desire to eat were evaluated using visual analogue scales (VAS), which were analyzed as incremental areas under the curve (iAUC) during the satiation and satiety periods.. We found that PDX supplementation increased plasma GLP-1 levels more than the placebo treatment (P = 0.02). In the whole group, GLP-1 concentrations found in participants older than 40 years old were significantly lower (P = 0.01) as compared to those aged 40 years or less. There were no statistically significant differences in postprandial ghrelin, CCK, or PYY responses. The lactic acid concentrations were significantly (P = 0.01) decreased in the PDX group, while no significant changes in SCFAs were found. PDX reduced iAUC for hunger by 40% (P = 0.03) and marginally increased satisfaction by 22.5% (P = 0.08) during the post-meal satiety period.. Polydextrose increased the postprandial secretion of the satiety hormone GLP-1 and reduced hunger after a high-fat meal. PDX also reduced the elevated postprandial lactic acid levels in plasma. Therefore, PDX may offer an additional means to regulate inter-meal satiety and improve postprandial metabolism in obese participants.

Topics: Adult; Age Factors; Body Mass Index; Cholecystokinin; Cross-Over Studies; Dietary Fats; Dietary Fiber; Double-Blind Method; Fatty Acids, Volatile; Female; Ghrelin; Glucagon-Like Peptide 1; Glucans; Humans; Lactic Acid; Male; Middle Aged; Obesity; Peptide YY; Placebos; Postprandial Period; Satiation

High-protein diets are an effective means for weight loss (WL), but the mechanisms are unclear. One hypothesis relates to the release of gut hormones by either protein or amino acids (AA). The present study involved overweight and obese male volunteers (n 18, mean BMI 36·8 kg/m2) who consumed a maintenance diet for 7 d followed by fully randomised 10 d treatments with three iso-energetic WL diets, i.e. with either normal protein (NP, 15% of energy) or high protein (HP, 30%) or with a combination of protein and free AA, each 15% of energy (NPAA). Psychometric ratings of appetite were recorded hourly. On day 10, plasma samples were taken at 30 min intervals over two consecutive 5 h periods (covering post-breakfast and post-lunch) and analysed for AA, glucose and hormones (insulin, total glucose-dependent insulinotropic peptide, active ghrelin and total peptide YY (PYY)) plus leucine kinetics (first 5 h only). Composite hunger was 16% lower for the HP diet than for the NP diet (P<0·01) in the 5 h period after both meals. Plasma essential AA concentrations were greatest within 60 min of each meal for the NPAA diet, but remained elevated for 3-5 h after the HP diet. The three WL diets showed no difference for either fasting concentrations or the postprandial net incremental AUC (net AUCi) for insulin, ghrelin or PYY. No strong correlations were observed between composite hunger scores and net AUCi for either AA or gut peptides. Regulation of hunger may involve subtle interactions, and a range of signals may need to be integrated to produce the overall response.

Topics: Adult; Aged; Amino Acids; Appetite; Area Under Curve; Blood Glucose; Body Composition; Body Mass Index; Body Weight; Diet, Reducing; Dietary Proteins; Gastric Inhibitory Polypeptide; Gastrointestinal Hormones; Ghrelin; Humans; Hunger; Intestinal Mucosa; Male; Middle Aged; Obesity; Peptide YY; Postprandial Period; Psychometrics; Tryptophan; Weight Loss; Young Adult

Determine subjective and physiological appetite responses and ad libitum intake to high-fat (HF) meals rich in either monounsaturated (MUFAs), polyunsaturated (PUFAs), or saturated fatty acids (SFAs) in women with obesity.. In this single-blind crossover study, three HF meals (70% of energy) rich in MUFAs, PUFAs, or SFAs in 16 women with obesity were tested. At each visit, anthropometrics and a fasting blood sample were collected. Participants then consumed one of the HF meals, and postprandial blood draws and visual analog scale (VAS) measures were collected over 5 h. An ad libitum buffet lunch was provided 5 h after the HF meal.. Decrease in ghrelin was significantly greater for PUFA (P < 0.05) and MUFA (P < 0.01) vs. SFA while the increase in peptide YY was significantly greater for PUFA vs. both SFA and MUFA (P < 0.05). Change in glucagon-like peptide-1, VAS measurements, or total energy consumed at the buffet showed no differences between HF meals (ns).. Fatty acid composition differentially affected physiological markers of hunger and satiety. However, it was unable to show changes in subjective appetite ratings or changes in energy intake when alterations were made to fatty acid composition from an acute HF meal.

Topics: Adult; Cross-Over Studies; Dietary Fats; Energy Intake; Fatty Acids; Fatty Acids, Monounsaturated; Fatty Acids, Unsaturated; Female; Ghrelin; Glucagon-Like Peptide 1; Humans; Obesity; Peptide YY; Postprandial Period; Satiation; Satiety Response; Single-Blind Method

Inhibition of diacylglycerol acyltransferase 1 (DGAT1) is a potential treatment modality for patients with type 2 diabetes mellitus and obesity, based on preclinical data suggesting it is associated with insulin sensitization and weight loss. This randomized, placebo-controlled, phase 1 study in 62 overweight or obese men explored the effects and tolerability of AZD7687, a reversible and selective DGAT1 inhibitor.. Multiple doses of AZD7687 (1, 2.5, 5, 10 and 20 mg/day, n = 6 or n = 12 for each) or placebo (n = 20) were administered for 1 week. Postprandial serum triacylglycerol (TAG) was measured for 8 h after a standardized 45% fat meal. Glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) were measured and a paracetamol challenge was performed to assess gastric emptying.. Dose-dependent reductions in postprandial serum TAG were demonstrated with AZD7687 doses ≥5 mg compared with placebo (p < 0.01). Significant (p < 0.001) increases in plasma GLP-1 and PYY levels were seen at these doses, but no clear effect on gastric emptying was demonstrated at the end of treatment. With AZD7687 doses >5 mg/day, gastrointestinal (GI) side effects increased; 11/18 of these participants discontinued treatment owing to diarrhoea.. Altered lipid handling and hormone secretion in the gut were demonstrated during 1-week treatment with the DGAT1 inhibitor AZD7687. However, the apparent lack of therapeutic window owing to GI side effects of AZD7687, particularly diarrhoea, makes the utility of DGAT1 inhibition as a novel treatment for diabetes and obesity questionable.

Topics: Acetates; Adult; Anti-Obesity Agents; Diabetes Mellitus, Type 2; Diacylglycerol O-Acyltransferase; Diarrhea; Dose-Response Relationship, Drug; Gastric Emptying; Glucagon-Like Peptide 1; Humans; Intestinal Absorption; Male; Middle Aged; Obesity; Peptide YY; Pyrazines; Treatment Outcome; Weight Loss

A 4-d 70% energy restriction enhances gastrointestinal sensitivity to nutrients associated with enhanced energy-intake suppression by lipid. To our knowledge, it is unknown whether these changes occur with 30% energy restriction and are sustained in the longer term.. We hypothesized that 1) a 4-d 30% energy restriction would enhance effects of intraduodenal lipid on gastrointestinal motility, gut hormones, appetite, and energy intake in lean and obese men and 2) a 12-wk energy restriction associated with weight loss would diminish effects of acute energy restriction on responses to lipid in in obese men.. Twelve obese males were studied before (day 0) and after 4 d (day 5), 4 wk (week 4), and 12 wk (week 12), and 12 lean males were studied before and after 4 d of consumption of a 30% energy-restricted diet. On each study day, antropyloroduodenal pressures, gut hormones, and appetite during a 120-min (2.86-kcal/min) intraduodenal lipid infusion and energy intake at a buffet lunch were measured.. On day 5, fasting cholecystokinin was less, and ghrelin was higher, in lean (P < 0.05) but not obese men, and lipid-stimulated cholecystokinin and peptide YY and the desire to eat were greater in both groups (P < 0.05), with no differences in energy intakes compared with on day 0. In obese men, a 12-wk energy restriction led to weight loss (9.7 ± 0.7 kg). Lipid-induced basal pyloric pressures (BPPs), peptide YY, and the desire to eat were greater (P < 0.05), whereas the amount eaten was less (P < 0.05), at weeks 4 and 12 compared with day 0.. A 4-d 30% energy restriction modestly affects responses to intraduodenal lipid in health and obesity but not energy intake, whereas a 12-wk energy restriction, associated with weight-loss, enhances lipid-induced BPP and peptide YY and reduces food intake, suggesting that energy restriction increases gastrointestinal sensitivity to lipid. This trial was registered at the Australian New Zealand Clinical Trials Registry (www.anzctr.org.au) as 12609000943246.

Topics: Adult; Anthropometry; Appetite; Cholecystokinin; Diet; Duodenum; Energy Intake; Fasting; Feeding Behavior; Gastrointestinal Motility; Ghrelin; Humans; Life Style; Lipid Metabolism; Male; Middle Aged; New Zealand; Obesity; Peptide YY; Pylorus; Thinness; Young Adult

Satiety and satiety-regulating gut hormone levels are abnormal in hyperglycemic individuals. We aimed to determine whether these abnormalities are secondary to hyperglycemia. Ten healthy overweight/obese subjects (age: 56 ± 3 yr; BMI: 30.3 ± 1.2 kg/m(2)) received three equicaloric meals at t = 0, 4, and 8 h in the absence (control trial) and presence of experimental hyperglycemia (hyperglycemia trial; 5.4 mM above basal). Circulating levels of glucose, insulin, ghrelin, and peptide YY (PYY)3-36 and visual analog scale ratings of satiety were measured throughout each trial. In the control trial, glucose, insulin, PYY3-36, and the feeling of fullness were increased in the postprandial periods, whereas ghrelin was decreased. In the hyperglycemia trial, in which plasma glucose was increased to 11.2 ± 0.1 mmol/l, postprandial meal responses (AUC: 0-2, 4-6, and 8-10 h) of PYY3-36 were lower (meal 1, P < 0.0001; meal 2, P < 0.001; meal 3, P < 0.05), whereas insulin (meal 1, P < 0.01; meal 2, P < 0.001; meal 3, P < 0.05) and ghrelin (meal 1, P < 0.05; meal 2, P > 0.05; meal 3, P > 0.05) were higher compared with the control trial. Furthermore, the incremental (Δ0-0.5, 4-4.5, and 8-8.5 h) ghrelin response to the first and third meals was higher in the hyperglycemia trial in contrast to control (Δ: 2.3 ± 8.0, P = 0.05; Δ: 14.4 ± 2.5, P < 0.05). Also, meal-induced fullness was prevented (meal 1, P = 0.06; meal 2, P = 0.01; meal 3, P = 0.08) by experimental hyperglycemia. Furthermore, trends in ghrelin, PYY3-36, and fullness were described by different polynomial functions between the trials. In conclusion, hyperglycemia abolishes meal-induced satiety and dysregulates postprandial responses of the gut hormones PYY3-36 and ghrelin in overweight/obese healthy humans.

Topics: Blood Glucose; Eating; Female; Ghrelin; Health; Humans; Hyperglycemia; Insulin; Male; Meals; Middle Aged; Obesity; Overweight; Peptide Fragments; Peptide YY; Satiety Response

Little information is available on how food intake regulatory hormones may be altered during pubertal development and across the weight spectrum in adolescents. Therefore, the effect of obesity, sex and pubertal status on subjective appetite and appetite hormones in response to a mixed glucose and whey protein drink was determined in 8-18 year old adolescents.. A cross-sectional cohort study was conducted at the Hospital for Sick Children, Toronto. After a 12 h fast, normal weight (n = 5 female, 4 male) and obese (n = 5 female, 4 male) adolescents (Experiment 1), and pre-early pubertal (n = 10) and mid-late pubertal (n = 10) obese male adolescents (Experiment 2) consumed a 250 ml glucose (30 g) and whey protein (30 g) beverage. Insulin, PYY, ghrelin and subjective appetite were measured over 120 min.. Obese adolescents (Experiment 1) have higher insulin, PYY and lower ghrelin (P < 0·006) than normal weight controls, with a more pronounced effect in males (P < 0·037). Puberty (Experiment 2) did not affect insulin (P = 0·305), but the change in PYY in response to the drink was greater (P = 0·032) and ghrelin was lower (P = 0·026) in mid-late pubertal than pre-early pubertal obese males. Average appetite 60 min post-drink was higher in obese and mid-late pubertal adolescents, but not related to hormone changes.. Obesity, sex and pubertal status affect macronutrient-stimulated appetite hormone secretion and these factors may alter food intake in obese children during pubertal development.

Topics: Adolescent; Appetite; Child; Cross-Sectional Studies; Female; Ghrelin; Glucose; Humans; Insulin; Male; Milk Proteins; Obesity; Peptide YY; Puberty; Sex Factors; Whey Proteins

To investigate the effect of nutrient stimulation of gut hormones by oligofructose supplementation on appetite, energy intake (EI), body weight (BW) and adiposity in overweight and obese volunteers.. In a parallel, single-blind and placebo-controlled study, 22 healthy overweight and obese volunteers were randomly allocated to receive 30 g day(-1) oligofructose or cellulose for 6 weeks following a 2-week run-in. Subjective appetite and side effect scores, breath hydrogen, serum short chain fatty acids (SCFAs), plasma gut hormones, glucose and insulin concentrations, EI, BW and adiposity were quantified at baseline and post-supplementation.. Oligofructose increased breath hydrogen (P < 0.0001), late acetate concentrations (P = 0.024), tended to increase total area under the curve (tAUC)420 mins peptide YY (PYY) (P = 0.056) and reduced tAUC450 mins hunger (P = 0.034) and motivation to eat (P = 0.013) when compared with cellulose. However, there was no significant difference between the groups in other parameters although within group analyses showed an increase in glucagon-like peptide 1 (GLP-1) (P = 0.006) in the cellulose group and a decrease in EI during ad libitum meal in both groups.. Oligofructose increased plasma PYY concentrations and suppressed appetite, while cellulose increased GLP-1 concentrations. EI decreased in both groups. However, these positive effects did not translate into changes in BW or adiposity.

Topics: Adiposity; Adult; Appetite; Appetite Regulation; Area Under Curve; Blood Glucose; Body Weight; Cellulose; Dietary Fiber; Dietary Supplements; Energy Intake; Fatty Acids; Female; Glucagon-Like Peptide 1; Healthy Volunteers; Humans; Insulin; Male; Middle Aged; Obesity; Oligosaccharides; Overweight; Patient Compliance; Peptide YY; Single-Blind Method; Young Adult

PYY is an appetite suppressing hormone. Low circulating PYY has been linked to greater BMI. However data is controversial and this association has not been verified in large human populations.. The purpose of this study was to investigate if fasting serum total PYY is associated with obesity status and/or adiposity at the population level.. A total of 2094 subjects (Male-523, Female-1571) participated in this investigation. Total PYY was measured in fasting serum by enzyme-linked immunosorbent assay. Obesity status (NW-normal-weight, OW-overweight and OB-obese) was determined by the Bray Criteria according to body fat percentage measured by dual-energy x-ray absorptiometry and the WHO criteria according to BMI. One-way ANOVA and multiple regression was used to assess the adiposity-specific association between PYY and the following; weight, BMI, waist-circumference, hip-circumference, waist-hip ratio, percent body fat (%BF), trunk fat (%TF), android fat (%AF) and gynoid fat (%GF).. PYY was not significantly different among NW, OW and OB groups defined by neither %BF nor BMI for both men and women. However among women, fasting PYY was positively associated with adiposity measures. Women with the highest (Top 33%) waist-circumference, %BF and %TF had significantly higher PYY (10.5%, 8.3% and 9.2% respectively) than women with the lowest (Bottom 33%). Age, smoking, medication use and menopause were all positively associated with PYY levels in women but not in men.. To our knowledge this is the largest population based study, with the most comprehensive analysis and measures of confounding factors, to explore the relationship of circulating PYY with obesity. Contrary to initial findings in the literature we discovered that PYY was positively associated with body fat measures (waist-circumference, %BF and %TF) in women. Although the effect size of the positive association of PYY with obesity in women is small, and potentially negligible, it may in fact represent a protective response against significant weight gain.

Topics: Adipose Tissue; Adult; Age Factors; Aged; Body Mass Index; Female; Humans; Male; Middle Aged; Obesity; Peptide YY; Risk Factors; Sex Factors

There is limited evidence with regard to the effect of different sources of protein on appetite during weight loss. Vegetarian and meat-based high-protein diets may have contrasting effects on appetite and biomarkers of protein-induced satiety.. The aim was to assess appetite response to meat or vegetarian high-protein weight-loss (HPWL) diets in obese men to monitor plasma amino acid profile and gut peptide response as potential satiety biomarkers.. Twenty obese [body mass index (in kg/m²): 34.8] men participated in a dietary intervention study. After 3 d of a maintenance diet, they were provided in a crossover design with either a vegetarian HPWL (Soy-HPWL) or a meat-based HPWL (Meat-HPWL) diet for 2 wk. Both diets comprised 30% protein, 30% fat, and 40% carbohydrate, provided to measured resting metabolic rate. Body weight and the motivation to eat were measured daily. Plasma satiety biomarkers were collected during a test-meal challenge (5 h) at the end of each diet period.. Over the 2 wk, subjects lost, on average, 2.41 and 2.27 kg with consumption of the Soy- and Meat-HPWL diets, respectively [P = 0.352; SE of the difference (SED): 0.1]. ANOVA confirmed that subjectively rated hunger (P = 0.569; SED: 3.8), fullness (P = 0.404; SED: 4.1), desire to eat (P = 0.356; SED: 3.7), preservation of lean body mass (P = 0.334; SED: 0.2), and loss of percentage fat mass (P = 0.179; SED: 0.2) did not differ between the 2 HPWL diets. There were differences in absolute concentrations of ghrelin and peptide YY between the 2 HPWL diets, although the response as net area under the curve was not different.. Appetite control and weight loss were similar for both HPWL diets. Gut hormone profile was similar between the diets, which suggests that vegetarian diets can be as effective as meat-based diets for appetite control during weight loss.

Topics: Adult; Aged; Amino Acids; Appetite Regulation; Biomarkers; Body Mass Index; Cross-Over Studies; Diet, Reducing; Diet, Vegetarian; Dietary Proteins; Food Preferences; Ghrelin; Humans; Male; Meat; Middle Aged; Obesity; Peptide YY; Plant Proteins, Dietary; Satiety Response; Scotland; Soybean Proteins; Weight Loss

Exercise is implicated in modifying subsequent energy intake (EI) through alterations in hunger and/or satiety hormones. Our aim was to examine the effects of aerobic exercise on hunger, satiety regulatory peptides, and EI in obese adolescents. Nine obese girls (age: 13-18 years old, BMI: 33.74 ± 4.04 kg/m2) participated in this randomized controlled crossover study. Each participant randomly underwent 2 experimental protocols: control (seated for 150 min) and exercise (exercised for 30 min on a treadmill performed at ventilatory threshold [VT] intensity and then remained seated for 120 min). Leptin, peptide YY(3-36) (PYY(3-36)), and subjective hunger were measured at baseline as well as 30 min and 150 min, followed by 24-hr EI measurement. Exercise session resulted in an acute increase in PYY(3-36) (p < .01) without changes in leptin and/or hunger scores. The control session increased hunger scores (p < .01) and decreased circulating leptin levels (p = .03). There was a strong effect size for carbohydrate intake (d = 2.14) and a modest effect size for protein intake (d = 0.61) after the exercise compared with the control session. Exercise performed at VT intensity in this study appears to provoke a state of transient anorexia in obese girls. These changes may be linked to an increase in circulating PYY3-36 and maintenance of leptin levels.

Topics: Adolescent; Cross-Over Studies; Exercise; Female; Humans; Hunger; Leptin; Obesity; Peptide Fragments; Peptide YY

This study determined the hormonal and subjective appetite responses to exercise (1-h continuous versus intermittent exercise throughout the day) in obese individuals.. Eleven obese subjects (>30 kg/m(2) ) underwent three 12-h study days: control condition [sedentary behavior (SED)], continuous exercise condition [(EX) 1-h exercise], and intermittent exercise condition [(INT) 12 hourly, 5-min bouts]. Blood samples (every 10 min) were measured for serum insulin and total peptide YY (PYY) concentrations, with ratings of appetite (visual analog scale [VAS): every 20 min]. Both total area under the curve (AUC), and subjective appetite ratings were calculated.. No differences were observed in total PYY AUC between conditions, but hunger was reduced with INT (INT < EX; P < 0.05), and satiety was increased with both SED and INT conditions (INT > EX and SED > EX; P < 0.05). A correlation existed between the change in total PYY and insulin levels (r = -0.81; P < 0.05), and total PYY and satiety (r = 0.80; P < 0.05) with the EX condition, not the SED and INT conditions.. The total PYY response to meals is not altered over the course of a 12-h day with either intermittent or continuous exercise; however, intermittent exercise increased satiety and reduced hunger to a greater extent than continuous exercise in obese individuals.

Topics: Adolescent; Adult; Appetite; Blood Glucose; Cross-Over Studies; Exercise; Female; Humans; Insulin; Male; Obesity; Peptide YY; Satiation; Satiety Response; Young Adult

Breakfast skipping is a common dietary habit practiced among adolescents and is strongly associated with obesity.. The objective was to examine whether a high-protein (HP) compared with a normal-protein (NP) breakfast leads to daily improvements in appetite, satiety, food motivation and reward, and evening snacking in overweight or obese breakfast-skipping girls.. A randomized crossover design was incorporated in which 20 girls [mean ± SEM age: 19 ± 1 y; body mass index (in kg/m(2)): 28.6 ± 0.7] consumed 350-kcal NP (13 g protein) cereal-based breakfasts, consumed 350-kcal HP egg- and beef-rich (35 g protein) breakfasts, or continued breakfast skipping (BS) for 6 d. On day 7, a 10-h testing day was completed that included appetite and satiety questionnaires, blood sampling, predinner food cue-stimulated functional magnetic resonance imaging brain scans, ad libitum dinner, and evening snacking.. The consumption of breakfast reduced daily hunger compared with BS with no differences between meals. Breakfast increased daily fullness compared with BS, with the HP breakfast eliciting greater increases than did the NP breakfast. HP, but not NP, reduced daily ghrelin and increased daily peptide YY concentrations compared with BS. Both meals reduced predinner amygdala, hippocampal, and midfrontal corticolimbic activation compared with BS. HP led to additional reductions in hippocampal and parahippocampal activation compared with NP. HP, but not NP, reduced evening snacking of high-fat foods compared with BS.. Breakfast led to beneficial alterations in the appetitive, hormonal, and neural signals that control food intake regulation. Only the HP breakfast led to further alterations in these signals and reduced evening snacking compared with BS, although no differences in daily energy intake were observed. These data suggest that the addition of breakfast, particularly one rich in protein, might be a useful strategy to improve satiety, reduce food motivation and reward, and improve diet quality in overweight or obese teenage girls. This trial was registered at clinicaltrials.gov as NCT01192100.

Topics: Adolescent; Adult; Appetite Regulation; Body Mass Index; Brain; Breakfast; Cross-Over Studies; Diet, High-Fat; Dietary Fats; Dietary Proteins; Eggs; Energy Intake; Female; Gastrointestinal Hormones; Ghrelin; Humans; Meals; Meat; Obesity; Peptide YY; Satiation; Signal Transduction; Young Adult

A diet rich in dairy and calcium (Ca) has been variably associated with improvements in body composition and decreased risk of type 2 diabetes. Our objective was to determine if a dietary pattern high in dairy and Ca improves weight loss and subjective appetite to a greater extent than a low dairy/Ca diet during energy restriction in overweight and obese adults with metabolic syndrome.. A total of 49 participants were randomized to one of two treatment groups: Control (low dairy, ≈ 700 mg/day Ca, -500 kcal/day) or Dairy/Ca (high dairy, ≈ 1400 mg/day Ca, -500 kcal/day) for 12 weeks. Body composition, subjective ratings of appetite, food intake, plasma satiety hormones, glycemic response and inflammatory cytokines were measured.. Control (-2.2 ± 0.5 kg) and Dairy/Ca (-3.3 ± 0.6 kg) had similar weight loss. Based on self-reported energy intake, the percentage of expected weight loss achieved was higher with Dairy/Ca (82.1 ± 19.4%) than Control (32.2 ± 7.7%; P=0.03). Subjects in the Dairy/Ca group reported feeling more satisfied (P=0.01) and had lower dietary fat intake (P=0.02) over 12 weeks compared with Control. Compared with Control, Dairy/Ca had higher plasma levels of peptide tyrosine tyrosine (PYY, P=0.01) during the meal tolerance test at week 12. Monocyte chemoattractant protein-1 was reduced at 30 min with Dairy/Ca compared with Control (P=0.04).. In conclusion, a dairy- and Ca-rich diet was not associated with greater weight loss than control. Modest increases in plasma PYY concentrations with increased dairy/Ca intake, however, may contribute to enhanced sensations of satisfaction and reduced dietary fat intake during energy restriction.

Topics: Adult; Appetite; Area Under Curve; Blood Glucose; Body Composition; Calcium, Dietary; Chemokine CCL2; Dairy Products; Diet, Reducing; Energy Intake; Female; Homeostasis; Humans; Insulin; Linear Models; Male; Middle Aged; Motor Activity; Obesity; Overweight; Peptide YY; Risk Factors; Weight Loss; Young Adult

Strong epidemiological evidence suggests that slow prenatal or postnatal growth is associated with an increased risk of CVD and other metabolic diseases. However, little is known whether early growth affects postprandial metabolism and, especially, the appetite regulatory hormone system. Therefore, we investigated the impact of early growth on postprandial appetite regulatory hormone responses to two high-protein and two high-fat content meals. Healthy, 65-75-year-old volunteers from the Helsinki Birth Cohort Study were recruited; twelve with a slow increase in BMI during the first year of life (SGI group) and twelve controls. Subjects ate a test meal (whey meal, casein meal, SFA meal and PUFA meal) once in a random order. Plasma glucose, insulin, TAG, NEFA, ghrelin, peptide tyrosine-tyrosine (PYY), glucose-dependent insulinotropic peptide, glucagon-like peptide-1 and a satiety profile were measured in the fasting state and for 4 h after each test meal. Compared with the controls, the SGI group had about 1·5-fold higher insulin responses after the whey meal (P= 0·037), casein meal (P= 0·023) and PUFA meal (P= 0·002). TAG responses were 34-69 % higher for the SGI group, but only the PUFA-meal responses differed significantly between the groups. The PYY response of the SGI group was 44 % higher after the whey meal (P= 0·046) and 115 % higher after the casein meal (P= 0·025) compared with the controls. No other statistically significant differences were seen between the groups. In conclusion, early growth may have a role in programming appetite regulatory hormone secretion in later life. Slow early growth is also associated with higher postprandial insulin and TAG responses but not with incretin levels.

Topics: Appetite Regulation; Body Mass Index; Case-Control Studies; Caseins; Diet, High-Fat; Dietary Fats; Dietary Proteins; Fatty Acids; Fatty Acids, Unsaturated; Female; Ghrelin; Growth; Humans; Incretins; Infant; Infant, Newborn; Insulin; Male; Milk Proteins; Obesity; Peptide Hormones; Peptide YY; Postprandial Period; Triglycerides; Whey Proteins

Reduced postprandial secretion of peptide YY (PYY), glucagon-like peptide-1 (GLP-1), cholecystokinin, and increased hunger was reported after a single dose of orlistat, an inhibitor of intestinal lipase. As yet, the influence of long-term therapy with orlistat on PYYand GLP-1 release has not been studied. Our study was aimed at assessing the influence of 8-week therapy with orlistat as a component of a weight loss program on pre-prandial circulating PYY and GLP-1 levels.. Forty obese women, without concomitant diseases, were randomly allocated to groups receiving orlistat or placebo during an 8-week weight management program. Body mass, body composition and plasma levels of PYY, GLP-1 and insulin (for QUICKI calculation) were determined prior to and at the end of therapy.. Women treated with orlistat obtained significantly greater body and fat mass loss than those receiving placebo (9.0 ± 3.1 vs. 5.9 ± 3.2% and 21.9 ± 10.9 vs. 7.4 ± 15.6%, respectively). Only in those treated with orlistat a slight, but significant increase of the QUICKI was found (8.0 ± 16.5 vs. -0.1 ± 12.7 %, respectively). Weight loss was followed by a significant increase of plasma levels of PYY and GLP-1 in group treated with orlistat, and was about 2-times greater than receiving placebo. The increase was independent of body mass changes.. The long-term inhibition of intestinal lipase by orlistat increases the pre-prandial levels of GLP-1 and PYY, independent of body mass changes. Therefore, it seems that long-term treatment with orlistat may exert hunger suppressing and insulin sensitizing incretin effect beyond weight reduction.

Topics: Body Mass Index; Body Weight; Double-Blind Method; Female; Glucagon-Like Peptide 1; Humans; Insulin; Intestinal Mucosa; Intestines; Lactones; Lipase; Obesity; Orlistat; Peptide YY; Weight Loss

The present study investigated the postprandial glycemic and insulinemic responses, the levels of satiety-related proteins, and substrate use after a single dose of a meal replacement (MR) with a high soy protein content and a low glycemic index (GI). The results were compared with a standardized breakfast showing a high GI and a low protein content.. Eleven overweight or obese male subjects with the metabolic syndrome and insulin resistance were included in the study. In the morning, each subject consumed, in a randomized design, 65 g of a MR or an isocaloric standardized breakfast. Four hours after breakfast, all subjects consumed the same standardized lunch. Blood levels of glucose, insulin, ghrelin, protein YY(PYY), oxygen uptake, and carbon dioxide production were determined and the respiratory quotient and substrate use were calculated.. The glycemic and insulinemic responses were considerably higher after the standardized breakfast. In addition, in these obese insulin-resistant subjects, the postprandial decease in fat oxidation was significantly less pronounced after intake of the MR. This effect was also detectable after lunch in terms of a second meal effect. Ghrelin levels were significantly lower 2 h after the intake of the MR and PYY levels tended higher.. Compared with the high GI/low-protein SB, a high soy protein MR with a low GI was associated with lower glycemia and insulinemia and relatively higher fat oxidation in the postprandial period. Together with a favorable course of appetite-regulating hormones, this could further help to explain the beneficial role of MR regimines high in soy protein for weight reduction and improvement of metabolic risk factors.

Topics: Appetite Regulation; Body Mass Index; Diet, Reducing; Energy Intake; Food, Formulated; Ghrelin; Glycemic Index; Humans; Hyperglycemia; Hyperinsulinism; Insulin Resistance; Lipid Metabolism; Male; Metabolic Syndrome; Middle Aged; Obesity; Overweight; Oxygen Consumption; Peptide YY; Postprandial Period; Soybean Proteins

Retraining obese adolescents to eat more slowly will lead to beneficial changes in circulating concentrations of gastrointestinal satiety hormones.. Ghrelin and peptide tyrosine-tyrosine were measured during an oral glucose tolerance test, at baseline and at 12 months during a randomized trial assessing the clinical effectiveness of a device (Mandometer) designed to retrain eating behavior. This computerized scale provided real-time feedback during meals in the intervention arm (n = 14) to slow down the speed of eating. The control group (n = 13) received only standard care aimed at improving lifestyle behavior. The Mandometer elicited greater improvements in weight loss than standard care.. Compared with baseline, only those using the Mandometer exhibited lower mean levels of fasting ghrelin (48.14 ± 18.47 vs. 68.45 ± 17.78 pg/ml; P = 0.002) and mean ghrelin area under the curve (72.08 ± 24.11 vs. 125.50 ± 29.72 pg/ml × min; P < 0.001) at 12 months. Absolute mean suppression in ghrelin at 60 min was enhanced (-40.50 ± 21.06 vs. -12.14 ± 19.74 pg/ml × min; P = 0.001). Peptide tyrosine-tyrosine response at 90 min remained unaltered in the standard care arm, whereas those in the Mandometer arm increased (P < 0.001): the mean 90-min response increased by 72 pg/ml [95% confidence interval (CI) 52-92 pg/ml] between baseline and 12 months. In a partial correlation analysis adjusting for change (Δ) in body mass index sd scores, Δ meal duration correlated negatively with Δ absolute suppression in ghrelin at 60 min (r = -0.58; P = 0.037; 95% CI -0.79 to -0.27) and Δ ghrelin area under the curve (r = -0.62; P = 0.025; 95% CI -0.81 to -0.31).. Retraining obese adolescents to eat more slowly has a significant impact on the gastrointestinal hormone response to a carbohydrate load, suggesting that externally modifiable eating behaviors actually regulate the hormonal response to food.

Topics: Adolescent; Body Weight; Child; Equipment and Supplies; Feeding Behavior; Female; Gastrointestinal Hormones; Ghrelin; Health; Humans; Life Style; Male; Obesity; Peptide YY; Treatment Outcome; Weight Reduction Programs

Although the α-glucosidase inhibitor miglitol (MG) has been reported to have anorexigenic effects, the mechanism remains to be elucidated. The objective of this study was to explore the effects of MG on appetite in relation to concomitant changes in postprandial gut hormone levels. This randomized open-label crossover study included 20 healthy volunteers. The effects of 50 mg MG on glucagon-like peptide-1 (GLP-1), peptide YY (PYY), and ghrelin levels were assessed in conjunction with a simultaneous determination of appetite scores using visual analogue scales (VAS) over 3 h after the ingestion of a 592 kcal test cookie. Additionally, the gastric emptying rate (GER) was measured using breath ¹³CO₂ appearance in 10 subjects. 12 subjects were administered 50 mg MG thrice a day for 1 week, and alterations of the gut hormone levels and the VAS scores for appetite were evaluated. MG pre-administration resulted in a significant enhancement of GLP-1 and PYY responses induced by the cookie ingestion. Following MG administration, ghrelin level declined at 1 h, with a persistent suppression during the postprandial phase in contrast to the restoration to the basal level without MG. Furthermore, MG pre-administration suppressed appetite and maintained satiety evaluated using a VAS rating with concomitant inhibition of GER after cookie ingestion. One-week administration of MG did not influence either gut hormone levels before a meal or VAS rating during a whole day. These observations suggest that MG exerts an anorexigenic effects with concomitant alterations of gut hormone secretions and gastric emptying after meal ingestion.

Topics: 1-Deoxynojirimycin; Adult; Appetite; Appetite Depressants; Female; Gastric Emptying; Ghrelin; Glucagon-Like Peptide 1; Humans; Male; Obesity; Peptide YY; Young Adult

Peptide YY (PYY), a gut hormone that inhibits appetite, has been linked to the development of obesity.. This study investigated the nutritional regulation of PYY after 7 d of overfeeding (70% above normal energy requirements) in normal-weight, overweight, and obese men.. Sixty-nine men (aged 19-29 y) participated in the study. We analyzed the relation between fasting serum PYY before and after a 7-d overfeeding challenge in normal-weight, overweight, and obese men. In addition, we analyzed PYY with obesity-related phenotypes including weight, percentage body fat (measured by dual-energy X-ray absorptiometry), body mass index (BMI), total cholesterol, HDL, LDL, glucose, insulin, insulin resistance, and β cell function evaluated by the homeostasis model assessment of insulin resistance (HOMA-IR) and β cell function (HOMA-β) at baseline and in response to the energy surplus.. Fasting serum PYY concentrations at baseline were not significantly different between the normal-weight, overweight, and obese subjects on the basis of dual-energy X-ray absorptiometry or BMI. Although the PYY concentration significantly increased due to overfeeding, no differences were observed between adiposity statuses. In addition, basal PYY was negatively correlated with the changes of total cholesterol, HDL, and LDL in normal weight. In addition, the increase in PYY after overfeeding was positively correlated with HDL cholesterol and glucose in normal-weight subjects.. Our findings suggest that fasting PYY concentrations are not associated with adiposity status. Moreover, the 7-d overfeeding challenge significantly increased fasting PYY, which is likely a protective response to the positive energy balance.

Topics: Absorptiometry, Photon; Adolescent; Adult; Blood Glucose; Body Composition; Body Mass Index; Cholesterol; Energy Intake; Humans; Male; Obesity; Overnutrition; Overweight; Peptide YY; Reference Values; Young Adult

Both orosensory stimulation and feedback from the gastrointestinal tract contribute to energy intake regulation.. We evaluated the hypothesis that overweight or obese subjects would be less sensitive to both oral and intraduodenal oleic acid exposure than would lean subjects.. Eleven overweight or obese and 8 lean men were studied on 2 occasions, during which antropyloroduodenal pressures, plasma cholecystokinin and peptide YY, and appetite were measured during 90-min intraduodenal infusions of saline or oleic acid (18:1 load: 0.78 kcal/min); energy intake (buffet lunch) was determined immediately afterward. Oral detection thresholds for 18:1 and recent dietary intake (2-d recall) were also quantified.. In lean subjects, the number of isolated pyloric pressure waves (IPPWs) was greater during 18:1 infusion than during saline infusion (P < 0.05); no significant differences were observed between the 18:1 and saline infusions in the overweight or obese subjects. In both groups, 18:1 stimulated plasma cholecystokinin and peptide YY and suppressed energy intake compared with saline (P < 0.05), with trends for reduced cholecystokinin and energy intake responses in the overweight or obese subjects. Detection thresholds for 18:1 were greater in overweight or obese (7.9 ± 0.1 mmol/L) than in lean (4.1 ± 0.4 mmol/L) subjects (P < 0.05). Overweight or obese subjects had greater recent energy (P < 0.05) and fat (P = 0.07) intakes than did lean subjects. There was a direct relation (r = 0.669) of body mass index with 18:1 detection thresholds and inverse relations (r < -0.51) of IPPWs with body mass index and 18:1 detection thresholds (P < 0.05).. The ability to detect oleic acid both orally and within the gastrointestinal tract is compromised in obese men, and oral and gastrointestinal responses to oleic acid are related. This trial was registered at www.actr.org.au (Australian New Zealand Clinical Trials Registry) as 12609000557235.

Topics: Adult; Appetite Regulation; Body Mass Index; Cholecystokinin; Dietary Fats; Duodenum; Energy Intake; Humans; Male; Middle Aged; Obesity; Oleic Acid; Peptide YY; Pressure; Pylorus; Reference Values; Sensory Thresholds; Taste; Thinness; Young Adult

The mechanism of the altered GH secretion in obesity is unclear. There is evidence that oral glucose (OG) administration initially decreases and subsequently stimulates GH secretion. Ghrelin is a peptide that displays strong growth hormone-releasing activity. Its physiological importance on GH regulation is unclear. Our aim was to study fasting GH concentrations and their response to OG administration in relation with ghrelin secretion in obese and healthy women, in order to elucidate the hypothetical participation of ghrelin on post-oral glucose GH secretion. 36 women were included in the study. After an overnight fast, 75 g of oral glucose was administered; glucose, insulin, ghrelin, and PYY (1-36) were obtained at baseline and during 300 min. The area under the curve between 0 and 300 min (AUC) of GH μ/l·min) was lower in obese patients than in controls; 262.5±57.5 vs. 534.9±95.6, p=0.01, for obese and controls respectively. GH peak (μg/l) was lower in obese patients than in controls; 3.7±0.7 vs. 7.1±1.0, p=0.012, for obese and controls, respectively. The AUC of total ghrelin (pg/ml·min) was lower in obese patients than in controls; 233,032±12,641 vs. 333,697±29,877, p=0.004, for the obese patients and controls respectively. PYY (1-36) was similar in obese and healthy women after OG. There were significant correlations between the different indices of post-oral glucose GH and ghrelin secretion. These data suggest that ghrelin is a physiological regulator of GH in the post-oral glucose state, and the decreased ghrelin secretion could be one of the mechanisms responsible for the altered GH secretion in obesity.

Topics: Administration, Oral; Adult; Case-Control Studies; Fasting; Female; Ghrelin; Glucose; Health; Human Growth Hormone; Humans; Obesity; Peptide YY

Obese patients have decreased fasting and postprandial levels of peptide YY (PYY), an anorexigenic peptide produced by the L cells of the gastrointestinal mucosa. Fatty nutrients are the most powerful stimulus for PYY release. Cholestyramine, an anion exchanger which adsorbs bile salts, reduces digestion of lipids. The aim of the present study was to investigate the effects of cholestyramine or placebo on PYY secretion in obese women administered a high-fat meal [n=8; age: 30.9±2.7 years; BMI: 47.3±3.3 kg/m2]. Postprandial PYY levels in obese women given placebo significantly increased in plasma at 30, 60, 90, and 120 min after meal ingestion. Cholestyramine administration significantly reduced postprandial PYY response at 15, 30, and 60 min. Percent fat mass (FM%) was negatively correlated with the percent increment of plasma PYY concentrations induced by meal administration at 30 min; conversely, there was a positive correlation between FM% and the percent decrement of plasma PYY concentrations induced by cholestyramine at the same time interval. These correlations failed to reach statistical significance when related to BMI. This study implies that in the obese state the altered PYY response to food consumption is a consequence of a dysfunction of L cells, which become less sensitive to the positive feedback effect of lipids.

Topics: Adiposity; Adult; Blood Glucose; Cholesterol; Cholestyramine Resin; Dietary Fats; Female; Humans; Insulin; Obesity; Peptide YY; Postprandial Period; Triglycerides

Roux-en-Y gastric bypass (gastric bypass) patients reportedly have changes in perception and consumption of sweet-tasting foods. This study aimed to further investigate alterations in sweet food intake in rats and sucrose detection in humans after gastric bypass. Wistar rats were randomized to gastric bypass or sham-operations and preference for sucrose (sweet), sodium chloride (salty), citric acid (sour) and quinine hydrochloride (bitter) was assessed with standard two-bottle intake tests (vs. water). Intestinal T1R2 and T1R3 expression and plasma levels of glucagon-like-peptide 1 (GLP-1) and peptide YY (PYY) were measured. Furthermore, obese patients and normal weight controls were tested for sucrose taste detection thresholds pre- and postoperatively. Visual analogue scales measuring hedonic perception were used to determine the sucrose concentration considered by patients and controls as "just about right" pre- and postoperatively. Gastric bypass reduced the sucrose intake relative to water in rats (p<0.001). Preoperative sucrose exposure reduced this effect. Preference or aversion for compounds representative of other taste qualities in naïve rats remained unaffected. Intestinal T1R2 and T1R3 expression was significantly decreased in the alimentary limb while plasma levels of GLP-1 and PYY were elevated after bypass in rats (p=0.01). Bypass patients showed increased taste sensitivity to low sucrose concentrations compared with controls (p<0.05), but both groups considered the same sucrose concentration as "just about right" postoperatively. In conclusion, gastric bypass reduces sucrose intake relative to water in sucrose-naïve rats, but preoperative sucrose experience attenuates this effect. Changes in sucrose taste detection do not predict hedonic taste ratings of sucrose in bypass patients which remain unchanged. Thus, factors other than the unconditional affective value of the taste may also play a role in determining food preferences after gastric bypass.

Topics: Analysis of Variance; Animals; Body Weight; Choice Behavior; Dose-Response Relationship, Drug; Drinking; Eating; Energy Intake; Female; Food Preferences; Gastric Bypass; Gene Expression Regulation; Glucagon-Like Peptide 1; Humans; Intestine, Small; Male; Obesity; Pain Measurement; Peptide YY; Rats; Rats, Wistar; Receptors, G-Protein-Coupled; RNA, Messenger; Sucrose; Sweetening Agents; Taste; Taste Threshold; Time Factors

Human duodenal mucosa secretes increased levels of satiety signals upon exposure to intact protein. However, after oral protein ingestion, gastric digestion leaves little intact proteins to enter the duodenum. This study investigated whether bypassing the stomach, through intraduodenal administration, affects hormone release and food-intake to a larger extent than orally administered protein in both lean and obese subjects.. Ten lean (BMI:23.0±0.7 kg/m²) and ten obese (BMI:33.4±1.4 kg/m²) healthy male subjects were included. All subjects randomly received either pea protein solutions (250 mg/kg bodyweight in 0.4 ml/kg bodyweight of water) or placebo (0.4 ml/kg bodyweight of water), either orally or intraduodenally via a naso-duodenal tube. Appetite-profile, plasma GLP-1, CCK, and PYY concentrations were determined over a 2 h period. After 2 h, subjects received an ad-libitum meal and food-intake was recorded.. CCK levels were increased at 10(p<0.02) and 20(p<0.01) minutes after intraduodenal protein administration (IPA), in obese subjects, compared to lean subjects, but also compared to oral protein administration (OPA)(p<0.04). GLP-1 levels increased after IPA in obese subjects after 90(p<0.02) to 120(p<0.01) minutes, compared to OPA. Food-intake was reduced after IPA both in lean and obese subjects (-168.9±40 kcal (p<0.01) and -298.2±44 kcal (p<0.01), respectively), compared to placebo. Also, in obese subjects, food-intake was decreased after IPA (-132.6±42 kcal; p<0.01), compared to OPA.. Prevention of gastric proteolysis through bypassing the stomach effectively reduces food intake, and seems to affect obese subjects to a greater extent than lean subjects. Enteric coating of intact protein supplements may provide an effective dietary strategy in the prevention/treatment of obesity.

Topics: Cholecystokinin; Eating; Ghrelin; Glucagon-Like Peptide 1; Humans; Male; Obesity; Peptide YY; Pisum sativum; Plant Proteins; Thinness

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.

Topics: Adult; Appetite; Body Weight; Brain; Eating; Energy Intake; Fasting; Female; Glucagon-Like Peptide 1; Humans; Immunoassay; Infusions, Intravenous; Magnetic Resonance Imaging; Male; Obesity; Peptide Fragments; Peptide YY; Postprandial Period; Single-Blind Method

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.. 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 peptide 1, amylin, pancreatic polypeptide, cholecystokinin, and insulin and subjective ratings of appetite.. 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).. 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.).

Topics: Body Mass Index; Body Weight; Cholecystokinin; Diet, Reducing; Female; Gastrointestinal Hormones; Ghrelin; Glucagon-Like Peptide 1; Humans; Intention to Treat Analysis; Leptin; Male; Middle Aged; Obesity; Peptide YY; Peptides; Postmenopause; Weight Loss

The purpose of this study was to determine the effects of dietary protein intake and eating frequency on perceived appetite, satiety, and hormonal responses in overweight/obese men. Thirteen men (age 51 +/- 4 years; BMI 31.3 +/- 0.8 kg/m(2)) consumed eucaloric diets containing normal protein (79 +/- 2 g protein/day; 14% of energy intake as protein) or higher protein (138 +/- 3 g protein/day; 25% of energy intake as protein) equally divided among three eating occasions (3-EO; every 4 h) or six eating occasions (6-EO; every 2 h) on four separate days in randomized order. Hunger, fullness, plasma glucose, and hormonal responses were assessed throughout 11 h. No protein x eating frequency interactions were observed for any of the outcomes. Independent of eating frequency, higher protein led to greater daily fullness (P < 0.05) and peptide YY (PYY) concentrations (P < 0.05). In contrast, higher protein led to greater daily ghrelin concentrations (P < 0.05) vs. normal protein. Protein quantity did not influence daily hunger, glucose, or insulin concentrations. Independent of dietary protein, 6-EO led to lower daily fullness (P < 0.05) and PYY concentrations (P < 0.05). The 6-EO also led to lower glucose (P < 0.05) and insulin concentrations (P < 0.05) vs. 3-EO. Although the hunger-related perceived sensations and hormonal responses were conflicting, the fullness-related responses were consistently greater with higher protein intake but lower with increased eating frequency. Collectively, these data suggest that higher protein intake promotes satiety and challenge the concept that increasing the number of eating occasions enhances satiety in overweight and obese men.

Topics: Appetite Regulation; Blood Glucose; Dietary Proteins; Feeding Behavior; Ghrelin; Humans; Hunger; Insulin; Male; Middle Aged; Obesity; Peptide Hormones; Peptide YY; Satiation

Peptide YY(3-36) (PYY(3-36)), a Y2 receptor agonist, and oxyntomodulin, a glucagon-like peptide 1 (GLP-1) receptor agonist, are cosecreted by intestinal L-cells after each meal. Separately each hormone acts as an endogenous satiety signal and reduces appetite in humans when infused intravenously. The aim of the current study was to investigate whether the anorectic effects of PYY(3-36) and oxyntomodulin can be additive.. Twelve overweight or obese human volunteers underwent a randomized, double-blinded, placebo-controlled study. An ad libitum test meal was used to measure energy intake during intravenous infusions of either PYY(3-36) or oxyntomodulin or combined PYY(3-36)/oxyntomodulin.. Energy intake during coadministration of PYY(3-36) and oxyntomodulin was reduced by 42.7% in comparison with the saline control and was significantly lower than that during infusions of either hormone alone.. The anorectic effects of PYY(3-36) and oxyntomodulin can be additive in overweight and obese humans. Coadministration of Y2 receptor agonists and GLP-1 receptor agonists may be a useful treatment strategy for obesity.

Topics: Adult; Dose-Response Relationship, Drug; Double-Blind Method; Drug Interactions; Eating; Energy Intake; Female; Humans; Male; Obesity; Overweight; Oxyntomodulin; Patient Selection; Peptide Fragments; Peptide YY; Surveys and Questionnaires

To evaluate the impact of gradual weight loss and the positive effect of sibutramine on metabolic parameters and the levels of serotonin and neuropeptide YY3-36 levels in patients with exogenous constitutional obesity (ECO).. The study included 36 patients (24 women and 12 men; mean age 37.56 +/- 0.9 years) with a verified diagnosis of ECO. The height, body weight, waist and hip circumference (WC and HC), and body mass index (BMI) were determined. Adipose tissue content was estimated by a bioimpedance method using an adipose mass analyzer. Serum peptide YY3-36 levels were measured by enzyme immunoassay and blood serotonin concentrations were estimated by high performance liquid chromatography with an electrochemical method.. 12-week sibutramine therapy caused a significant reduction in body weight, WC, HC, and BMI (p < 0.05) in all the patients. At the same time they were found to have a considerable body composition change (total body and visceral fat was decreased, total body water increased, and systemic metabolism was lowered). The mean peptide YY3-36 level was significantly decreased. Sibutramine did not affect the serum content of total serotonin in the sera of patients.. Sibutramine used in the combined therapy in patients with ECO contributes to an effective and steady-state weight loss. Sibutramine treatment causes a reduction in total neuropeptide YY3-36, systemic metabolism, and adipose tissue at the expense of the visceral depot.

Topics: Adult; Anthropometry; Appetite Depressants; Body Composition; Body Weight; Combined Modality Therapy; Cyclobutanes; Female; Humans; Male; Obesity; Peptide Fragments; Peptide YY; Serotonin; Treatment Outcome

Increased per capita consumption of sweeteners may be responsible in part for the rising prevalence of obesity in the United States. Recent studies suggest that consumption of honey is not associated with this same obesogenic effect and may have beneficial effects neuro on body weight. The purpose of this study was to evaluate whether the meal-induced responses of ghrelin and peptide YY(3-36) (PYY(3-36)) and/or meal-induced thermogenesis differ following a honey- versus a sucrose-containing meal.. In a double-blind randomly assigned study, appetite hormones (ghrelin, PYY(3-36), leptin) and glycemic and thermic responses were evaluated following isoglucidic ∼450 kcal honey- or sucrose-containing breakfasts in 14 healthy, nonobese women (22 ± 3 y). Blood samples and hunger ratings were obtained at baseline and every 30 minutes for 240 minutes following the meal. Meal-induced thermogenesis was measured by indirect calorimetry. Ad libitum food intake was evaluated from a free-choice meal following the test meal.. Honey consumption delayed the postprandial ghrelin response (p = 0.037), enhanced the total PYY (p = 0.007) response, and blunted the glucose response (p = 0.039) compared with consumption of the sucrose-containing meal. Meal-induced insulin response, hunger ratings, thermogenesis, and subsequent ad libitum food intake, however, did not differ (p > 0.10) between diet treatments.. Alterations in meal-induced responses of ghrelin and PYY(3-36) but not meal-induced thermogenesis may be responsible in part for the potential "obesity protective" effect(s) of honey consumption. A blunted glycemic response may be beneficial for reducing glucose intolerance. Further research is required to determine if these findings hold true for obese individuals, for males, or with habitual consumption.

Topics: Adult; Appetite; Blood Glucose; Dietary Sucrose; Female; Ghrelin; Honey; Humans; Obesity; Peptide YY; Postprandial Period; Sucrose; Sweetening Agents; Thermogenesis; United States; Young Adult

The primary goal of this study was to determine the acute glycemic and endocrine responses to the reduction of fat content from a meal. On three separate occasions, nine overweight subjects (body mass index = 30 +/- 1 kg/m(2); 5 men, 4 women) consumed 1) a control meal ( approximately 800 kcal; 100 g of carbohydrate, 31 g of fat, and 30 g of protein), 2) a low-fat meal ( approximately 530 kcal; 100 g of carbohydrate, 1 g of fat, and 30 g of protein), or 3) a low-fat meal plus lipid infusion [same meal as low-fat meal, but the total energy provided was the same as control (800 kcal), with the "missing" fat ( approximately 30 g) provided via an intravenous lipid infusion]. All three meals contained [(13)C]glucose (3 mg/kg body wt) to assess the bioavailability of ingested glucose. During the 5-h period after each meal, we measured the recovery of [(13)C]glucose in plasma, plasma glucose, and insulin concentrations. We also measured plasma concentration of the gastrointestinal peptides: glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and peptide YY(3-36) (PYY(3-36)). The recovery of the ingested [(13)C]glucose in the hour after ingestion was greater (P < 0.05) after the low-fat than after the control meal [area under the curve (AUC): 1,206 +/- 252 and 687 +/- 161 microM.h, respectively]. However, removing dietary fat from the meal did not affect the plasma concentration of glucose or insulin. Importantly, [(13)C]glucose recovery was not different during the low-fat and lipid infusion trials (AUC: 1,206 +/- 252 and 1,134 +/- 247 microM.h, respectively), indicating that the accelerated delivery of exogenous glucose found after removing fat from the meal is due exclusively to the reduction of fat in the gastrointestinal tract. In parallel with these findings, the reduction in fat calories from the meal reduced plasma concentration of GIP, GLP-1, and PYY(3-36). In summary, these data suggest that removing fat from the diet expedited exogenous glucose delivery into the systemic circulation and reduced the concentration of key gastrointestinal peptides, yet maintained plasma glucose concentration at control levels.

Topics: Adult; Biological Availability; Blood Glucose; Carbon Isotopes; Diet, Fat-Restricted; Dietary Carbohydrates; Emulsions; Fat Emulsions, Intravenous; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Hunger; Insulin; Male; Obesity; Overweight; Peptide Fragments; Peptide YY; Phospholipids; Postprandial Period; Safflower Oil; Satiety Response; Soybean Oil; Treatment Outcome; Young Adult

We aimed to test the effects of three different weight maintenance diets on appetite, glucose and fat metabolism following an initial low-energy diet (LED) induced body weight loss. Following an 8-week LED and a 2-3-week refeeding period, 131 subjects were randomized to three diets for 6 months: MUFA, moderate-fat (35-45 energy percentage (E%) fat), high in MUFA with low glycaemic index; LF, low fat (20-30 E% fat) or CTR, control (35 E% fat). A meal test study was performed in a subgroup, before and after the 6-month dietary intervention, with forty-two subjects completing both meal tests. No difference in body weight, energy intake or appetite ratings were observed between diets. Both the LF and MUFA diets compared to CTR diet reduced postprandial glycaemia and insulinaemia and lowered fasting insulin from month 0 to month 6. Following the 8-week LED period lower levels of the appetite regulating peptides, pancreatic polypeptide, peptide YY, glucagon-like peptide-1 and glucagon-like peptide-2, along with increased appetite scores were seen in comparison to measurements performed after the 6-month dietary intervention. In conclusion, the two competing diets, MUFA and LF, were equally good with respect to glucose metabolism, whereas the CTR diet resembling the typical Western diet, high in SFA, sugar and high glycaemic carbohydrates, indicated associations to lowering of insulin sensitivity. Lower levels of appetite regulatory peptides along with increased appetite scores following an 8-week LED and 2-3-week refeeding period, suggest that strategies for physiological appetite control following a LED period are needed, in order to prevent weight regain.

Topics: Adult; Analysis of Variance; Appetite Regulation; Area Under Curve; Blood Glucose; Body Mass Index; Body Weight; Diet, Fat-Restricted; Energy Intake; Fatty Acids, Monounsaturated; Female; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Glycemic Index; Humans; Insulin; Male; Obesity; Pancreatic Polypeptide; Peptide YY; Time Factors; Triglycerides

Orlistat, an inhibitor of digestive lipases, is widely used for the treatment of obesity. Previous reports on the effect of orally ingested orlistat together with a meal on gastric emptying and secretion of gut peptides that modulate postprandial responses are controversial. We investigated the effect of ingested orlistat on gastric emptying and plasma responses of gut peptides in response to a solid mixed meal with a moderate energy load. In healthy subjects, gastric emptying was determined using scintigraphy and studies were performed without and with 120 mg of orlistat in pellet form in random order. Orlistat shortened t lag and t half and decreased the area under the gastric emptying curve. Orlistat significantly attenuated the secretion of glucose-dependent insulinotropic polypeptide (GIP) but did not alter the plasma responses of cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1), pancreatic polypeptide (PP), and insulin. There was no peptide YY (PYY) response. Area under the curve of gastric emptying was positively correlated with integrated secretion of GIP (r=0.786) in orlistat and was negatively correlated with integrated plasma response of GLP-1 (r=-0.75) in control experiments, implying that inhibition of fat absorption modifies determinants of gastric emptying of a meal. Orlistat administered similar to its use in obesity treatment accelerates gastric emptying of a solid mixed meal with a moderate energy load and profoundly attenuates release of GIP without appreciably altering plasma responses of CCK, GLP-1, and PP. Since GIP is being implemented in the development of obesity, its role in weight control attained by orlistat awaits further investigation.

Topics: Adult; Anti-Obesity Agents; Blood Glucose; Eating; Enteric Nervous System; Gastric Emptying; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Insulin; Lactones; Male; Obesity; Orlistat; Peptide YY; Radionuclide Imaging; Stomach; Young Adult

Depending on type and inclusion level, dietary fibre may increase and maintain satiety and postpone the onset of hunger. This 7-week study evaluated the effect of fibre fermentability on physiological satiety-related metabolites and voluntary food intake (VFI) in dogs. Sixteen healthy adult dogs were fed a low-fermentable fibre (LFF) diet containing 8.5 % cellulose or a high-fermentable fibre (HFF) diet containing 8.5 % sugarbeet pulp and 2 % inulin. Large intestinal fibre degradation was evaluated by apparent faecal digestibility of nutrients and faecal SCFA and NH3 concentrations. Postprandial blood samples were obtained to determine postprandial plasma glucose, insulin, total peptide tyrosine-tyrosine (PYY), total glucagon-like peptide-1 (GLP-1) and total ghrelin concentrations. At the end of the study, the dogs were given a single meal of a dry dog food to determine VFI. Dogs fed the HFF diet had a significantly higher large intestinal fibre degradation and production of SCFA compared with the dogs fed the LFF diet. The HFF-fed dogs tended (P = 0.058) to show a lower VFI at the end of the study. No treatment effects were found for postprandial plasma glucose, PYY, GLP-1 and ghrelin responses. The concentrations of these metabolites could not be related to the observed difference in VFI. The inclusion of fermentable fibre in canine diets may contribute to the prevention or mitigation of obesity through its effects on satiety. The underlying mechanisms require further investigation.

Topics: Ammonia; Animals; Blood Glucose; Cellulose; Dietary Fiber; Dog Diseases; Dogs; Eating; Fatty Acids, Volatile; Feces; Female; Fermentation; Ghrelin; Glucagon-Like Peptide 1; Insulin; Inulin; Male; Obesity; Peptide YY; Satiation; Vegetables

Orexigenic and anorexigenic pathways mediate food intake and may be affected by meal composition. Our objective was to determine whether changes in levels of active ghrelin and peptide YY (PYY) differ in obese vs. normal-weight adolescent girls following specific macronutrient intake and predict hunger and subsequent food intake. We enrolled 26 subjects: 13 obese and 13 normal-weight girls, 12-18 years old, matched for maturity (as assessed by bone age) and race. Subjects were assigned a high-carbohydrate, high-protein, and high-fat breakfast in random order. Active ghrelin and PYY were assessed for 4 h after breakfast and 1 h after intake of a standardized lunch. Hunger was assessed using a standardized visual analog scale (VAS). No suppression in active ghrelin levels was noted following macronutrient intake in obese or normal-weight girls. Contrary to expectations, active ghrelin increased in obese girls following the high-carbohydrate breakfast, and the percent increase was higher than in controls (P = 0.046). Subsequent food intake at lunch was also higher (P = 0.03). Following the high-fat breakfast, but not other breakfasts, percent increase in PYY was lower (P = 0.01) and subsequent lunch intake higher (P = 0.005) in obese compared with normal-weight girls. In obese adolescents, specific intake of high-carbohydrate and high-fat breakfasts is associated with greater increases in ghrelin, lesser increases in PYY, and higher intake at a subsequent meal than in controls. Changes in anorexigenic and orexigenic hormones in obese vs. normal-weight adolescents following high-carbohydrate and high-fat meals may influence hunger and satiety signals and subsequent food intake.

Topics: Adolescent; Adolescent Behavior; Biomarkers; Child; Dietary Carbohydrates; Dietary Fats; Dietary Proteins; Eating; Feeding Behavior; Female; Ghrelin; Humans; Hunger; Obesity; Peptide Fragments; Peptide YY; Postprandial Period; Satiety Response; Time Factors; Up-Regulation

Aging and obesity are characterized by decreased beta-cell sensitivity and defects in the potentiation of nutrient-stimulated insulin secretion by GIP. Exercise and diet are known to improve glucose metabolism and the pancreatic insulin response to glucose, and this effect may be mediated through the incretin effect of GIP. The purpose of this study was to assess the effects of a 12-wk exercise training intervention (5 days/wk, 60 min/day, 75% Vo(2 max)) combined with a eucaloric (EX, n = 10) or hypocaloric (EX-HYPO, pre: 1,945 +/- 190, post: 1,269 +/- 70, kcal/day; n = 9) diet on the GIP response to glucose in older (66.8 +/- 1.5 yr), obese (34.4 +/- 1.7 kg/m(2)) adults with impaired glucose tolerance. In addition to GIP, plasma PYY(3-36), insulin, and glucose responses were measured during a 3-h, 75-g oral glucose tolerance test. Both interventions led to a significant improvement in Vo(2 max) (P < 0.05). Weight loss (kg) was significant in both groups but was greater after EX-HYPO (-8.3 +/- 1.1 vs. -2.8 +/- 0.5, P = 0.002). The glucose-stimulated insulin response was reduced after EX-HYPO (P = 0.02), as was the glucose-stimulated GIP response (P < 0.05). Furthermore, after the intervention, changes in insulin (DeltaI(0-30)/DeltaG(0-30)) and GIP (Delta(0-30)) secretion were correlated (r = 0.69, P = 0.05). The PYY(3-36) (Delta(0-30)) response to glucose was increased after both interventions (P < 0.05). We conclude that 1) a combination of caloric restriction and exercise reduces the GIP response to ingested glucose, 2) GIP may mediate the attenuated glucose-stimulated insulin response after exercise/diet interventions, and 3) the increased PYY(3-36) response represents an improved capacity to regulate satiety and potentially body weight in older, obese, insulin-resistant adults.

Topics: Aged; Blood Glucose; Body Mass Index; Diet, Reducing; Eating; Exercise; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Male; Obesity; Peptide Fragments; Peptide YY; Physical Fitness; Satiety Response

Rodent studies show that oligofructose promotes weight loss, stimulates satiety hormone secretion, reduces energy intake, and improves lipid profiles.. Our objective was to examine the effects of oligofructose supplementation on body weight and satiety hormone concentrations in overweight and obese adults.. This study was a randomized, double-blind, placebo-controlled trial. Forty-eight otherwise healthy adults with a body mass index (in kg/m2) > 25 were randomly assigned to receive 21 g oligofructose/d or a placebo (maltodextrin) for 12 wk. Body composition (by dual-energy X-ray absorptiometry); meal tolerance tests, including satiety hormone response; food intake; and subjective appetite ratings were determined.. There was a reduction in body weight of 1.03 +/- 0.43 kg with oligofructose supplementation, whereas the control group experienced an increase in body weight of 0.45 +/- 0.31 kg over 12 wk (P = 0.01). A lower area under the curve (AUC) for ghrelin (P = 0.004) and a higher AUC for peptide YY (PYY) with oligofructose (P = 0.03) coincided with a reduction in self-reported caloric intake (P < or = 0.05). Glucose decreased in the oligofructose group and increased in the control group between initial and final tests (P < or = 0.05). Insulin concentrations mirrored this pattern (P < or = 0.05). Oligofructose supplementation did not affect plasma active glucagon-like peptide 1 secretion. According to a visual analog scale designed to assess side effects, oligofructose was well tolerated.. Independent of other lifestyle changes, oligofructose supplementation has the potential to promote weight loss and improve glucose regulation in overweight adults. Suppressed ghrelin and enhanced PYY may contribute in part to the reduction in energy intake. The trial was registered at clinicaltrials.gov as NCT00522353.

Topics: Adult; Area Under Curve; Blood Glucose; Dietary Supplements; Energy Intake; Female; Ghrelin; Glucagon-Like Peptide 1; Humans; Insulin; Male; Middle Aged; Obesity; Oligosaccharides; Overweight; Peptide YY; Weight Loss

Peptide Y-Y (PYY) is an anorexigenic hormone implicated in appetite control, and beta-glucan is a fiber known to affect appetite. We hypothesized that plasma PYY levels would increase in overweight human adults consuming increasing doses of beta-glucan. The objective was to test whether the effect could be seen with beta-glucan delivered through extruded cereals containing a high beta-glucan oat bran with demonstrated high molecular weight and solubility. Fourteen subjects consumed a control meal and 3 cereals of varying beta-glucan concentration (between 2.2 and 5.5 g), and blood samples were collected over 4 hours. Analysis of raw PYY data showed a trend toward significant increases over 4 hours. An increasing dose of beta-glucan resulted in higher levels of plasma PYY, with significant differences between groups from 2 to 4 hours post test-meal. Data for the area under the curve analysis also approached significance, with post hoc analysis showing a difference (P = .039) between the control and the highest dose of beta-glucan (5.5 g). The PYY levels at 4 hours were significantly different between the control and high-dose meal test (P = .036). There was a significant dose response, with a positive correlation between the grams of beta-glucan and PYY area under the curve (r(2) = 0.994, P = .003). The optimal dose of beta-glucan appears to lie between 4 and 6 g, with the effects on PYY mediated by viscosity and concentration. Meal-test studies examining a range of hormones should measure hormones over a minimum of 4 hours and record meal intake for even longer time frames.

Topics: Adult; Area Under Curve; Avena; beta-Glucans; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Obesity; Peptide YY; Plant Preparations; Seeds

BED is characterized by overeating with a loss of control. The primary aim of the study was to measure plasma concentrations of three key gut peptides influencing hunger (ghrelin) and satiety (PYY, GLP-1) to ascertain potential abnormalities in BED. The participants were 10 obese BED and 9 obese nonBED premenopausal women. They did not differ in age, 30.1+/-8.1 SD, BMI, 36.2+/-5.9, or % body fat, 43.3+/-5.7. Following a13-h overnight fast, blood was drawn (-15, 0, 5, 15, 30, 60, 90, 120 min) for measurement of total plasma concentrations of ghrelin, PYY and GLP-1, pre and post ingestion of a nutritionally complete liquid meal (1256 kJ) at 9 am (0-5 min). Ratings of hunger and fullness preceded each blood draw. Ghrelin was significantly lower premeal at -15 min (P=.05) and postmeal at 90 min (P=.027) and 120 min (P=.025) in the BED group as compared to the nonBED group. Ghrelin also declined less postprandially in the BED group (P=.019) with a longer time to the nadir value (P=.004). However, fasting and meal-related changes in levels of PYY and GLP-1 did not differ between the groups nor did ratings of hunger and fullness. Following a randomized cognitive behavior and dietary intervention, the ghrelin values in BED normalized. Prior to treatment, the lower fasting ghrelin in BED may be a consequence of down regulation by overeating. The lack of differences in the satiety promoting hormones, PYY and GLP-1, makes them unlikely contributors to the binge eating in BED.

Topics: Adult; Analysis of Variance; Appetite Regulation; Bulimia Nervosa; Cognitive Behavioral Therapy; Counseling; Female; Ghrelin; Glucagon-Like Peptide 1; Humans; Linear Models; Obesity; Peptide YY; Postprandial Period; Satiation

This study investigated the effect of macronutrient composition of meals on postprandial peptide YY(3-36) (PYY(3-36)) response in obese hyperinsulinemic females.. Eight obese females consumed three iso-energetic meals of different macronutrient composition, high carbohydrate (HC; 60% CHO, 20% protein, 20% fat), high fat (HF; 30% CHO, 20% protein, 50% fat) and high protein (HP; 30% CHO, 50% protein, 20% fat), on three separate occasions, 1 month apart. PYY(3-36), insulin and glucose were measured before and 15, 30, 60, 120 and 180 min following each meal.. PYY(3-36) levels increased significantly following the three meals, with the HC meal resulting in a sustained postprandial increase in PYY(3-36) level throughout the experimental period. Comparing the three meals, the HF meal induced a significantly higher increase in postprandial PYY(3-36) levels, at 15 and 30 min as compared to the HP meal (p < 0.05), whereas the postprandial increase following the HP meal became significantly higher than that following the HF meal at 120 min. Postprandial increase in PYY(3-36) was highest in the first hour following the HF meal, while that following the HP meal was delayed by 1 h.. Increasing both protein and fat content of a meal may induce an immediate and prolonged increase in PYY(3-36), resulting in increased satiety and its maintenance for a longer period of time.

Topics: Adult; Area Under Curve; Blood Glucose; Cross-Over Studies; Dietary Carbohydrates; Dietary Fats; Dietary Proteins; Female; Humans; Obesity; Peptide Fragments; Peptide YY; Postprandial Period; Satiety Response

Ghrelin and peptide YY (PYY) are both hormones derived from the gastrointestinal tract involved in appetite regulation. The cholinergic part of the vagal nerve is involved in the regulation of glucose and insulin. The aim of this study was to examine the effects of the cholinergic antagonist atropine on ghrelin, PYY, glucose, and insulin under basal conditions and after meal ingestion in lean and obese subjects.. Eight lean and eight obese subjects were included in a randomized, double-blind, placebo-controlled crossover study with 4 study days in randomized order (atropine/placebo +/- breakfast). Plasma ghrelin, PYY, insulin, and glucose were measured. Hunger and satiety feelings were rated on a 10-cm visual analog scale.. In lean individuals, atropine led to a decrease in ghrelin concentrations comparable and nonadditive with breakfast ingestion and a significant decrease in both basal and meal-induced PYY concentrations. In obese subjects, atropine did not significantly change ghrelin or PYY concentrations, whereas it induced a comparable increase in heart rate and meal-induced glucose concentrations in the two study groups. Only lean, not obese, subjects experienced sustained feelings of satiety after breakfast.. The impaired cholinergic regulation of the postprandial drop in ghrelin concentrations and rise in PYY concentrations might be part of the deregulated food intake in obese subjects.

Topics: Adult; Atropine; Blood Glucose; Body Weight; Cholinergic Fibers; Cross-Over Studies; Eating; Female; Gastrointestinal Tract; Ghrelin; Heart Rate; Humans; Insulin; Insulin Resistance; Male; Obesity; Parasympatholytics; Peptide YY; Postprandial Period; Satiety Response; Vagus Nerve

Peptide YY (PYY)(3-36) has been shown to produce dramatic reductions in energy intake (EI), but no human data exist regarding energy expenditure (EE), glucose and fat metabolism. Nothing is known regarding PYY1-36. To compare effects of PYY(1-36) and PYY(3-36) on appetite, EI, EE, insulin, glucose and free fatty acids (FFA) concentrations, 12 lean and 12 obese males participated in a blinded, randomized, crossover study with 90-min infusions of saline, 0.8 pmol x kg(-1) x min(-1) PYY(1-36) and PYY(3-36). Only four participants completed PYY(3-36) infusions because of nausea. Subsequently, six lean and eight obese participants completed 0.2 pmol x kg(-1) x min(-1) PYY(3-36) and 1.6 pmol x kg(-1) x min(-1) PYY(1-36) infusions. PYY(3-36) [corrected] produced [corrected] lower ratings of well-being and [corrected] increases in heart rate, [corrected] FFA, and [corrected] postprandial [corrected] insulin concentrations. Furthermore, high-dose [corrected] PYY(3-36) (0.8 [corrected] pmol x kg(-1) x min(-1)) produced decreased [corrected] EI and increased postprandial [corrected] glucose concentrations and tendency to reduced EE [corrected]

Topics: Adult; Appetite; Blood Glucose; Cross-Over Studies; Dose-Response Relationship, Drug; Energy Intake; Energy Metabolism; Fatty Acids, Nonesterified; Glucose; Heart Rate; Humans; Insulin; Lipolysis; Male; Obesity; Osmolar Concentration; Peptide Fragments; Peptide YY; Postprandial Period; Thermogenesis

The gastrointestinal peptide hormone, peptide YY(3-36) (PYY(3-36)), is implicated to be a postprandial satiety factor.. The aim of this study is to assess the safety, tolerability, and efficacy of intranasal PYY(3-36) to induce weight loss in obese patients.. The study was designed as a randomized, 2-wk, single-blind placebo run-in followed by a 12-wk double-blind, placebo-controlled treatment period.. The study was set within a private and institutional practice.. A total of 133 obese patients (body mass index, 30-43 kg/m(2); age, 18-65 yr) participated in the study.. Placebo or 200- or 600-microg PYY(3-36) was administered as an intranasal spray 20 min before breakfast, lunch, and dinner in conjunction with a hypocaloric diet and exercise.. Body weight was the main outcome measure.. The number of patients completing 12 wk on the drug was 38 of 43 (88%), 31 of 44 (70%), and 12 of 46 (26%) for placebo, 200 microg three times a day (t.i.d.) and 600 microg t.i.d., respectively. In the 600 microg t.i.d. group, 27 of 46 (59%) patients discontinued due to nausea and vomiting. Among all randomized patients who took at least one drug dose and had a postbaseline measurement, the mean body weight change from baseline was -2.8, -3.7, and -1.4 kg for placebo, 200 and 600 microg, respectively. The least squares mean difference (95% confidence interval) between placebo and 200 microg was -0.9 (-2.6, 0.7) kg (P = 0.251). A difference of 2.11 kg was sought. No meaningful inference can be drawn from the few patients who completed the study on 600 microg.. Intranasal PYY(3-36) as administered at these intervention doses and preprandial timing is not efficacious in inducing weight loss in obese patients after 12 wk of treatment.

Topics: Administration, Intranasal; Adolescent; Adult; Aged; Body Mass Index; Body Weight; Diet, Reducing; Dose-Response Relationship, Drug; Double-Blind Method; Exercise Therapy; Female; Humans; Male; Middle Aged; Obesity; Peptide Fragments; Peptide YY; Treatment Outcome; Weight Loss

Intraveneous (i.v.) PYY(3-36) infusions have been reported to reduce energy intake (EI) in humans, whereas few studies exist on effects of PYY(1-36). The aim of the present study was to examine effects of subcutaneous (sc) injections of PYY(1-36) and PYY(3-36) on appetite, ad libitum EI, plasma concentrations of PYY and free fatty acids (FFA) in obese males. Twenty-four males (BMI 27-40 kg/m(2)) were randomly assigned to two groups receiving sc injections of either PYY(1-36) or PYY(3-36) in a blinded, placebo-controlled, dose-escalating, cross-over study. Subjects were studied 5 days in succession, with escalating doses of PYY(1-36) [saline, 50, 100, 150, and 200 pmol PYY(1-36)/kg lean body mass (LBM)], or PYY(3-36) (saline, 25, 50, 75, and 100 pmol PYY(3-36)/kg LBM), respectively. PYY injections resulted in dose-dependent increases in plasma PYY levels but no effect on EI in either the PYY(1-36) or the PYY(3-36) group. However, increasing doses of PYY(3-36), but not PYY(1-36), resulted in increased ratings of satiety and decreased ratings of hunger, thirst, and prospective food consumption. Although not dose dependently, significant elevation of plasma FFA was seen after injection of PYY(3-36), but not PYY(1-36). Although sc administration of PYY was well tolerated, it remains to be determined whether high-dose PYY(3-36) is sufficient in reducing EI in long-term trials, and if so, whether the reduction in EI occurs without nausea. PYY(1-36) is unlikely to be important in regulating energy intake. The PYY(3-36) administrations caused a non-dose-dependent mobilization of FFA, likely through a direct effect.

Topics: Adult; Appetite; Dose-Response Relationship, Drug; Double-Blind Method; Energy Intake; Fatty Acids, Nonesterified; Feeding Behavior; Humans; Hunger; Injections, Subcutaneous; Male; Middle Aged; Obesity; Peptide Fragments; Peptide YY; Placebos; Satiety Response

Peptide YY (PYY) is released from the distal small intestine and colon after meals and reduces appetite by increasing satiety. The amount of PYY released is proportional to calories ingested. Fat ingestion has also been reported to stimulate PYY release.. The objective of the study was to determine whether macronutrient composition influences postprandial serum PYY levels by comparing 1 wk of a weight-maintenance low-carbohydrate, high-fat (LCHF) diet with a low-fat, high-carbohydrate (LFHC) diet.. In this randomized crossover study, 18 obese subjects (14 females, 4 males, mean body mass index 35.6 +/- 2.9 kg/m(2)) were randomly assigned initially to 1 wk of a weight-maintenance LCHF or LFHC diet, after which a test meal of identical composition was given and serum PYY levels were assessed for 2.5 h postprandially. After a 1-wk washout period, subjects were crossed over and retested.. After 1 wk, mean postprandial area under the curve PYY after the LCHF test meal was 1.5-fold greater than after the LFHC test meal (P < 0.001). The LCHF diet led to 55% higher levels of postprandial serum PYY levels, compared with the LFHC diet (P = 0.005).. These data show that a LCHF diet stimulates PYY secretion more than a LFHC diet in obese individuals.

Topics: Adiponectin; Adult; Blood Glucose; Body Weight; Cross-Over Studies; Diet, Carbohydrate-Restricted; Diet, Fat-Restricted; Dietary Carbohydrates; Dietary Fats; Energy Intake; Female; Homeostasis; Humans; Insulin; Insulin Resistance; Leptin; Male; Middle Aged; Obesity; Peptide YY; Postprandial Period

We tested the hypothesis that variants in the gene encoding the prepropeptide YY (PYY) associate with type 2 diabetes and/or obesity. Mutation analyses of DNA from 84 patients with obesity and familial type 2 diabetes identified two polymorphisms, IVS3 + 68C>T and Arg72Thr, and one rare variant, +151C>A of PYY. The common allele of the Arg72Thr variant associated with type 2 diabetes with an allele frequency of the Arg allele of 0.667 (95% CI 0.658-0.677) among 4,639 glucose-tolerant subjects and 0.692 (0.674-0.710) among 1,326 patients with type 2 diabetes (P = 0.005, odds ratio 1.19 [95% CI 1.05-1.35]). The same polymorphism associated with overweight (25 < or = BMI < 30 kg/m2) (P = 0.018, 1.15 [1.02-1.28]). In quantitative trait analyses of a population-based sample of 6,022 subjects, the Arg allele was associated with an increased plasma glucose level 2 h after an oral glucose tolerance test (OGTT) (P = 0.03), an increased area under the curve for the post-OGTT plasma glucose level (P = 0.03), and a lower insulinogenic index (P = 0.01). In conclusion, the common Arg allele of the PYY Arg72Thr variant modestly associates with type 2 diabetes and with type 2 diabetes-related quantitative traits.

Topics: Arginine; Body Mass Index; Diabetes Mellitus, Type 2; DNA; DNA Mutational Analysis; Female; Humans; Male; Obesity; Odds Ratio; Pedigree; Peptide YY; Polymorphism, Genetic; Risk Factors; Sequence Deletion

Peptide YY (PYY) and glucagon like peptide (GLP)-1 are cosecreted from intestinal L cells, and plasma levels of both hormones rise after a meal. Peripheral administration of PYY(3-36) and GLP-1(7-36) inhibit food intake when administered alone. However, their combined effects on appetite are unknown. We studied the effects of peripheral coadministration of PYY(3-36) with GLP-1(7-36) in rodents and man. Whereas high-dose PYY(3-36) (100 nmol/kg) and high-dose GLP-1(7-36) (100 nmol/kg) inhibited feeding individually, their combination led to significantly greater feeding inhibition. Additive inhibition of feeding was also observed in the genetic obese models, ob/ob and db/db mice. At low doses of PYY(3-36) (1 nmol/kg) and GLP-1(7-36) (10 nmol/kg), which alone had no effect on food intake, coadministration led to significant reduction in food intake. To investigate potential mechanisms, c-fos immunoreactivity was quantified in the hypothalamus and brain stem. In the hypothalamic arcuate nucleus, no changes were observed after low-dose PYY(3-36) or GLP-1(7-36) individually, but there were significantly more fos-positive neurons after coadministration. In contrast, there was no evidence of additive fos-stimulation in the brain stem. Finally, we coadministered PYY(3-36) and GLP-1(7-36) in man. Ten lean fasted volunteers received 120-min infusions of saline, GLP-1(7-36) (0.4 pmol/kg.min), PYY(3-36) (0.4 pmol/kg.min), and PYY(3-36) (0.4 pmol/kg.min) + GLP-1(7-36) (0.4 pmol/kg.min) on four separate days. Energy intake from a buffet meal after combined PYY(3-36) + GLP-1(7-36) treatment was reduced by 27% and was significantly lower than that after either treatment alone. Thus, PYY(3-36) and GLP-1(7-36), cosecreted after a meal, may inhibit food intake additively.

Topics: Animals; Behavior, Animal; Diabetes Mellitus; Dose-Response Relationship, Drug; Double-Blind Method; Drug Combinations; Drug Synergism; Eating; Energy Intake; Feeding Behavior; Female; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Humans; Immunohistochemistry; Injections, Intraperitoneal; Male; Mice; Mice, Inbred C57BL; Motor Activity; Obesity; Peptide Fragments; Peptide YY; Rats

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.. 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.. 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).. 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.

Topics: Appetite; Cross-Over Studies; Double-Blind Method; Eating; Female; Ghrelin; Humans; Insulin; Leptin; Male; Obesity; Peptide Fragments; Peptide Hormones; Peptide YY

Peripheral administration of glucagon-like peptide-1 (GLP-1) for four hours, to normal weight and obese humans, decreases food intake and suppresses appetite.. The aim of this study was to assess the effect of an eight hour infusion of GLP-1 on appetite and energy intake at lunch and dinner in obese subjects.. Randomised, blinded cross-over design with intravenous infusion of GLP-1 (0.75 pmol x kg(-1) min(-1)) or saline.. Eight obese (body mass index, BMI, 45.5 +/- 2.3 kg/m2) male subjects.. Ad libitum energy intake at lunch (12.00 h) and dinner (16.00 h) after an energy fixed breakfast (2.4 MJ) at 08.00 h. Appetite sensations using visual analogue scales, (VAS) immediately before and after meals and hourly in-between. Blood samples for the analysis of glucose, insulin, C-peptide, GLP-1 and peptide YY. Gastric emptying after breakfast and lunch using a paracetamol absorption technique.. Hunger ratings were significantly lower with GLP-1 infusion. The summed ad libitum energy intake at lunch and dinner was reduced by 1.7 +/- 0.5 MJ (21 +/- 6%) by GLP-1 infusion (P = 0.01). Gastric emptying was delayed by GLP-1 infusion, and plasma glucose concentrations decreased (baseline: 6.6 +/- 0.35 mmol/L; nadir: 5.3 +/- 0.15 mmol/L). No nausea was recorded during GLP-1 infusion.. Our results demonstrate that GLP-1 decreases feelings of hunger and reduces energy intake in obese humans. One possible mechanism for this finding might be an increased satiety primarily mediated by gastric vagal afferent signals.

Topics: Adult; Appetite; Blood Glucose; Body Mass Index; C-Peptide; Cross-Over Studies; Double-Blind Method; Eating; Energy Intake; Gastric Emptying; Glucagon; Glucagon-Like Peptide 1; Humans; Hunger; Infusions, Intravenous; Insulin; Male; Obesity; Peptide Fragments; Peptide YY; Protein Precursors

Observational study in 10 healthy nonobese volunteers and 30 participants with obesity who underwent RYGB (n = 24) or SG (n = 6) at the Imperial Weight Centre [NCT01945840]. Participants were studied using a standardized mixed meal test (MMT) before and 1 year after surgery. The outcome measures were PYY. Presurgery, the fasting and postprandial levels of PYY. There appears to be no difference in PYY secretion between nonobese and obese volunteers at baseline. At 1 year after surgery, RYGB, but not SG, is associated with increased postprandial secretion of PYY

Topics: Blood Glucose; Chromatography, Liquid; Gastrectomy; Gastric Bypass; Humans; Obesity; Peptide YY; Tandem Mass Spectrometry; Tyrosine

Obesity and metabolic dysfunction are implicated in colorectal cancer development. Appetite-regulating gut hormones might have a role in colorectal cancer risk. We investigated whether circulating levels of the gut hormones ghrelin (analyzed as acyl ghrelin) and Peptide YY (PYY) were associated with subsequent colorectal cancer risk, including clinical and molecular tumor subtypes. We also provide descriptive data on these hormones in relation to background participant characteristics and metabolic biomarkers. This population-based study included 1,010 matched case-control pairs with a median of 12.3 years of follow-up. Acyl ghrelin and PYY were measured by multiplex immunoassay. Data on KRAS and BRAF mutations and microsatellite instability (MSI) status were available for 704 and 708 cases, respectively. Conditional logistic regression models estimated association to colorectal cancer risk. Partial correlation and linear regression were used to investigate relationships between background and metabolic variables and variation in plasma gut hormone concentrations. Acyl ghrelin was not clearly associated with colorectal cancer risk (multivariable OR per 1 SD increase: 1.11; 95% CI, 1.00-1.23). Positive associations were observed for specific subtypes, in particular BRAF-mutated colorectal cancer and right-sided colon cancer, although with nonsignificant heterogeneity. PYY was not related to colorectal cancer risk (multivariable OR per 1 SD: 1.04; 95% CI, 0.95-1.14) or any tumor subtype. In the control participants, ghrelin was inversely correlated with BMI, and PYY was positively correlated with C-peptide and insulin levels. These findings provide limited support for a possible role for ghrelin in colorectal cancer development, primarily in specific anatomical and molecular tumor subtypes.. The findings of this study do not support a major role for the metabolic gut hormones ghrelin and PYY in colorectal cancer development but suggest the possibility of an involvement for ghrelin in specific tumor subtypes. Elucidating subtype-specific risk factors and mechanisms of carcinogenesis may have implications for precision prevention.

Topics: Colorectal Neoplasms; Gastrointestinal Hormones; Humans; Obesity; Peptide YY

The role of fat-free mass loss (FFML) in modulating weight regain in individuals with obesity, as well as the potential mechanisms involved, remain inconsistent.. The aim of this study was to determine if % FFML following weight loss (WL) is a predictor of weight regain and to investigate the association between %FFML and changes in appetite markers.. WL at week 9 was 17.5 ± 4.3kg and %FFML 20.4 ± 10.6%. Weight regain at 1 y was 1.7 ± 8.2 kg (8.8 ± 45.0%). After adjusting for WL and fat mass at baseline, %FFML at week 9 was not a significant predictor of weight regain. Similar results were seen at week 13. The greater the %FFML at week 9, but not 13, the smaller the reduction, or greater the increase in basal ghrelin concentration (β: -3.2; 95% CI: -5.0, -1.1; P = 0.003), even after adjusting for WL and β-hydroxybutyrate.. %FFML was not a significant predictor of weight regain at 1 y in individuals with obesity. However, a greater %FFML was accompanied by a greater increase in ghrelin secretion under ketogenic conditions, suggesting a link between fat-free mass and appetite regulation. This trial was registered at clinicaltrials.gov as NCT01834859.

Topics: 3-Hydroxybutyric Acid; Adult; Appetite; Ghrelin; Humans; Male; Middle Aged; Obesity; Peptide YY; Weight Gain; Weight Loss

Weight loss is associated with a disproportionate reduction in energy expenditure, along with increases in hunger feelings and ghrelin concentrations. These changes are presumed to be homeostatic mechanisms to counteract the energy deficit. The possibility that these 2 components of the energy balance equation are mechanistically linked has never been examined.. This study aimed to determine if the disproportionate reduction in resting metabolic rate (RMR) seen with weight loss is associated with changes in the plasma concentration of gastrointestinal hormones involved in appetite regulation and subjective appetite ratings.. This was a longitudinal study with repeated measurements. Fifty-six individuals with obesity (body mass index [BMI]: 34.5±0.5 kg/m. A 14.2±0.6 kg weight loss was seen at Wk9 and maintained at Wk13. RQ was significantly reduced at Wk9 (0.82±0.06 vs. 0.76±0.05, P< 0.001) but returned to baseline at Wk13. Metabolic adaptation was seen at Wk9, but not Wk13 (-341±58, P <0.001 and -75±72 kJ/d, P = 0.305, respectively). The larger the difference between measured and predicted RMR at both timepoints, the greater the increase in hunger, desire to eat, and composite appetite score (fasting and postprandial at Wk9, postprandial only at Wk13), even after adjusting for weight loss and RQ.. A larger metabolic adaptation during weight loss is accompanied by a greater drive to eat. This might help explain the interindividual differences in weight loss outcomes to dietary interventions.

Topics: Appetite; Ghrelin; Humans; Longitudinal Studies; Male; Middle Aged; Obesity; Peptide YY; Postprandial Period; Weight Loss

People who are severely obese due to melanocortin-4 receptor (MC4R) deficiency experience hyperphagia and impaired fullness after a meal (satiety). Meal-induced satiety is influenced by hormones, such as peptide-YY (PYY), which are released by enteroendocrine cells upon nutrient delivery to the small intestine.. We investigated whether gastric emptying and PYY levels are altered in MC4R deficiency.. Gastric emptying was measured with a gastric scintigraphy protocol using technetium-99m (. We found that gastric emptying time was significantly delayed and percentage meal retention increased in individuals with MC4R deficiency compared to obese controls. In addition, fasting and mean PYY secretion throughout the day were decreased in MC4R deficiency, whereas postprandial PYY secretion was unaltered.. Delayed gastric emptying and reduced basal PYY secretion may contribute to impaired satiety in people with obesity due to MC4R deficiency.

Topics: Gastroparesis; Humans; Obesity; Peptide YY; Postprandial Period; Receptor, Melanocortin, Type 4

The aim of this study was to compare gastrointestinal (GI) hormones and subjective ratings of appetite among obesity classes, and between classes of obesity and controls. Ninety-eight adult individuals with obesity, divided into class I (n = 35), II (n = 44) and III (n = 19), together with 45 controls without obesity were included in this cross-sectional analysis. Body weight/composition, and basal and postprandial (after a 600 kcal fixed breakfast) plasma concentrations of acylated ghrelin, active glucagon-like peptide 1 (GLP-1), total peptide YY (PYY), cholecystokinin (CCK) and insulin, as well as subjective ratings of hunger, fullness, desire to eat (DTE) and prospective food consumption (PFC) were measured. There were no differences in the plasma concentration of GI hormones (either basal or postprandial) among obesity classes, except for insulin. In general, obesity was associated with impaired secretion of GI hormones. Ghrelin secretion did not decline postprandially in class-III obesity. GLP-1 peak for obesity class I and II was early and lower, while class III showed no postprandial GLP-1 response. Postprandial PYY response for obesity class II and III was absent, and class III showed a delayed and shortened postprandial CCK response. Obesity class II and III had greater basal insulin concentration compared to controls and postprandial insulin was greater in obesity class III versus class II, class I and controls. No differences were found for appetite ratings among obesity classes. In conclusion, obesity is characterized by impaired secretion of GI hormones, with reduced postprandial satiety, particularly in individuals with obesity class III. This abnormal pattern may lead to overeating.

Topics: Adult; Appetite; Cholecystokinin; Cross-Sectional Studies; Gastrointestinal Hormones; Ghrelin; Glucagon-Like Peptide 1; Humans; Insulin; Obesity; Peptide YY; Postprandial Period

Mimetics of the anorexigenic gut hormone glucagon-like peptide 1 (GLP-1) were originally developed as insulinotropic anti-diabetic drugs but also evoke significant weight loss, leading to their recent approval as obesity therapeutics. Co-activation of receptors for GLP-1 and other gut hormones which reduce food intake - peptide YY (PYY

Topics: Gastric Inhibitory Polypeptide; Gastrointestinal Hormones; Glucagon-Like Peptide 1; Humans; Obesity; Peptide YY; Weight Loss

The enteroendocrine system coordinates the physiological response to food intake by regulating rates of digestion, nutrient absorption, insulin secretion, satiation and satiety. Gut hormones with important anorexigenic and/or insulinotropic roles include glucagon-like peptide 1 (GLP-1), peptide YY (PYY

Topics: Cholecystokinin; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Obesity; Peptide YY

The induction of nausea and emesis is a major barrier to maximizing the weight loss profile of obesity medications, and therefore, identifying mechanisms that improve tolerability could result in added therapeutic benefit. The development of peptide YY (PYY)-based approaches to treat obesity are no exception, as PYY receptor agonism is often accompanied by nausea and vomiting. Here, we sought to determine whether glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) agonism reduces PYY-induced nausea-like behavior in mice. We found that central and peripheral administration of a GIPR agonist reduced conditioned taste avoidance (CTA) without affecting hypophagia mediated by a PYY analog. The receptors for GIP and PYY (Gipr and Npy2r) were found to be expressed by the same neurons in the area postrema (AP), a brainstem nucleus involved in detecting aversive stimuli. Peripheral administration of a GIPR agonist induced neuronal activation (cFos) in the AP. Further, whole-brain cFos analyses indicated that PYY-induced CTA was associated with augmented neuronal activity in the parabrachial nucleus (PBN), a brainstem nucleus that relays aversive/emetic signals to brain regions that control feeding behavior. Importantly, GIPR agonism reduced PYY-mediated neuronal activity in the PBN, providing a potential mechanistic explanation for how GIPR agonist treatment reduces PYY-induced nausea-like behavior. Together, the results of our study indicate a novel mechanism by which GIP-based therapeutics may have benefit in improving the tolerability of weight loss agents.

Topics: Animals; Anti-Obesity Agents; Mice; Nausea; Obesity; Peptide YY; Receptors, Gastrointestinal Hormone

Obesity interventions often result in increased motivation to eat.. We investigated relationships between obesity outcomes and changes in brain activation by visual food cues and hormone levels in response to obesity intervention by family-based behavioral treatment (FBT).. Neuroimaging and hormone assessments were conducted before and after 24-week FBT intervention in children with obesity (OB, n = 28), or children of healthy weight without intervention (HW, n = 17), all 9- to 11-year-old boys and girls. We evaluated meal-induced changes in neural activation to high- vs low-calorie food cues across appetite-processing brain regions and gut hormones.. Among children with OB who underwent FBT, greater declines of BMI z-score were associated with lesser reductions after the FBT intervention in meal-induced changes in neural activation to high- vs low-calorie food cues across appetite-processing brain regions (P < 0.05), and the slope of relationship was significantly different compared with children of HW. In children with OB, less reduction in brain responses to a meal from before to after FBT was associated with greater meal-induced reduction in ghrelin and increased meal-induced stimulation in peptide YY and glucagon-like peptide-1 (all P < 0.05).. In response to FBT, adaptations of central satiety responses and peripheral satiety-regulating hormones were noted. After weight loss, changes of peripheral hormone secretion support weight loss, but there was a weaker central satiety response. The findings suggest that even when peripheral satiety responses by gut hormones are intact, the central regulation of satiety is disturbed in children with OB who significantly improve their weight status during FBT, which could favor future weight regain.

Topics: Behavior Therapy; Brain; Child; Family Relations; Female; Gastrointestinal Hormones; Ghrelin; Humans; Male; Obesity; Peptide YY; Postprandial Period; Satiety Response; Weight Loss

Reproduction and metabolism are intricately linked. Gut hormones play key roles in the regulation of body weight and glucose homeostasis, factors that influence the functioning of the hypothalamic-pituitary-gonadal axis and reproductive outcomes. Data from rodent models suggest gut hormones may have direct stimulatory effects on reproductive hormone release. However, the effects of gut hormones on reproductive function in humans are more complex, with possible involvement of direct (e.g. via gut hormone receptor agonism) as well as indirect (e.g. via weight reduction in people with obesity) mechanisms. The use of gut hormone receptor agonists has become an integral part of the management of metabolic diseases (including obesity and type 2 diabetes), with additional indications for their use on the horizon. Future work may identify specific roles for gut hormone receptor agonists in the treatment of reproductive co-morbidities that are increasingly being recognised in people with metabolic diseases.

Topics: Diabetes Mellitus, Type 2; Gastrointestinal Hormones; Glucagon-Like Peptide 1; Humans; Obesity; Peptide YY; Reproduction

Peptides are notoriously known to display very short in vivo half-lives often measured in minutes which in many cases greatly reduces or eliminates sufficient in vivo efficacy. To obtain long half-lives allowing for up to once-weekly dosing regimen, fatty acid acylation (lipidation) have been used to non-covalently associate the peptide to serum albumin thus serving as a circulating depot. This approach is generally considered in the scientific and patent community as a standard approach to protract almost any given peptide. However, it is not trivial to prolong the half-life of peptides by lipidation and still maintain high potency and good formulation properties. Here we show that attaching a fatty acid to the obesity-drug relevant peptide PYY

Topics: Acetylation; Animals; Anti-Obesity Agents; CHO Cells; Cricetinae; Cricetulus; Drug Combinations; Fatty Acids; Female; Half-Life; HEK293 Cells; Humans; Liraglutide; Obesity; Oligopeptides; Peptide YY; Protein Binding; Receptors, Neuropeptide Y; Swine; Swine, Miniature

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

Gastrointestinal hormones regulate intestinal transit, control digestion, influence appetite and promote satiety. Altered production or action of gut hormones, including glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and peptide YY (PYY), may contribute to the biological basis of obesity and altered glucose homeostasis. However, challenges in analytical methodology and lack of clarity on expected values for healthy individuals have limited progress in this field. The aim of this study was to describe expected concentrations of gastrointestinal and pancreatic hormones in healthy volunteers following a standardized meal test (SMT) or 75 g oral glucose tolerance test (OGTT).. A total of 28 healthy volunteers (12 men, 16 women; mean age 31.3 years; mean body mass index 24.9 kg/m. Ranges of expected values were created for glucose, insulin, glucagon, GLP-1, GIP, PYY and free fatty acids in response to a standardized mixed liquid meal or OGTT. Intact proinsulin and C-peptide levels were also measured following the OGTT.. These ranges of expected values can now be used to compare gut hormone concentrations between healthy individuals and patient groups.

Topics: Adolescent; Adult; Aged; Blood Glucose; Fasting; Female; Gastric Inhibitory Polypeptide; Gastrointestinal Hormones; Glucagon; Glucagon-Like Peptide 1; Glucose Tolerance Test; Healthy Volunteers; Humans; Insulin; Male; Middle Aged; Obesity; Pancreatic Hormones; Peptide YY; Postprandial Period; Reference Values; Young Adult

Obesity is an important independent risk factor for type 2 diabetes, cardiovascular diseases, and many other chronic diseases. The objective of this study was to determine the role of adenosine deaminase acting on RNA 1 (ADAR1) in the development of obesity and insulin resistance. Wild-type (WT) and heterozygous ADAR1-deficient (

Topics: Adenosine Deaminase; Animals; Appetite; Body Composition; Diet, High-Fat; Dyslipidemias; Eating; Ghrelin; Glucose Tolerance Test; Insulin Resistance; Male; Mice; Mice, Knockout; Obesity; Peptide YY

Topics: Animals; Biomarkers; Body Composition; Diet, High-Fat; Dietary Supplements; Epigenesis, Genetic; Fathers; Female; Fertility; Gastrointestinal Microbiome; Glucagon-Like Peptide 1; Male; MicroRNAs; Obesity; Peptide YY; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Sucrose

To assess if habitual sleep duration/quality was associated with appetite in individuals with obesity, and if the association was modulated by sex.. Sleep duration/quality was measured with Pittsburgh Sleep Quality Index score in 95 healthy adults with obesity (BMI: 36.6 ± 4.2 kg/m. No significant associations were found between sleep duration, or overall quality, and appetite in all participants. However, a worse sleep efficiency was associated with lower postprandial CCK, a shorter habitual sleep was associated with lower postprandial desire to eat and a lower daytime dysfunction was associated with higher prospective food consumption in fasting (P<0.05, for all). In males, a shorter habitual sleep duration and a worse subjective sleep quality were associated with increased basal and postprandial active ghrelin (P<0.05, P<0.01, P<0.01 and P<0.05, respectively). Also, a shorter habitual sleep was associated with lower basal and postprandial insulin (P<0.05 for both) and a worse overall sleep quality with lower postprandial insulin (P<0.05). In females, a worse overall sleep quality was associated with lower postprandial active ghrelin (P<0.05), and short habitual sleep with higher postprandial insulin (P<0.05).. A worse habitual sleep efficiency is associated with blunted postprandial CCK secretion in individuals with obesity. The association between habitual sleep duration/quality and insulin and active ghrelin seems to be modulated by sex, but more studies are needed to confirm these findings.

Topics: Adult; Appetite; Female; Ghrelin; Humans; Insulin; Male; Obesity; Peptide YY; Postprandial Period; Prospective Studies; Sleep

Neuropeptide Y (NPY) and peptide YY (PYY) are involved in metabolic regulation. The purpose of the study was to assess the serum levels of NPY and PYY in adolescents with anorexia nervosa (AN) or obesity (OB), as well as in a healthy control group (CG). The effects of potential confounders on their concentrations were also analysed. Eighty-nine adolescents were included in this study (AN = 30, OB = 30, and CG = 29). Anthropometric measurements and psychometric assessment of depressive symptoms, eating behaviours, body attitudes, and fasting serum levels of NPY and PYY were analysed. The AN group presented severe depressive symptoms, while the OB group held different attitudes towards the body. The levels of NPY were lower in the AN and OB groups as compared with the CG. The PYY levels were higher in the OB group than in the AN group and the CG. The severity of eating disorder symptoms predicted fasting serum concentrations of NPY. Lower levels of NPY in AN, as well as in OB suggests the need to look for a common link in the mechanism of this effect. Higher level of PYY in OB may be important in explaining complex etiopathogenesis of the disease. The psychopathological symptoms may have an influence on the neurohormones regulating metabolism.

Topics: Adolescent; Anorexia Nervosa; Blood Glucose; Body Mass Index; Child; Depression; Fasting; Feeding Behavior; Female; Humans; Insulin; Male; Neuropeptide Y; Obesity; Peptide YY

Obesity is a complex disease associated with a high risk of comorbidities. Gastric bypass surgery, an invasive procedure with low patient eligibility, is currently the most effective intervention that achieves sustained weight loss. This beneficial effect is attributed to alterations in gut hormone signaling. An attractive alternative is to pharmacologically mimic the effects of bariatric surgery by targeting several gut hormonal axes. The G protein-coupled receptor 39 (GPR39) expressed in the gastrointestinal tract has been shown to mediate ghrelin signaling and control appetite, food intake, and energy homeostasis, but the broader effect on gut hormones is largely unknown. A potent and efficacious GPR39 agonist (Cpd1324) was recently discovered, but the in vivo function was not addressed. Herein we studied the efficacy of the GPR39 agonist, Cpd1324, on metabolism and gut hormone secretion.. Body weight, food intake, and energy expenditure in GPR39 agonist-treated mice and GPR39 KO mice were studied in calorimetric cages. Plasma ghrelin, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and peptide YY (PYY) levels were measured. Organoids generated from murine and human small intestine and mouse colon were used to study GLP-1 and PYY release. Upon GPR39 agonist administration, dynamic changes in intracellular GLP-1 content were studied via immunostaining and changes in ion transport across colonic mucosa were monitored in Ussing chambers. The G protein activation underlying GPR39-mediated selective release of gut hormones was studied using bioluminescence resonance energy transfer biosensors.. The GPR39 KO mice displayed a significantly increased food intake without corresponding increases in respiratory exchange ratios or energy expenditure. Oral administration of a GPR39 agonist induced an acute decrease in food intake and subsequent weight loss in high-fat diet (HFD)-fed mice without affecting their energy expenditure. The tool compound, Cpd1324, increased GLP-1 secretion in the mice as well as in mouse and human intestinal organoids, but not in GPR39 KO mouse organoids. In contrast, the GPR39 agonist had no effect on PYY or GIP secretion. Transepithelial ion transport was acutely affected by GPR39 agonism in a GLP-1- and calcitonin gene-related peptide (CGRP)-dependent manner. Analysis of Cpd1324 signaling properties showed activation of Gα. The GPR39 agonist described in this study can potentially be used by oral administration as a weight-lowering agent due to its stimulatory effect on GLP-1 secretion, which is most likely mediated through a unique activation of Gα subunits. Thus, GPR39 agonism may represent a novel approach to effectively treat obesity through selective modulation of gastrointestinal hormonal axes.

Topics: Animals; Appetite Regulation; Bariatric Surgery; Body Weight; Eating; Enteroendocrine Cells; Gastric Inhibitory Polypeptide; Gastrointestinal Hormones; Ghrelin; Glucagon-Like Peptide 1; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Peptide YY; Receptors, G-Protein-Coupled; Receptors, Gastrointestinal Hormone; Weight Loss

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

Human beings are often driven to exhibit dietary preference according to their hedonic characteristics. Though previous studies proposed that the fat taste preference of an obese individual was associated with BMI, the perception of fat taste differs for every individual. The genetic variation among populations in taste receptor genes such as CD36 may be a contributing factor for this difference. Satiety peptides can also play a role in the regulation of fat taste perception. Generally, this hormone helps us to feel the sense of satiety.. We have analysed the relationship among oro-gustatory perception of dietary lipids, salivary peptide-YY and genetic polymorphism in CD36. Oral fatty acid sensitivity analysis was performed by alternative forced choice method. Salivary peptide-YY concentration was analysed by ELISA and single nucleotide polymorphism (SNP) in CD36 gene was determined by Real-Time PCR experiments.. We observed that the SNP at rs1761667 of CD36 and oral detection threshold for linoleic acid (LA) are associated with choice of food, lipid profiles, peptide-YY as well as adiposity parameters in obese population. Obese peoples had significantly low levels of peptide YY than people with BMI less than 25. These factors possibly play a role in preference for energy rich diets, development of obesity and associated complications.. This study provides a solid foundation for understanding the alterations in the dietary fat intake and levels of peptide-YY, which are associated with polymorphism in fat taste receptor. This is the first report that shows a significant relationship between the satiety hormone level, SNP in CD36 gene and oral fat detection threshold in human subjects.

Topics: CD36 Antigens; Gene Expression Regulation; Genetic Variation; Humans; Obesity; Peptide YY; Polymorphism, Single Nucleotide

Obesity is a common disease worldwide and there is an urgent need for strategies to preventing obesity.. The anti-obesity effect and mechanism of Ligilactobacillus salivarius LCK11 (LCK11) is studied using a C57BL/6J male mouse model in which obesity is induced by a high-fat diet (HFD). Results show that LCK11 can prevent HFD-induced obesity, reflected as inhibited body weight gain, abdominal and liver fat accumulation and dyslipidemia. Analysis of its mechanism shows that on the one hand, LCK11 can inhibit food intake through significantly improving the transcriptional and translational levels of peptide YY (PYY) in the rectum, in addition to the eventual serum PYY level; this is attributed to the activation of the toll-like receptor 2/nuclear factor-κB signaling pathway in enteroendocrine L cells by the peptidoglycan of LCK11. On the other hand, LCK11 supplementation effectively reduces the Firmicutes/Bacteroidetes ratio and shifts the overall structure of the HFD-disrupted gut microbiota toward that of mice fed on a low-fat diet; this also contributes to preventing obesity.. LCK11 shows the potential to be used as a novel probiotic for preventing obesity by both promoting PYY secretion to inhibit food intake and regulating gut microbiota.

Topics: Adipose Tissue; Animals; Anti-Obesity Agents; Diet, High-Fat; Dyslipidemias; Eating; Enteroendocrine Cells; Gastrointestinal Microbiome; Intestines; Lactobacillaceae; Liver; Male; Mice, Inbred C57BL; Obesity; Peptide YY; Probiotics; Weight Gain

Alterations in several gastrointestinal hormones are implicated in the postoperative suppression of food intake leading to weight loss after Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG). The aim was to evaluate changes in responses of gastrointestinal hormones after RYGB and SG and the associations of these changes with weight loss, energy intake, and food preferences.. Forty-two subjects with severe obesity were included (32 RYGB; 10 SG). Postprandial responses of glicentin, oxyntomodulin, glucagon-like peptide-1 (GLP-1), peptide YY (PYY), and ghrelin were measured before and 6 months after surgery. Energy intake and energy density were assessed before and 6 months after surgery using a buffet meal test and weight loss was assessed 18 months after surgery.. Postprandial concentrations of glicentin, oxyntomodulin, GLP-1, and ghrelin differed between RYGB and SG (all P ≤ .02). Enhanced responses of glicentin and oxyntomodulin predicted a greater weight loss (both P < .01) and were associated with a larger decrease in energy density (P ≤ .04). No associations were found for GLP-1, PYY, and ghrelin, and changes were not associated with changes in energy intake. When combing all hormones, 60%, 19%, and 33% of the variations in weight loss, energy intake, and energy density, respectively, could be explained.. Postprandial responses of gastrointestinal hormones differed between RYGB and SG. Enhanced responses of glicentin and oxyntomodulin predicted a better weight loss and were associated with a decreased preference for energy-dense foods. Replication of these results could imply an opportunity to identify patients in need of additional support after surgical treatments of obesity.

Topics: Adult; Bariatric Surgery; Biomarkers; Case-Control Studies; Energy Intake; Female; Follow-Up Studies; Food Preferences; Gastrectomy; Gastric Bypass; Glicentin; Humans; Male; Obesity; Oxyntomodulin; Peptide YY; Prognosis; Weight Loss

To compare appetite markers in reduced-obese individuals with a nonobese control group.. A total of 34 adults with obesity who lost 17% body weight at week 13 and maintained this weight loss (WL) at 1 year were compared with 33 nonobese controls matched for body composition. Basal and postprandial subjective appetite ratings and appetite-related hormone concentrations (ghrelin, total peptide YY, peptide YY3-36, total and active glucagon-like peptide 1, and cholecystokinin) were measured in all participants and repeated at week 13 and 1 year in the weight-reduced group.. WL led to a reduction in prospective food consumption and an increase in feelings of hunger, fullness, and ghrelin secretion (basal and postprandial), but these new ratings were no different from those seen in controls. Postprandial concentrations of active glucagon-like peptide 1, total peptide YY, and cholecystokinin were lower in individuals with obesity at all time points compared with controls.. The increased drive to eat (both subjective feelings of hunger and ghrelin concentrations) seen in reduced-obese individuals, both after acute and sustained WL, reflects a normalization toward a lower body weight. Overall, WL does not have a sustained negative impact on satiety peptide secretion, despite a blunted secretion in individuals with obesity compared with nonobese controls.

Topics: Adult; Appetite; Body Mass Index; Body Weight; Cholecystokinin; Eating; Female; Ghrelin; Glucagon-Like Peptide 1; Homeostasis; Humans; Male; Middle Aged; Obesity; Peptide YY; Satiation; Weight Loss

Food cues affect hunger and nutritional choices. Omnipresent stimulation with palatable food contributes to the epidemics of obesity. The objective of the study was to investigate the impact of food cues on appetite-related hormones and to assess the functionality of the secreted hormones on macronutrient uptake in healthy subjects. Additionally, we aimed at verifying differences in the response of total and active ghrelin to stimulation with food pictures and to a meal followed by the stimulation. We were also interested in the identification of factors contributing to response to food cues. We recruited healthy, non-obese participants for two independent cross-over studies. During the first study, the subjects were presented random non-food pictures on the first day and pictures of foods on the second day of the study. Throughout the second study, following the picture session, the participants were additionally asked to drink a milkshake. Concentrations of blood glucose, triglycerides and hunger-related hormones were measured. The results showed that concentrations of several hormones measured in the blood are interdependent. In the case of ghrelin and gastric inhibitory peptide (GIP) as well as ghrelin and glucagon-like peptide-1 (GLP-1), this co-occurrence relies on the visual cues. Regulation of total ghrelin concentration following food stimulation is highly individual and responders showed upregulated total ghrelin, while the concentration of active ghrelin decreases following a meal. Protein content and colour intensity of food pictures reversely correlated with participants' rating of the pictures. We conclude that observation of food pictures influences the concentration of several appetite-related hormones. The close link of visual clues to physiological responses is likely of clinical relevance. Additionally, the protein content of displayed foods and green colour intensity in pictures may serve as a predictor of subjective attractiveness of the presented meal.

Topics: Adolescent; Adult; Appetite; Blood Glucose; Choice Behavior; Cues; Feeding Behavior; Female; Gastric Inhibitory Polypeptide; Ghrelin; Glucagon-Like Peptide 1; Humans; Hunger; Insulin; Male; Nutrients; Obesity; Peptide YY; Photic Stimulation

Rapid gastric emptying, increased food intake, and alterations in gastrointestinal hormones are associated with obesity. The effect of regular physical activity (PA) on food intake, gastric emptying (GE), gastric accommodation, and gastrointestinal (GI) hormones in adults with obesity remains unclear. Our aim was to compare, at time of presentation, weight trends, eating behavior, GE, and GI hormone levels among individuals with obesity who engage in regular PA compared to those who do not.. In 270 participants with obesity, we performed validated measurements of GI phenotypes: GE of solids and liquids, gastric volume (GV) during fasting and after consumption of 200 mL Ensure®, satiety by kcal intake (T-kcal) during a buffet meal, satiation (volume to fullness [VTF] and maximal tolerated volume [MTV]) of a liquid nutrient, and plasma levels of fasting and postprandial GLP-1, PYY, CCK, and ghrelin. Physical Activity Stages of Change Questionnaire was used to assess whether participants were regularly PA or not.. Physical activity is associated with lower BMI, but faster GE and higher postprandial ghrelin levels, two factors that are also associated with obesity.

Topics: Adult; Body Mass Index; Case-Control Studies; Cholecystokinin; Exercise; Female; Gastric Emptying; Ghrelin; Glucagon-Like Peptide 1; Humans; Male; Obesity; Peptide YY; Postprandial Period; Satiation

Gut-derived satiety hormones provide negative feedback to suppress food intake and maintain metabolic function in peripheral tissues. Despite the wealth of knowledge of the systemic effects of these hormones, very little is known concerning the mechanisms by which nutrients, such as dietary fats, can promote the expression of genes involved in L-cell hormone production. We have tested the role of various dietary fats and found that after hydrolysis into free fatty acids (FFA's), there is a differential response in the extent to which they induce PYY gene and protein production. The effect of FFA's also seems to relate to triglyceride (TG) re-esterification rate, with MUFA re-esterifying faster with lower PYY production. We have also found that there are differences in potency of FFA's based on their desaturation patterns in vitro. The potency effect of FFA's is influenced by the rate of TG re-esterification, such that the longer FFA's are in contact with L-cells, the more PYY they produce. We found that chronic consumption of high-fat diets enables the small intestine to re-esterify FFA's into TG faster and earlier which resulted in a blunted postprandial PYY response. Lastly, we found that FFA's induce X-box-binding protein-1 activation (Xbp1s) in L-cells and that adenoviral delivery of Xbp1s was sufficient to induce PYY gene expression. Taken together, the present work indicates that dietary fat can induce satiety, in part, prior to re-esterification. Chronic high-fat diet consumption increases the rate of re-esterification which diminishes satiety and may lead to increased food intake. Targeting intestinal TG synthesis may prove beneficial in restoring obesity-associated reductions in postprandial satiety.

Topics: Animals; Cell Line, Tumor; Diet, High-Fat; Eating; Fatty Acids; Fatty Acids, Monounsaturated; Fatty Acids, Nonesterified; Female; Gene Expression Regulation; L Cells; Lipid Metabolism; Lipogenesis; Male; Mice; Mice, Inbred C57BL; Obesity; Peptide YY; Postprandial Period; RNA Splicing; Satiety Response; Triglycerides; X-Box Binding Protein 1

G protein-coupled bile acid receptor (TGR5) is involved in a number of metabolic diseases. The aim of this study was to identify the role of TGR5 after Roux-en-Y gastric bypass (GBP).. Wild type and TGR5 knockout mice (tgr5-/-) were fed a high-fat diet (HFD) to establish the obesity model. GBP was performed. The changes in body weight and food intake were measured. The levels of TGR5 and peptide YY (PYY) were evaluated by RT-PCR, Western blot, and ELISA. Moreover, the L-cells were separated from wild type and tgr5-/- mice. The levels of PYY in L-cells were evaluated by ELISA.. The body weights were significantly decreased after GBP in wild type mice (p<0.05), but not tgr5-/- mice (p>0.05). Food intake was reduced after GBP in wild type mice, but also not significantly affected in tgr5-/- mice (p>0.05). The levels of PYY were significantly increased after GBP compared with the sham group (p<0.05); however, in tgr5-/- mice the expression of PYY was not significantly affected (p>0.05). After INT-777 stimulation in L-cells obtained from murine intestines, the levels of PYY were significantly increased in L-cells tgr5+/+ (p<0.05).. Our study suggests that GBP up-regulated the expression of TGR5 in murine intestines, and increased the levels of PYY, which further reduced food intake and decreased the body weight.

Topics: Animals; Diet, High-Fat; Eating; Gastric Bypass; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Obesity; Peptide YY; Receptors, G-Protein-Coupled

Bariatric surgery results in increased intestinal secretion of hormones GLP-1 and anorexigenic PYY, which is believed to contribute to the clinical efficacy associated with the procedure. This observation raises the question whether combination treatment with gut hormone analogs might recapitulate the efficacy and mitigate the significant risks associated with surgery. Despite PYY demonstrating excellent efficacy and safety profiles with regard to food intake reduction, weight loss, and glucose control in preclinical animal models, PYY-based therapeutic development remains challenging given a low serum stability and half-life for the native peptide. Here, combined peptide stapling and PEG-fatty acid conjugation affords potent PYY analogs with >14 h rat half-lives, which are expected to translate into a human half-life suitable for once-weekly dosing. Excellent efficacy in glucose control, food intake reduction, and weight loss for lead candidate

Topics: Amino Acid Sequence; Animals; Body Weight; Drug Interactions; Eating; Engineering; Glucagon-Like Peptide-1 Receptor; Half-Life; Models, Molecular; Obesity; Peptide YY; Polyethylene Glycols; Protein Conformation; Rats; Receptors, Neuropeptide Y

Combination therapies of anorectic gut hormones partially mimic the beneficial effects of bariatric surgery. Thus far, the effects of a combined chronic systemic administration of Glucagon-like peptide-1 (GLP-1) and peptide tyrosine tyrosine 3-36 (PYY. High-fat diet (HFD)-induced obese male Wistar rats were randomized into six treatment groups: (1) RYGB, (2) sham-operation (shams), (3) liraglutide, (4) PYY. RYGB reduced food intake and achieved sustained weight loss. Combined PYY. Liraglutide and PYY

Topics: Animals; Body Weight; Combined Modality Therapy; Diet, High-Fat; Eating; Food Preferences; Gastric Bypass; Hypoglycemic Agents; Liraglutide; Male; Obesity; Peptide YY; Rats; Rats, Wistar

The central mechanisms underlying the marked beneficial metabolic effects of bariatric surgery are unclear. Here, we characterized global gene expression in the hypothalamic arcuate nucleus (Arc) in diet-induced obese (DIO) rats following Roux-en-Y gastric bypass (RYGB). 60 days post-RYGB, the Arc was isolated by laser-capture microdissection and global gene expression was assessed by RNA sequencing. RYGB lowered body weight and adiposity as compared to sham-operated DIO rats. Discrete transcriptome changes were observed in the Arc following RYGB, including differential expression of genes associated with inflammation and neuropeptide signaling. RYGB reduced gene expression of glial cell markers, including Gfap, Aif1 and Timp1, confirmed by a lower number of GFAP immunopositive astrocyte profiles in the Arc. Sham-operated weight-matched rats demonstrated a similar glial gene expression signature, suggesting that RYGB and dietary restriction have common effects on hypothalamic gliosis. Considering that RYGB surgery also led to increased orexigenic and decreased anorexigenic gene expression, this may signify increased hunger-associated signaling at the level of the Arc. Hence, induction of counterregulatory molecular mechanisms downstream from the Arc may play an important role in RYGB-induced weight loss.

Topics: Adiposity; Animals; Arcuate Nucleus of Hypothalamus; Astrocytes; Biomarkers; Diet, High-Fat; Diet, Reducing; Eating; Gastric Bypass; Gene Expression Profiling; Gene Expression Regulation; Glial Fibrillary Acidic Protein; Gliosis; Glucagon-Like Peptide 1; Inflammation; Laser Capture Microdissection; Male; Neuropeptides; Obesity; Peptide YY; Rats; Rats, Sprague-Dawley; Sequence Analysis, RNA; Weight Loss

Better understanding of feeding behaviour will be vital in reducing obesity and metabolic syndrome, but we lack a standard model that captures the complexity of feeding behaviour. We construct an accurate stochastic model of rodent feeding at the bout level in order to perform quantitative behavioural analysis. Analysing the different effects on feeding behaviour of peptide YY3-36 (PYY3-36), lithium chloride, glucagon-like peptide 1 (GLP-1), and leptin shows the precise behavioural changes caused by each anorectic agent. Our analysis demonstrates that the changes in feeding behaviour evoked by the anorectic agents investigated do not mimic the behaviour of well-fed animals and that the intermeal interval is influenced by fullness. We show how robust homeostatic control of feeding thwarts attempts to reduce food intake and how this might be overcome. In silico experiments suggest that introducing a minimum intermeal interval or modulating upper gut emptying can be as effective as anorectic drug administration.

Topics: Animals; Appetite Depressants; Eating; Feeding Behavior; Glucagon-Like Peptide 1; Homeostasis; Leptin; Male; Mice; Obesity; Peptide Fragments; Peptide YY; Rats

The current study aimed to assess profiles of peptide YY and ghrelin, visual analog scales (VAS) for hunger and satiety, and ad libitum intake in obese and non-obese women.. This open-label non-randomized interventional study involved obese (BMI ≥ 25-35 kg/m2) and non-obese (BMI 18.5-23.0 kg/m2) women subjects. Levels of peptide YY and ghrelin were determined by radioimmunoassay and enzyme-linked immunosorbent assay (ELISA), respectively, while the degrees of hunger and satiety were measured using visual analog scale (VAS) questionnaires. The results were compared in fasting condition and in 15, 60, 120, and 180 minutes after breakfast with balance composition formulation. This study also compared the ad libitum intake within 4 hours after breakfast.. As compared to the non-obese group, the obese group have significantly lower levels of peptide YY in fasting, and in 15, 60, 120, and 180 minutes post-prandial, and smaller AUC (Area Under the Curve) of fasting peptide YY. Furthermore, the obese group showed significantly higher ad libitum intake. The obese group also have lower levels of ghrelin and lower VAS for hunger and higher in VAS for satiety as compared to the non-obese group.. There were significant differences in peptide YY level, 4 hours after breakfast ad libitum intake, ghrelin level, and VAS for hunger and satiety, between obese group and non-obese one.

Topics: Adult; Area Under Curve; Female; Ghrelin; Humans; Hunger; Indonesia; Insulin Resistance; Obesity; Peptide YY; Satiation; Visual Analog Scale

Behavioral studies suggest that responses to food consumption are altered in children with obesity (OB).. To test central nervous system and peripheral hormone response by functional MRI and satiety-regulating hormone levels before and after a meal.. Cross-sectional study comparing children with OB and children of healthy weight (HW) recruited from across the Puget Sound region of Washington.. Children (9 to 11 years old; OB, n = 54; HW, n = 22), matched for age and sex.. Neural activation to images of high- and low-calorie food and objects was evaluated across a set of a priori appetite-processing regions that included the ventral and dorsal striatum, amygdala, substantia nigra/ventral tegmental area, insula, and medial orbitofrontal cortex. Premeal and postmeal hormones (insulin, peptide YY, glucagon-like peptide-1, active ghrelin) were measured.. In response to a meal, average brain activation by high-calorie food cues vs objects in a priori regions was reduced after meals in children of HW (Z = -3.5, P < 0.0001), but not in children with OB (z = 0.28, P = 0.78) despite appropriate meal responses by gut hormones. Although premeal average brain activation by high-calorie food cues was lower in children with OB vs children of HW, postmeal activation was higher in children with OB (Z = -2.1, P = 0.04 and Z = 2.3, P = 0.02, respectively). An attenuated central response to a meal was associated with greater degree of insulin resistance.. Our data suggest that children with OB exhibit an attenuated central, as opposed to gut hormone, response to a meal, which may predispose them to overconsumption of food or difficulty with weight loss.

Topics: Appetite; Biomarkers; Brain; Case-Control Studies; Child; Cross-Sectional Studies; Female; Follow-Up Studies; Ghrelin; Glucagon-Like Peptide 1; Humans; Insulin; Magnetic Resonance Imaging; Male; Meals; Obesity; Peptide YY; Postprandial Period; Prognosis; Satiation

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

The gut hormone peptide YY (PYY) secreted from intestinal L-cells has been implicated in the mechanisms of satiation via Y2-receptor (Y2R) signaling in the brain and periphery and is a major candidate for mediating the beneficial effects of bariatric surgery on appetite and body weight.. Here we assessed the role of Y2R signaling in the response to low- and high-fat diets and its role in the effects of Roux-en-Y gastric bypass (RYGB) surgery on body weight, body composition, food intake, energy expenditure and glucose handling, in global Y2R-deficient (Y2RKO) and wildtype (WT) mice made obese on high-fat diet.. Both male and female Y2RKO mice responded normally to low- and high-fat diet in terms of body weight, body composition, fasting levels of glucose and insulin, as well as glucose and insulin tolerance for up to 30 weeks of age. Contrary to expectations, obese Y2RKO mice also responded similarly to RYGB compared to WT mice for up to 20 weeks after surgery, with initial hypophagia, sustained body weight loss, and significant improvements in fasting insulin, glucose tolerance, insulin resistance (HOMA-IR), and liver weight compared to sham-operated mice. Furthermore, non-surgical Y2RKO mice weight-matched to RYGB showed the same improvements in glycemic control as Y2RKO mice with RYGB that were similar to WT mice.. PYY signaling through Y2R is not required for the normal appetite-suppressing and body weight-lowering effects of RYGB in this global knockout mouse model. Potential compensatory adaptations of PYY signaling through other receptor subtypes or other gut satiety hormones such as glucagon-like peptide-1 (GLP-1) remain to be investigated.

Topics: Animals; Diet, High-Fat; Gastric Bypass; Male; Mice; Mice, Knockout; Obesity; Peptide YY; Receptors, Gastrointestinal Hormone

Bariatric surgery is associated with significant and sustained weight loss and improved metabolic outcomes. It is unclear if weight loss alone is the main mechanism of improved metabolic health. The purpose of this trial was to compare indices of appetite regulation, insulin sensitivity and energy intake (EI) between participants achieving 10 kg of weight loss via Roux-en-Y Gastric Bypass (RYGB) or dietary restriction (DIET); intake of a very low calorie liquid diet (800 kcal/d; 40% protein, 40% fat, 20% carbohydrate that matched the post-RYGB dietary protocol). Adults qualifying for bariatric surgery were studied before and after 10 kg of weight loss (RYGB [n = 6]) or DIET [n = 17]). Appetite (hunger, satiety, and prospective food consumption [PFC]), appetite-related hormones, and metabolites (ghrelin, PYY, GLP-1, insulin, glucose, free fatty acids [FFA], and triglycerides [TG]) were measured in the fasting state and every 30 min for 180 min following breakfast. Participants were provided lunch to evaluate acute ad libitum EI, which was similarly reduced in both groups from pre to post weight loss. Fasting ghrelin was reduced to a greater extent following RYGB compared to DIET (P = 0.04). Area under the curve (AUC) for ghrelin (P = 0.01), hunger (P < 0.01) and PFC (P < 0.01) increased after DIET compared to RYGB, following 10 kg weight loss. Satiety AUC increased after RYGB and decreased after DIET (P < 0.01). Glucose and insulin (fasting and AUC) decreased in both groups. FFA increased in both groups, with a greater increase in AUC seen after RYGB versus DIET (P = 0.02). In summary, appetite-related indices were altered in a manner that, if maintained, may promote a sustained reduction in energy intake with RYGB compared to DIET. Future work with a larger sample size and longer follow-up will be important to confirm and extend these findings.

Topics: Adult; Appetite; Appetite Regulation; Blood Glucose; Body Mass Index; Diet, Reducing; Energy Intake; Female; Gastric Bypass; Ghrelin; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Male; Middle Aged; Obesity; Peptide YY; Postprandial Period; Satiation; Weight Loss

This study was undertaken to compare gut hormone secretion between high-fat-fed and control rats, and to examine the corresponding changes in the expression of sweet taste receptors and glucose transporters in the small intestine and hypothalamus.. Four-week-old male Sprague Dawley rats were fed a standard or high-fat diet for 8 weeks (10 in each group), followed by an oral glucose tolerance test (50% glucose solution, 2 g/kg). Blood was sampled for glucose, insulin, glucagon-like peptide-1 (GLP-1) and polypeptide YY (PYY) assays. One week later, small intestinal and hypothalamic tissue were analyzed for sweet taste receptor and glucose transporter expression by real-time PCR.. After oral glucose, plasma GLP-1 concentrations were higher in high-fat-fed than standard-fat-fed rats (group × time interaction, p < 0.01) with significant differences at t = 15 min (p < 0.01) and 30 min (p < 0.05). Plasma PYY concentrations were lower in high-fat-fed than control rats at t = 0, 15 min (p < 0.05, respectively) and 120 min (p < 0.01). There were no differences in the expression of sweet taste receptors or glucose transporters between high-fat-fed and control rats in the duodenum, ileum, or hypothalamus.. Changes in GLP-1 and PYY secretion after a high-fat diet appear unrelated to any changes in the expression of sweet taste receptors or glucose transporters. Impaired PYY secretion with high-fat feeding suggests that PYY analogues may provide a potential therapy in the treatment of obesity.

Topics: Animals; Diet, High-Fat; Gastrointestinal Hormones; Gene Expression; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; Glucose Transport Proteins, Facilitative; Ileum; Insulin; Male; Obesity; Peptide YY; Rats; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled; Taste; Taste Perception

Understanding the mechanisms underlying the remarkable beneficial effects of gastric bypass surgery is important for the development of non-surgical therapies or less invasive surgeries in the fight against obesity and metabolic disease. Although the intestinal L-cell hormones glucagon-like peptide-1 (GLP-1) and peptide tyrosine-tyrosine (PYY) have attracted the most attention, direct tests in humans and rodents with pharmacological blockade or genetic deletion of either the GLP1-receptor (GLP1R) or the Y2-receptor (Y2R) were unable to confirm their critical roles in the beneficial effects gastric bypass surgery on body weight and glucose homeostasis. However, new awareness of the power of combinatorial therapies in the treatment of metabolic disease would suggest that combined blockade of more than one signaling pathway may be necessary to reverse the beneficial effects of bariatric surgery.. The metabolic effects of high-fat diet and the ability of Roux-en-Y gastric bypass surgery to lower food intake and body weight, as well as improve glucose handling, was tested in GLP1R and Y2R-double knockout (GLP1RKO/Y2RKO) and C57BL6J wildtype (WT) mice.. GLP1RKO/Y2RKO and WT mice responded similarly for up to 20 weeks on high-fat diet and 16 weeks after RYGB. There were no significant differences in loss of body and liver weight, fat mass, reduced food intake, relative increase in energy expenditure, improved fasting insulin, glucose tolerance, and insulin tolerance between WT and GLP1RKO/Y2RKO mice after RYGB.. Combined loss of GLP1R and Y2R-signaling was not able to negate or attenuate the beneficial effects of RYGB on body weight and glucose homeostasis in mice, suggesting that a larger number of signaling pathways is involved or that the critical pathway has not yet been identified.

Topics: Animals; Bariatric Surgery; Blood Glucose; Body Weight; Diet, High-Fat; Energy Metabolism; Gastric Bypass; Gene Expression Regulation; Glucagon-Like Peptide-1 Receptor; Insulin; Insulin Resistance; Male; Metabolic Diseases; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Peptide YY; Receptors, G-Protein-Coupled; Transcriptome

Peptide YY

Topics: Anti-Obesity Agents; Arrestins; Drug Design; Half-Life; HEK293 Cells; Humans; Intravital Microscopy; Lipids; Liposomes; Models, Biological; Models, Chemical; Molecular Structure; Obesity; Peptide Fragments; Peptide YY; Polyethylene Glycols; Receptors, Neuropeptide Y; Structure-Activity Relationship

The fat mass and obesity-associated gene (FTO) rs9939609 A-allele has been associated with obesity risk. Although the exact mechanisms involved remain unknown, the FTO rs9939609 A-allele has been associated with an impaired postprandial suppression of appetite.. To explore the influence of FTO rs9939609 genotype on fasting and postprandial appetite-related hormones and perceived appetite in a heterogeneous sample of men and women.. 112 healthy men and women aged 18-50-years-old completed three laboratory visits for the assessment of FTO rs9939609 genotype, body composition, aerobic fitness, resting metabolic rate, visceral adipose tissue, liver fat, fasting leptin, and fasting and postprandial acylated ghrelin, total PYY, insulin, glucose and perceived appetite. Participants wore accelerometers for seven consecutive days for the assessment of physical activity and sedentary behaviour. Multivariable general linear models quantified differences between FTO rs9939609 groups for fasting and postprandial appetite outcomes, with and without the addition of a priori selected physiological and behavioural covariates. Sex-specific univariable Pearson's correlation coefficients were quantified between the appetite-related outcomes and individual characteristics.. 95% confidence intervals for mean differences between FTO rs9939609 groups overlapped zero in unadjusted and adjusted general linear models for all fasting (P ≥ 0.28) and postprandial (P ≥ 0.19) appetite-related outcomes. Eta. Associations between the FTO rs9939609 genotype and fasting or postprandial appetite-related outcomes were weak in healthy men and women.

Topics: Adolescent; Adult; Alpha-Ketoglutarate-Dependent Dioxygenase FTO; Appetite; Blood Glucose; Body Mass Index; Fasting; Female; Genotype; Ghrelin; Humans; Insulin; Leptin; Male; Middle Aged; Obesity; Oxygen Consumption; Peptide YY; Postprandial Period; Young Adult

A premeal load of protein can increase satiety and reduce energy intake. Dietary fiber also conveys metabolic benefits by modulating energy intake. We made a protein-enriched, dietary fiber-fortified bar (PFB) and aimed to investigate its effects on food intake and gut hormone secretion in healthy individuals.. Twenty subjects with normal glucose tolerance were enrolled. On three separate visits, the subjects received, in a randomized order, one of the following: a PFB containing 73 kcal with 10.7 g of protein and 12.7 g of dietary fiber; a usual bar (UB) containing the same calories as the PFB but only 0.9 g of protein and no dietary fiber; or water (control). After 15 minutes, the subjects had. Total energy intake, including the bar and the test meal, was significantly reduced with the PFB preload compared to the water (904.4±534.9 kcal vs. 1,075.0±508.0 kcal,. In healthy individuals, a premeal supplementation of PFB reduced total energy intake and decreased postprandial glucose excursion. This finding necessitates long-term studies regarding clinical use in obesity.

Topics: Adult; Appetite; Blood Glucose; Dietary Fiber; Eating; Energy Intake; Female; Glucagon-Like Peptide 1; Healthy Volunteers; Humans; Insulin; Male; Meals; Obesity; Peptide YY; Postprandial Period; Proteins; Satiation; Young Adult

The gastric mucosa is an endocrine organ that regulates satiation pathways by expression of orexigenic and anorexigenic hormones. Vertical sleeve gastrectomy (VSG) excludes gastric mucosa and reduces gastric volume. Our study aimed to investigate the independent effects of altering gastric mucosa on obesity and its related comorbidities.. Gastric mucosa devitalization (GMD) of 70% of the stomach was achieved by argon plasma coagulation in a high-fat diet rat model and was compared with VSG and sham surgery. In an 8-week follow-up study, we quantified body weight, visceral adiposity, insulin resistance index, cholesterol profiles, and free fatty acid profiles by enzyme-linked immunosorbent assay (ELISA). Following a 2-hour oral glucose tolerance test, the kinetics of ghrelin, glucagon-like peptide-1, peptide YY, and serum and liver bile acid levels were measured. Liver lipid content was quantified by ELISA.. GMD resulted in significant reductions in body weight, visceral and subcutaneous adipose tissue, and hepatic steatosis as well as an improvement in lipid metabolism. GMD resulted in significant reductions in food intake and intestinal malabsorption of free fatty acids, both contributing to improved body composition and metabolic profile. Mechanistically, GMD resulted in a significant reduction in serum palmitate levels as well as an increase in serum and liver bile acid levels, known to alter glucose and lipid metabolism. Similar changes were noted when VSG rats were compared with sham surgery rats.. Devitalization of gastric mucosa, independent of altering gastric volume, was able to reduce obesity-related comorbidities. The gastric mucosa may be a potential target for treating obesity and its associated comorbidities.

Topics: Adiposity; Animals; Argon Plasma Coagulation; Bile Acids and Salts; Blood Glucose; C-Reactive Protein; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Diet, High-Fat; Enzyme-Linked Immunosorbent Assay; Fatty Acids, Nonesterified; Gastrectomy; Gastric Mucosa; Ghrelin; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; Insulin Resistance; Interleukin-6; Intra-Abdominal Fat; Lipid Metabolism; Liver; Male; Obesity; Peptide YY; Rats; Rats, Sprague-Dawley; Stomach; Triglycerides

Early-life obesity predisposes to obesity in adulthood, a condition with broad medical implications including sleep disorders, which can exacerbate metabolic disturbances and disrupt cognitive and affective behaviors. In this study, we examined the long-term impact of transient peripubertal diet-induced obesity (ppDIO, induced between 4 and 10 weeks of age) on sleep-wake behavior in male mice. EEG and EMG recordings revealed that ppDIO increases sleep during the active phase but reduces resting-phase sleep quality. This impaired sleep phenotype persisted for up to 1 year, although animals were returned to a non-obesiogenic diet from postnatal week 11 onwards. To better understand the mechanisms responsible for the ppDIO-induced alterations in sleep, we focused on the lateral hypothalamus (LH). Mice exposed to ppDIO did not show altered mRNA expression levels of orexin and melanin-concentrating hormone, two peptides that are important for sleep-wake behavior and food intake. Conversely, the LH of ppDIO-exposed mice had reduced contents of serotonin (5-hydroxytryptamine, 5-HT), a neurotransmitter involved in both sleep-wake and satiety regulation. Interestingly, an acute peripheral injection of the satiety-signaling peptide YY 3-36 increased 5-HT turnover in the LH and ameliorated the ppDIO-induced sleep disturbances, suggesting the therapeutic potential of this peptide. These findings provide new insights into how sleep-wake behavior is programmed during early life and how peripheral and central signals are integrated to coordinate sleep.

Topics: Animals; Homeostasis; Hypothalamic Area, Lateral; Male; Mice; Mice, Inbred C57BL; Obesity; Peptide Fragments; Peptide YY; Serotonin; Sleep Wake Disorders

Neuropeptide Y2 receptor (Y2R) agonism is an important anorectic signal and a target of antiobesity drug discovery. Recently, we synthesized a short-length Y2R agonist, PYY-1119 (4-imidazolecarbonyl-[d-Hyp

Topics: Alkylation; Amino Acid Sequence; Animals; Anti-Obesity Agents; Dogs; Emetics; Half-Life; Infusions, Subcutaneous; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Peptide YY; Polyethylene Glycols; Receptors, Neuropeptide Y; Vomiting

The impact of lifestyle-induced weight loss (WL) on appetite in patients with obesity remains controversial. This study aimed to assess the short- and long-term impact of WL achieved by diet and exercise on appetite in patients with obesity. Thirty-five (22 females) adults with severe obesity (body mass index: 42.5 ± 5.0 kg/m

Topics: Adult; Anaerobic Threshold; Appetite Regulation; Body Mass Index; Diet, Reducing; Exercise; Female; Glucagon-Like Peptide 1; Humans; Hunger; Life Style; Male; Middle Aged; Obesity; Obesity, Morbid; Patient Care Team; Peptide YY; Weight Loss

To investigate the physiological mechanisms leading to rapid improvement in diabetes after Roux-en-Y gastric bypass (RYGB) and specifically the contribution of the concurrent peri-operative dietary restrictions, which may also alter glucose metabolism.. In order to assess the differential contributions of diet and surgery to the mechanisms leading to the rapid improvement in diabetes after RYGB we enrolled 10 patients with type 2 diabetes scheduled to undergo RYGB. All patients underwent a 10-day inpatient supervised dietary intervention equivalent to the peri-operative diet (diet-only period), followed by, after a re-equilibration (washout) period, an identical period of pair-matched diet in conjunction with RYGB (diet and RYGB period). We conducted extensive metabolic assessments during a 6-hour mixed-meal challenge test, with stable isotope glucose tracer infusion performed before and after each intervention.. Similar improvements in glucose levels, β-cell function, insulin sensitivity and post-meal hepatic insulin resistance were observed with both interventions. Both interventions led to significant reductions in fasting and postprandial acyl ghrelin. The diet-only intervention induced greater improvements in basal hepatic glucose output and post-meal gastric inhibitory polypeptide (GIP) secretion. The diet and RYGB intervention induced significantly greater increases in post-meal glucagon-like peptide-1 (GLP-1), peptide YY (PYY) and glucagon levels.. Strict peri-operative dietary restriction is a main contributor to the rapid improvement in glucose metabolism after RYGB. The RYGB-induced changes in the incretin hormones GLP-1 and PYY probably play a major role in long-term compliance with such major dietary restrictions through central and peripheral mechanisms.

Topics: Blood Glucose; Caloric Restriction; Diabetes Mellitus, Type 2; Fasting; Female; Gastric Bypass; Gastric Inhibitory Polypeptide; Ghrelin; Glucagon; Glucagon-Like Peptide 1; Humans; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Liver; Male; Middle Aged; Obesity; Peptide YY; Postprandial Period; Remission Induction

To examine the effect of different feeding routes on appetite and metabolic responses after Roux-en-Y gastric bypass (RYGB).. A standard liquid meal was administered either orally, into the gastric remnant, or intraduodenally 6 months after RYGB. Changes in plasma glucose, insulin, glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), peptide YY (PYY), and appetite were measured pre- and postprandially.. Postprandial GLP-1 and PYY responses were similar, whereas glucose, insulin, and GIP levels differed markedly after oral versus intraduodenal feeding. Intraduodenal feeding prompted an intermediate appetite response (i.e., between oral and intragastric). For postprandial glucose, insulin, and GIP levels, the intraduodenal route was more similar to the intragastric than the oral route. Intragastric administration did not evoke changes in appetite, glucose, or insulin; however, it slightly increased GLP-1 and PYY and moderately increased GIP.. Appetite and metabolic responses after RYGB depend on the route by which nutrients enter the gastrointestinal tract.

Topics: Adult; Appetite; Blood Glucose; Duodenum; Enteral Nutrition; Female; Food; Gastric Bypass; Gastric Inhibitory Polypeptide; Gastric Mucosa; Gastrointestinal Hormones; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Male; Meals; Obesity; Peptide YY; Postprandial Period; Stomach

Topics: Adiponectin; Adult; alpha-MSH; Energy Metabolism; Female; Gastric Bypass; Humans; Leptin; Male; Middle Aged; Obesity; Peptide YY; Prospective Studies; Treatment Outcome; Weight Loss

Dietary intake of barley β-glucan (BG) is known to affect energy metabolism. However, its underlying mechanism remains poorly understood because studies have presented inconsistent results, with both positive and negative effects reported in terms of satiety, energy intake, weight loss, and glycemic control. The objective of this study was to clarify the physiological role underlying the metabolic benefits of barley BG using a mouse model of high fat diet (HFD)-induced obesity. Male 4-wk-old C57BL/6J mice were fed an HFD with 20% barley flour containing either high BG (HBG; 2% BG) or low BG (LBG; 0.6% BG) levels under conventional and germ-free (GF) conditions for 12 wks. In addition, mice were fed either an HFD with 5% cellulose (HFC; high fiber cellulose) or 5% barley BG (HFB; high fiber β-glucan) for 12 wks. Then, metabolic parameters, gut microbial compositions, and the production of fecal short-chain fatty acids (SCFAs) were analyzed. The weight gain and fat mass of HBG-fed mice were lower than those of control mice at 16-wk-old. Moreover, the secretion of the gut hormones PYY and GLP-1 increased in HBG-fed mice, thereby reducing food intake and improving insulin sensitivity by changing the gut microbiota and increasing SCFAs (especially, butyrate) under conventional condition. These effects in HBG-fed mice were abolished under GF conditions. Moreover, the HFB diets also increased PYY and GLP-1 secretion, and decreased food intake compared with that in HFC-fed mice. These results suggest that the beneficial metabolic effects of barley BG are primary due to the suppression of appetite and improvement of insulin sensitivity, which are induced by gut hormone secretion promoted via gut microbiota-produced SCFAs.

Topics: Actinobacteria; Animals; Appetite; beta-Glucans; Bifidobacterium; Diet, High-Fat; Fatty Acids, Volatile; Gastrointestinal Microbiome; Glucagon-Like Peptide 1; Hordeum; Intestinal Mucosa; Intestines; Male; Mice; Mice, Inbred C57BL; Obesity; Peptide YY

Schizophrenia is among the top half of the 25 leading causes of disabilities worldwide with a 10-20 year decrease in life expectancy. Ineffective pharmacotherapy in the management of cognitive deficits and weight gain are known to be significant contributors; therefore interventions that may mitigate one, or both, of these parameters would be highly beneficial. Manipulation of the gut microbiome using dietary supplements such as prebiotics may be one such intervention. Preclinical studies have shown that a 2-4 week dietary supplementation with a prebiotic has beneficial effects on learning and memory, and prevents pro-inflammatory signals that are detrimental to cognitive processes. Furthermore, prebiotics influence metabolism, and in obesity they increase the expression of anorexigenic gut hormones such as peptide tyrosine tyrosine, glucagon-like peptide 1 and leptin, as well as decrease levels of orexigenic hormones such as ghrelin. Despite compelling evidence for the pro-cognitive and neuroprotective effects of prebiotics in rodents, their ability to alleviate cognitive deficits or enhance cognition needs to be evaluated in humans. Here we suggest that important symptoms associated with schizophrenia, such as cognitive impairment and weight gain, may benefit from concurrent prebiotic therapy.

Topics: Cognition; Dietary Supplements; Gastrointestinal Microbiome; Ghrelin; Glucagon-Like Peptide 1; Humans; Leptin; Obesity; Peptide YY; Prebiotics; Schizophrenia; Weight Gain

Diet-induced weight loss (WL) leads to increased hunger and reduced fullness feelings, increased ghrelin and reduced satiety peptides concentration (glucagon-like peptide-1 (GLP-1), cholecystokinin (CCK) and peptide YY (PYY)). Ketogenic diets seem to minimise or supress some of these responses. The aim of this study was to determine the timeline over which changes in appetite occur during progressive WL with a ketogenic very-low-energy diet (VLED).. Thirty-one sedentary adults (18 men), with obesity (body mass index: 37±4.5 kg m. A significant increase in fasting hunger was observed by day 3 (2±1% WL), (P<0.01), 5% WL (12±8 days) (P<0.05) and wk 13 (17±2% WL) (P<0.05). Increased desire to eat was observed by day 3 (P<0.01) and 5% WL (P<0.05). Postprandial prospective food consumption was significantly reduced at wk 9 (16±2% WL) (P<0.01). Basal total PYY was significantly reduced at 10% WL (32±8 days) (P<0.05). Postprandial active GLP-1 was increased at 5% WL (P<0.01) and CCK reduced at 5 and 10% WL (P<0.01, for both) and wk 9 (P<0.001). Basal and postprandial AG were significantly increased at wk 13 (P<0.001, both).. WL with a ketogenic VLED transiently increases the drive to eat up to 3 weeks (5% WL). After that, and while participants are ketotic, a 10-17% WL is not associated with increased appetite. However, hunger feelings and AG concentrations increase significantly from baseline, once refeeding occurs.

Topics: Adult; Appetite Regulation; Area Under Curve; Body Mass Index; Cholecystokinin; Diet, Ketogenic; Fasting; Female; Ghrelin; Glucagon-Like Peptide 1; Humans; Hunger; Longitudinal Studies; Male; Middle Aged; Norway; Obesity; Peptide YY; Postprandial Period; Satiety Response; Time Factors; Weight Loss

Systemic inflammation, which can be induced by metabolic endotoxemia, and corresponding high‑fat diet‑mediated metabolic disorders are associated with gut microbiota. In the present study reverse transcription-polymerase chain reaction, immunofluorescence, pyrosequencing, ELISA and Oil Red O staining were performed to assess whether berberine can protect against diet-induced obesity, through modulating the gut microbiota and consequently improving metabolic endotoxemia and gastrointestinal hormone levels. Alterations in the gut microbiota induced by berberine resulted in a significant reduction in bacterial lipopolysaccharide levels in portal plasma. Levels of inflammatory and oxidative stress markers, as well as the mRNA expression levels of macrophage infiltration markers in visceral adipose tissue, were also reduced by berberine. Inhibition of the inflammatory response was associated with a reduction in intestinal permeability and an increase in the expression of tight junction proteins. In addition, berberine was reported to restore aberrant levels of gut hormones in the portal plasma, such as glucagon‑like peptide‑1 and ‑2, peptide YY, glucose‑dependent insulinotropic polypeptide and pancreatic polypeptide. The present findings indicated that berberine, through modulating gut microbiota, restored the gut barrier, reduced metabolic endotoxemia and systemic inflammation, and improved gut peptide levels in high‑fat diet‑fed rats. The present study suggests that berberine may be an effective therapeutic strategy for the treatment of obesity and insulin resistance.

Topics: Animals; Berberine; Dietary Fats; Endotoxemia; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Male; Obesity; Peptide YY; Rats; Rats, Sprague-Dawley

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

Topics: Animals; Anti-Obesity Agents; Dose-Response Relationship, Drug; Eating; Injections, Intravenous; Injections, Subcutaneous; Mice; Mice, Inbred C57BL; Mice, Obese; Molecular Structure; Obesity; Peptide YY; Receptors, Neuropeptide Y; Structure-Activity Relationship

Whey protein promotes weight loss and improves diabetic control, however, less is known of its bioactive components that produce such benefits. We compared the effects of normal protein (control) diet with high protein diets containing whey, or its fractions lactalbumin and lactoferrin, on energy balance and metabolism. Diet-induced obese rats were randomized to isocaloric diets: Control, Whey, Lactalbumin, Lactoferrin, or pair-fed to lactoferrin. Whey and lactalbumin produced transient hypophagia, whereas lactoferrin caused prolonged hypophagia; the hypophagia was likely due to decreased preference. Lactalbumin decreased weight and fat gain. Notably, lactoferrin produced sustained weight and fat loss, and attenuated the reduction in energy expenditure associated with calorie restriction. Lactalbumin and lactoferrin decreased plasma leptin and insulin, and lactalbumin increased peptide YY. Whey, lactalbumin and lactoferrin improved glucose clearance partly through differential upregulation of glucoregulatory transcripts in the liver and skeletal muscle. Interestingly, lactalbumin and lactoferrin decreased hepatic lipidosis partly through downregulation of lipogenic and/or upregulation of β-oxidation transcripts, and differentially modulated cecal bacterial populations. Our findings demonstrate that protein quantity and quality are important for improving energy balance. Dietary lactalbumin and lactoferrin improved energy balance and metabolism, and decreased adiposity, with the effects of lactoferrin being partly independent of caloric intake.

Topics: Adiposity; Animals; Body Weight; Diet; Energy Intake; Energy Metabolism; Insulin; Lactalbumin; Lactoferrin; Leptin; Male; Obesity; Peptide YY; Rats; Whey Proteins

The duodenal-jejunal bypass sleeve ((DJBS) or EndoBarrier Gastrointestinal Liner) induces weight loss in obese subjects and may improve glucose homeostasis in patients with type 2 diabetes (T2D). To explore the underlying mechanisms, we evaluated postprandial physiology including glucose metabolism, gut hormone secretion, gallbladder emptying, appetite and food intake in patients undergoing DJBS treatment.. A total of 10 normal glucose-tolerant (NGT) obese subjects and 9 age-, body weight- and body mass index-matched metformin-treated T2D patients underwent a liquid mixed meal test and a subsequent ad libitum meal test before implantation with DJBS and 1 week (1w) and 26 weeks (26w) after implantation.. At 26w, both groups had achieved a weight loss of 6 to 7 kg. Postprandial glucagon-like peptide-1 (GLP-1) and peptide YY responses increased at 1w and 26w, but only in T2D subjects. In contrast, glucose-dependent insulinotropic polypeptide responses were reduced only by DJBS in the NGT group. Postprandial glucose, insulin, C-peptide, glucagon, cholecystokinin and gastrin responses were unaffected by DJBS in both groups. Satiety and fullness sensations were stronger and food intake was reduced at 1w in NGT subjects; no changes in appetite measures or food intake were observed in the T2D group. No effect of DJBS on postprandial gallbladder emptying was observed, and gastric emptying was not delayed.. DJBS-induced weight loss was associated with only marginal changes in postprandial physiology, which may explain the absence of effect on postprandial glucose metabolism.

Topics: Adult; Appetite; Bariatric Surgery; Blood Glucose; Body Composition; C-Peptide; Case-Control Studies; Cholecystokinin; Comorbidity; Diabetes Mellitus, Type 2; Eating; Female; Gallbladder Emptying; Gastric Emptying; Gastric Inhibitory Polypeptide; Gastrins; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Insulin; Male; Middle Aged; Obesity; Peptide YY; Postprandial Period; Prospective Studies; Satiety Response; Treatment Outcome

Apolipoprotein A-IV (ApoA-IV) has been shown to be involved in obesity and diabetes pathogenesis in animal studies, but its role in humans is uncertain.. The objective of this study was to determine the relation of ApoA-IV with changes in glucose metabolism and weight after bariatric surgery.. University Hospital.. The patients (n = 49) included lean controls (n = 8) and patients before and after a mean of 7 months after laparoscopic adjustable gastric banding (LAGB, n = 12), laparoscopic Roux-en-Y gastric bypass (RYGB, n = 22), or laparoscopic sleeve gastrectomy (SG, n = 11). ApoA-IV and other hormone assays were performed in the fasting and the postprandial state. Pearson's correlation analyses controlled for baseline BMI and percent excess weight loss (EWL) were used to determine relationships between ApoA-IV levels and insulin resistance (HOMA-IR).. With all bariatric procedures combined, the change in ApoA-IV [533 versus 518 microg/L, P = .813] or ApoA-IV area under the curve (AUC - 1072 versus 1042, P = .939) was not significant. None of the surgeries individually affected levels of fasting or ApoA-IV AUC. Bariatric surgery resulted in a decrease in HOMA-IR (5.3 versus 2.0, P<.001). In the RYGB group, higher baseline ApoA-IV levels correlated with decrease in HOMA-IR [r = -.6, P = .008]. This relationship was independent of EWL and was not observed in the LAGB or SG group. There was no association of ApoA-IV levels with EWL, insulin secretion, Peptide-YY, or leptin levels.. Preoperative ApoA-IV levels, rather than changes in levels, positively correlate with improvements in insulin sensitivity independent of weight loss after RYGB.

Topics: Adult; Apolipoproteins A; Blood Glucose; Body Mass Index; Case-Control Studies; Diabetes Mellitus, Type 2; Fasting; Female; Gastrectomy; Gastric Bypass; Gastroplasty; Humans; Insulin Resistance; Laparoscopy; Male; Obesity; Peptide YY; Postoperative Care; Postprandial Period; Preoperative Care; Weight Loss

Topics: Fermentation; Glucagon-Like Peptide 1; Obesity; Peptide YY; Satiation; Satiety Response

Dietary supplementation with fermentable carbohydrate protects against body weight gain. Fermentation by the resident gut microbiota produces short-chain fatty acids, which act at free fatty acid receptor 2 (FFAR2). Our aim was to test the hypothesis that FFAR2 is important in regulating the beneficial effects of fermentable carbohydrate on body weight and to understand the role of gut hormones PYY and GLP-1.. Wild-type or. We provide new mechanistic insight into how fermentable carbohydrate regulates metabolism. Using mice that lack FFAR2, we demonstrate that the fermentable carbohydrate inulin acts via this receptor to drive an 87% increase in the density of cells that produce the appetite-suppressing hormone peptide YY (PYY), reduce food intake, and prevent diet-induced obesity.. Our results demonstrate that FFAR2 is predominantly involved in regulating the effects of fermentable carbohydrate on metabolism and does so, in part, by enhancing PYY cell density and release. This highlights the potential for targeting enteroendocrine cell differentiation to treat obesity.

Topics: Animals; Body Weight; Colon; Dietary Carbohydrates; Dietary Supplements; Eating; Fatty Acids, Volatile; Fermentation; Fermented Foods; Gastrointestinal Hormones; Gastrointestinal Microbiome; Glucagon-Like Peptide 1; Inulin; Male; Mice; Mice, Knockout; Obesity; Peptide YY; Receptors, Cell Surface; Weight Gain

The gastrointestinal tract, the key interface between ingested nutrients and the body, plays a critical role in regulating energy homeostasis. Gut-derived signals convey information regarding incoming nutrients to the brain, initiating changes in eating behavior and energy expenditure, to maintain energy balance. Here we review hormonal, neural, and nutrient signals emanating from the gastrointestinal tract and evidence for their role in controlling feeding behavior. Mechanistic studies that have utilized pharmacologic and/or transgenic approaches targeting an individual hormone/mediator have yielded somewhat disappointing body weight changes, often leading to the hormone/mediator in question being dismissed as a potential obesity therapy. However, the recent finding of sustained weight reduction in response to systemic administration of a long-acting analog of the gut-hormone glucagon-like peptide-1 highlights the therapeutic potential of gut-derived signals acting via nonphysiologic mechanisms. Thus, we also review therapeutics strategies being utilized or developed to leverage gastrointestinal signals in order to treat obesity.

Topics: Animals; Apolipoproteins A; Calcium-Binding Proteins; Cholecystokinin; DNA-Binding Proteins; Eating; Energy Metabolism; Enteroendocrine Cells; Gastrointestinal Hormones; Gastrointestinal Tract; Ghrelin; Glucagon-Like Peptide 1; Homeostasis; Humans; Leptin; Natriuretic Peptides; Nerve Tissue Proteins; Neurons, Afferent; Neurotensin; Nucleobindins; Obesity; Oxyntomodulin; Peptide YY; Receptors, G-Protein-Coupled

(1) The objective of this study is to analyze differences in smell-taste capacity between females in extreme weight/eating conditions (EWC) and (2) to explore the interaction between smell/taste capacity, gastric hormones, eating behavior and body mass index (BMI). The sample comprised 239 females in EWC [64 Anorexia nervosa (AN) and 80 age-matched healthy-weight controls, and 59 obese and 36 age-matched healthy-weight controls]. Smell and taste assessments were performed through "Sniffin' Sticks" and "Taste Strips," respectively. The assessment measures included the eating disorders inventory-2, the symptom check list 90-revised, and The Dutch Eating Behavior Questionnaire, as well as peptides from the gastrointestinal tract [Ghrelin, peptide YY, cholecystokinin]. Smell capacity was differentially associated across EWC groups. Smell was clearly impaired in obese participants and increased in AN (hyposmia in Obesity was 54.3 and 6.4 % in AN), but taste capacity did not vary across EWC. Ghrelin levels were significantly decreased in obese subjects and were related to smell impairment. EWC individuals showed a distinct smell profile and circulating ghrelin levels compared to controls. Smell capacity and ghrelin may act as moderators of emotional eating and BMI.

Topics: Adolescent; Adult; Anorexia Nervosa; Body Weight; Cholecystokinin; Feeding Behavior; Female; Ghrelin; Humans; Middle Aged; Obesity; Olfaction Disorders; Peptide YY; Smell; Taste; Taste Disorders; Young Adult

Our objectives were to measure plasma concentrations of glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and peptide YY (PYY) in client-owned newly diagnosed diabetic cats and nondiabetic lean or overweight cats and to determine whether circulating concentrations of these hormones differed between study groups and if they increased postprandially as seen in other species. A total of 31 cats were recruited and placed into 1 of 3 study groups: lean (body condition score 4-5 on a scale of 1-9; n = 10), overweight (body condition score 6-8; n = 11), or diabetic (n = 10). Diabetics were newly diagnosed and had not had prior insulin therapy. Preprandial (fasting) and postprandial (60 min after meal) plasma hormone and glucose concentrations were measured at baseline and 2 and 4 wk. All cats were exclusively fed a commercially available high-protein and low-carbohydrate diet commonly prescribed to feline diabetic patients for 2 wk before the 2-wk assessment and continued through the 4-wk assessment. Results showed that plasma concentrations of GLP-1, GIP, PYY, and insulin increased in general after a meal in all study groups. Plasma PYY concentrations did not differ (P > 0.10) between study groups. Diabetics had greater plasma concentrations of GLP-1 and GIP compared with the other study groups at baseline (P < 0.05), and greater preprandial and postprandial GLP-1 concentrations than lean cats at 2 and 4 wk (P < 0.05). Preprandial plasma GIP concentrations were greater in diabetics than obese and lean (P < 0.05) cats at week 4. Postprandial plasma GIP concentrations in diabetics were greater than lean (P < 0.05) at week 2 and obese and lean cats (P < 0.05) at week 4. Together, our findings suggest that diabetic status is an important determinant of circulating concentrations of GLP-1 and GIP, but not PYY, in cats. The role of GLP-1, GIP, and PYY in the pathophysiology of feline obesity and diabetes remains to be determined.

Topics: Animals; Cat Diseases; Cats; Diabetes Mellitus; Fasting; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Insulin; Obesity; Overweight; Peptide YY; Postprandial Period

To investigate the anorectic effect of L-arginine (L-Arg) in rodents.. 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.. 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.. 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.

Topics: Animals; Appetite Depressants; Arginine; Cells, Cultured; Dietary Supplements; Energy Intake; Energy Metabolism; Gastrointestinal Agents; Glucagon-Like Peptide 1; In Vitro Techniques; Injections, Intraperitoneal; Injections, Intraventricular; Intestinal Mucosa; Male; Mice, Inbred C57BL; Mice, Knockout; Obesity; Peptide YY; Random Allocation; Rats, Wistar; Receptors, G-Protein-Coupled; Weight Loss

Bitter taste receptors (T2Rs) are expressed in the mammalian gastrointestinal mucosa. In the mouse colon, T2R138 is localized to enteroendocrine cells and is upregulated by long-term high fat diet that induces obesity. The aims of this study were to test whether T2R38 expression is altered in overweight/obese (OW/OB) compared to normal weight (NW) subjects and characterize the cell types expressing T2R38, the human counterpart of mouse T2R138, in human colon. Colonic mucosal biopsies were obtained during colonoscopy from 35 healthy subjects (20 OW/OB and 15 NW) and processed for quantitative RT-PCR and immunohistochemistry using antibodies to T2R38, chromogranin A (CgA), glucagon like peptide-1 (GLP-1), cholecystokinin (CCK), or peptide YY (PYY). T2R38 mRNA levels in the colonic mucosa of OW/OB were increased (> 2 fold) compared to NW subjects but did not reach statistical significance (P = 0.06). However, the number of T2R38 immunoreactive (IR) cells was significantly increased in OW/OB vs. NW subjects (P = 0.01) and was significantly correlated with BMI values (r = 0.7557; P = 0.001). In both OW/OB and NW individuals, all T2R38-IR cells contained CgA-IR supporting they are enteroendocrine. In both groups, T2R38-IR colocalized with CCK-, GLP1- or PYY-IR. The overall CgA-IR cell population was comparable in OW/OB and NW individuals. This study shows that T2R38 is expressed in distinct populations of enteroendocrine cells in the human colonic mucosa and supports T2R38 upregulation in OW/OB subjects. T2R38 might mediate host functional responses to increased energy balance and intraluminal changes occurring in obesity, which could involve peptide release from enteroendocrine cells.

Topics: Adult; Cholecystokinin; Chromogranin A; Colon; Enteroendocrine Cells; Female; Glucagon-Like Peptide 1; Humans; Intestinal Mucosa; Male; Middle Aged; Obesity; Overweight; Peptide YY; Receptors, G-Protein-Coupled; RNA, Messenger; Young Adult

Obesity and type 2 diabetes mellitus are increasing worldwide, reaching pandemic proportions. The understanding of the role of functional restriction and gut hormones can be a beneficial tool in treating obesity and diabetes. However, the exact hormonal profiles in different metabolic states and surgical models are not known.. The HIPER-1 Study is a single-centre cross-sectional study in which 240 patients (in different metabolic states and surgical models) will receive an oral mixed-meal tolerance test (OMTT). At baseline and after 30, 60 and 120 min, peptide YY and glucagon-like peptide 1 levels and glucose and insulin sensitivity will be measured. The primary end point of the study will be the area under the glucagon-like peptide 1 and peptide YY curves after the OMTT. Secondary study end points will include examination of the difference in plasma levels of the distal ileal hormones in subjects with various health statuses and in patients who have been treated with different surgical techniques.. An independent ethics committee, the Institutional Review Board of Istanbul Sisli Kolan International Hospital, Turkey, has approved the study protocol. Dissemination will occur via publication, national and international conference presentations, and exchanges with regional, provincial and national stakeholders.. NCT02532829; Pre-results.

Topics: Adult; Blood Glucose; Case-Control Studies; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Digestive System Surgical Procedures; Female; Gastrointestinal Hormones; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Male; Middle Aged; Models, Anatomic; Obesity; Peptide YY; Prospective Studies; Research Design; Turkey

Obesity-related nonalcoholic fatty liver disease (NAFLD) is now the most common chronic liver disease. Exercise and diet are uniformly prescribed treatments for NAFLD; however, there are limited empirical data on the effects of exercise training on metabolic function in these patients. The purpose of this study was to investigate the fasting and glucose-stimulated adaptation of gut peptides to short-term aerobic exercise training in patients with NAFLD. Twenty-two obese subjects, 16 with NAFLD [body mass index (BMI), 33.2 ± 1.1 (SE) kg/m(2)] and 6 obese controls (BMI, 31.3 ± 1.2 kg/m(2)), were enrolled in a supervised aerobic exercise program (60 min/day, 85% of their heart rate maximum, for 7 days). Fasting and glucose-stimulated glucagon-like peptide-1 (GLP-17-36) and peptide tyrosine tyrosine (PYYTotal) concentrations in plasma were assessed before and after the exercise program. Initially, the NAFLD group had higher fasting PYY (NAFLD = 117 ± 18.6, control = 47.2 ± 6.4 pg/ml, P < 0.05) and GLP-1 (NAFLD = 12.4 ± 2.2, control = 6.2 ± 0.2 pg/ml, P < 0.05) and did not significantly increase GLP-1 or PYY in response to glucose ingestion. After the exercise program, fasting GLP-1 was reduced in the NAFLD group (10.7 ± 2.0 pg/ml, P < 0.05). Furthermore, exercise training led to significant increase in the acute (0-30 min) PYY and GLP-1 responses to glucose in the NAFLD group, while the total area under the glucose-stimulated GLP-1 response curve was reduced in both NAFLD and controls (P < 0.05). In summary, 7 days of vigorous aerobic exercise normalized the dynamic PYY and GLP-1 responses to nutrient stimulation and reduced the GLP-1 response in NAFLD, suggesting that exercise positively modulates gut hormone regulation in obese adults with NAFLD.

Topics: Blood Glucose; Exercise; Fasting; Female; Gastrointestinal Tract; Glucagon-Like Peptide 1; Glucose; Heart Rate; Humans; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Obesity; Peptide YY

To determine whether fasting and meal-induced appetite-regulating hormones are altered during lactation and associated with body weight retention after childbearing, we studied 24 exclusively breastfeeding women (BMI = 25.2 ± 3.6 kg/m(2)) at 4-5 weeks postpartum and 20 never-pregnant controls (BMI = 24.0 ± 3.1 kg/m(2)). Ghrelin, PYY, GLP-1, and appetite ratings were measured before/and 150 minutes after a standardized breakfast and 60 minutes after an ad libitum lunch. Body weight/composition were measured at 6 and 12 months. Fasting and area under-the-curve responses for appetite-regulating hormones did not differ between lactating and control groups; ghrelinacyl, however, tended to track higher after the standardized breakfast in lactating women and was higher (p < 0.05) after the ad libitum lunch despite a 24% higher energy intake (p < 0.05). By 12 months, lactating women lost 5.3 ± 2.2 kg (n = 18), whereas control women (n = 15) remained weight stable (p = 0.019); fifteen of the lactating women returned to within ±2.0 kg of prepregnancy weight but three retained >6.0 kg. The retainers had greater (p < 0.05) postmeal ghrelin rebound responses following breakfast. Overall these studies do not support the hypothesis that appetite-regulating hormones are altered during lactation and associated with postpartum weight retention. Altered ghrelin responses, however, deserve further exploration.

Topics: Adult; Appetite; Body Weight Maintenance; Case-Control Studies; Female; Ghrelin; Glucagon-Like Peptide 1; Humans; Lactation; Obesity; Peptide YY; Pregnancy; Puerperal Disorders

Interleukin-7 (IL-7) is a cytokine involved in energy homeostasis as demonstrated in rodents. Anorexia nervosa is characterized by restrained eating behavior despite adaptive orexigenic regulation profile including high ghrelin plasma levels. Constitutional thinness is a physiological condition of resistance to weight gain with physiological anorexigenic profile including high Peptide YY plasma level. Healthy obesity can be considered as a physiological state of resistance to weight loss with opposite appetite regulating profile to constitutional thinness including low Peptide YY plasma level. No studies in IL-7 are yet available in those populations. Therefore we evaluated circadian plasma levels of IL-7 in anorexia nervosa compared to constitutional thinness, healthy obese and control females.. 10 restrictive-type anorexia nervosa women, 5 bingeing/purging anorexia nervosa woman, 5 recovered restrictive anorexia nervosa women, 4 bulimic females, 10 constitutional thinness women, 7 healthy obese females, and 10 normal weight women controls were enrolled in this cross-sectional study, performed in endocrinology unit and academic laboratory. Twelve-point circadian profiles of plasma IL-7 levels were measured in each subject.. 24h mean IL-7 plasma levels (pg/ml, mean±SEM) were decreased in restrictive-type anorexia nervosa (123.4±14.4, p<0.0037), bingeing/purging anorexia nervosa (24.2±5.6, p<0.001), recovered restrictive anorexia nervosa (64.2±16.1, p = 0.01) and healthy obese patients (51±3.2, p<0.001) compared to controls (187.7±28.6). Bulimic patients (197.4±42.7) and constitutional thinness patients (264.3±35.8) were similar to controls.. Low IL-7 is part of the adaptive profile in restrictive-type anorexia nervosa, confirming its difference with constitutional thinness. Healthy obesity, with low IL-7, is once again in mirror image of constitutional thinness with normal high IL-7.

Topics: Adult; Anorexia Nervosa; Body Composition; Cross-Sectional Studies; Female; Ghrelin; Humans; Interleukin-7; Obesity; Peptide YY; Thinness; Young Adult

Improved appetite control, possibly mediated by exaggerated gut peptide responses to eating, may contribute to weight loss after Roux-en-Y gastric bypass (RYGB). This study compared brain responses to food ingestion between post-RYGB (RYGB), normal weight (NW), and obese (Ob) unoperated subjects and explored the role of gut peptide responses in RYGB.. Neuroimaging with [(18)F]-fluorodeoxyglucose (FDG) positron emission tomography was performed in 12 NW, 21 Ob, and 9 RYGB (18 ± 13 months postsurgery) subjects after an overnight fast, once FED (400 kcal mixed meal), and once FASTED, in random order. RYGB subjects repeated the studies with somatostatin infusion and basal insulin replacement. Fullness, sickness, and postscan ad libitum meal consumption were measured. Regional brain FDG uptake was compared using statistical parametric mapping.. RYGB subjects had higher overall fullness and food-induced sickness and lower ad libitum consumption. Brain responses to eating differed in the hypothalamus and pituitary (exaggerated activation in RYGB), left medial orbital cortex (OC) (activation in RYGB, deactivation in NW), right dorsolateral frontal cortex (deactivation in RYGB and NW, absent in Ob), and regions mapping to the default mode network (exaggerated deactivation in RYGB). Somatostatin in RYGB reduced postprandial gut peptide responses, sickness, and medial OC activation.. RYGB induces weight loss by augmenting normal brain responses to eating in energy balance regions, restoring lost inhibitory control, and altering hedonic responses. Altered postprandial gut peptide responses primarily mediate changes in food-induced sickness and OC responses, likely to associate with food avoidance.

Topics: Adult; Body Mass Index; Brain; Eating; Female; Fluorodeoxyglucose F18; Gastric Bypass; Glucagon-Like Peptide 1; Humans; Hypothalamus; Insulin; Magnetic Resonance Imaging; Male; Middle Aged; Neuroimaging; Obesity; Peptide YY; Postprandial Period; Somatostatin; Young Adult

Lesions of hypothalamus or adjacent brain structures by the craniopharyngioma (CP) and/or its treatment, as well as changes in orexigenic and anorexigenic hormones, are possible pathogenic factors for the obesity observed in CP patients. This study assessed anthropometric measurements, food intake, and biochemical markers of CP patients.. Weight, height, skinfold thicknesses, circumferences, body composition, food intake evaluation, basal glucose, lipids, insulin, ghrelin, PYY, and HOMA-IR calculation were obtained from CP children (n = 10, 4F, aged 12 ± 4.2yr) and CP adults (n = 27,13F aged 42 ± 13 yr) and from 32 gender and age matched controls.. Overweight/obesity was observed in 51.4% of the patients at the diagnosis and increased to 86.5% at the time of the study. Obesity was more frequent in patients with grade 2 hypothalamic involvement. Most anthropometric measurements were similar in patients and controls. Caloric intake was lower in CP adults, without difference between children. Lipid intake was higher in CP patients. Carbohydrate and protein intakes were lower in CP children, with no difference between adult groups. There were no differences in micronutrients intake as well as in insulin and PYY levels, and HOMA-IR between patients and controls. HDL-c was lower in CP adults and ghrelin higher in CP children.. There is a high rate of overweight/obesity in CP patients at the diagnosis and throughout the follow-up period. Obesity was associated with degree of hypothalamic involvement but not with caloric intake. Obesity and a lipid rich diet may have contributed to the dyslipidemia observed in CP patients.

Topics: Adolescent; Adult; Anthropometry; Biomarkers; Blood Glucose; Body Composition; Case-Control Studies; Child; Craniopharyngioma; Dyslipidemias; Eating; Energy Intake; Female; Ghrelin; Humans; Hypothalamus; Insulin; Lipids; Male; Middle Aged; Nutritional Status; Obesity; Peptide Hormones; Peptide YY; Pituitary Neoplasms; Time Factors; Young Adult

The aim of this study was to investigate effects and mechanisms of chronic electrical stimulation at acupoints (CEA) using surgically implanted electrodes on food intake, body weight, and metabolisms in diet-induced obese (DIO) rats.. Thirty-six DIO rats were chronically implanted with electrodes at acupoints ST-36 (Zusanli). Three sets of parameters were tested: electrical acupuncture (EA) 1 (2-s on, 3-s off, 0.5 ms, 15 Hz, 6 mA), EA2 (same as EA1 but continuous pulses), and EA3 (same as EA2 but 10 mA). A chronic study was then performed to investigate the effects of CEA on body weight and mechanisms involving gastrointestinal hormones and autonomic functions.. EA2 significantly reduced food intake without uncomfortable behaviors. CEA at EA2 reduced body weight and epididymal fat pad weight (P < 0.05). CEA reduced both postprandial blood glucose and HbA1c (P < 0.05). CEA delayed gastric emptying (P < 0.03) and increased small intestinal transit (P < 0.02). CEA increased fasting plasma level of glucagon-like peptide-1 (GLP-1) and peptide YY (P < 0.05); the increase of GLP-1 was inversely correlated with postprandial blood glucose (R (2) = 0.89, P < 0.05); and the plasma ghrelin level remained unchanged. EA increased sympathetic activity (P < 0.01) and reduced vagal activity (P < 0.01).. CEA at ST-36 reduces body weight and improves blood glucose possibly attributed to multiple mechanisms involving gastrointestinal motility and hormones via the autonomic pathway.

Topics: Acupuncture Points; Animals; Autonomic Nervous System; Blood Glucose; Body Weight; Eating; Electric Stimulation Therapy; Fasting; Gastrointestinal Motility; Ghrelin; Glucagon-Like Peptide 1; Male; Obesity; Obesity, Morbid; Peptide YY; Postprandial Period; Rats; Rats, Sprague-Dawley; Vagus Nerve

The microbial community populating the human digestive tract has been linked to the development of obesity, diabetes and liver diseases. Proposed mechanisms on how the gut microbiota could contribute to obesity and metabolic diseases include: (1) improved energy extraction from diet by the conversion of dietary fibre to SCFA; (2) increased intestinal permeability for bacterial lipopolysaccharides (LPS) in response to the consumption of high-fat diets resulting in an elevated systemic LPS level and low-grade inflammation. Animal studies indicate differences in the physiologic effects of fermentable and non-fermentable dietary fibres as well as differences in long- and short-term effects of fermentable dietary fibre. The human intestinal microbiome is enriched in genes involved in the degradation of indigestible polysaccharides. The extent to which dietary fibres are fermented and in which molar ratio SCFA are formed depends on their physicochemical properties and on the individual microbiome. Acetate and propionate play an important role in lipid and glucose metabolism. Acetate serves as a substrate for de novo lipogenesis in liver, whereas propionate can be utilised for gluconeogenesis. The conversion of fermentable dietary fibre to SCFA provides additional energy to the host which could promote obesity. However, epidemiologic studies indicate that diets rich in fibre rather prevent than promote obesity development. This may be due to the fact that SCFA are also ligands of free fatty acid receptors (FFAR). Activation of FFAR leads to an increased expression and secretion of enteroendocrine hormones such as glucagon-like-peptide 1 or peptide YY which cause satiety. In conclusion, the role of SCFA in host energy balance needs to be re-evaluated.

Topics: Animals; Dietary Fiber; Energy Metabolism; Fatty Acids, Volatile; Gastrointestinal Microbiome; Glucagon-Like Peptide 1; Glucose; Humans; Incretins; Inflammation; Intestinal Mucosa; Intestines; Lipid Metabolism; Lipopolysaccharides; Obesity; Peptide YY; Permeability; Satiation

The majority of weight loss studies fail to standardize conditions such as diet and exercise via a weight maintenance period prior to commencement of the trial. This study aimed to determine whether a weight stabilization period is necessary to establish stable baseline hormone concentrations. Fifty-one obese male participants with a body mass index of 30-40 kg m(-2) and aged 25-54 years underwent 4 weeks on an energy balance diet that was designed to achieve weight stability. Blood samples were collected in the fasting state at commencement and completion of the 4-week period, and circulating concentrations of 18 commonly measured hormones were determined. During the 4-week weight maintenance period, participants achieved weight stability within -1.5 ± 0.2 kg (-1.4 ± 0.2%) of their initial body weight. Significant reductions in serum insulin (by 18 ± 6.5%) and leptin (by 21 ± 6.0%) levels occurred, but no significant changes were observed for gut-derived appetite-regulating hormones (ghrelin and peptide YY), nor thyroid, adrenal, gonadal or somatotropic hormones. There were no significant correlations between the change in body weight and the change in circulating concentrations of insulin or leptin over the 4-week period, indicating that the observed changes were not due to weight loss, albeit significant negative correlations were observed between the changes in body weight and plasma ghrelin and peptide YY levels. This study demonstrates the need for baseline weight maintenance periods to stabilize serum levels of insulin and leptin in studies specifically investigating effects on these parameters in the obese. However, this does not apply to circulating levels of gut-derived appetite-regulating hormones (ghrelin and peptide YY), nor thyroid, adrenal, gonadal or somatotropic hormones.

Topics: Adult; Clinical Trials as Topic; Diet; Energy Metabolism; Ghrelin; Hormones; Humans; Insulin; Leptin; Male; Middle Aged; Obesity; Peptide YY; Research Design; Weight Loss

To identify metabolic factors controlling appetite and insulin sensitivity in PWS and assess effects of GH treatment.. We compared amino acids, fatty acids and acylcarnitines in GH-treated and untreated PWS children and obese and lean controls to identify biomarkers associated with ghrelin, peptide YY and markers of insulin sensitivity (adiponectin and HOMA-IR).. Compared with obese controls (OC), children with PWS had fasting hyperghrelinaemia, hyperadiponectinaemia, hypoinsulinaemia and increased ghrelin/PYY. Hyperghrelinaemia, hyperadiponectinaemia and hypoinsulinaemia were more striking in PWS females than males, and decreases in BCAA were detected only in PWS females. GH-treated PWS subjects had lower leptin and higher IGF-1 and adiponectin than untreated subjects; fasting ghrelin, PYY and insulin levels were comparable. Ghrelin correlated inversely with BCAA in PWS but not OC. Adiponectin correlated negatively with BMIz and HOMA-IR in PWS; in contrast, adiponectin correlated more strongly with BCAA than BMIz or HOMA-IR in OC.. BCAA levels were lower in PWS females than OC females and correlated inversely with ghrelin. Low BCAA in PWS females may promote hyperghrelinaemia and hyperphagia, while hyperadiponectinaemia may maintain insulin sensitivity despite excess weight gain. GH treatment may reduce leptin and increase adiponectin, but does not affect fasting ghrelin or PYY.

Topics: Adiponectin; Adolescent; Child; Fasting; Female; Ghrelin; Growth Hormone; Humans; Insulin; Leptin; Male; Obesity; Peptide YY; Prader-Willi Syndrome

Topics: Exercise; Female; Humans; Hunger; Leptin; Obesity; Peptide Fragments; Peptide YY

Monoacylglycerol acyltransferase 2 (MGAT2) plays an important role in intestinal fat absorption. We discovered the novel MGAT2 inhibitor, JTP-103237, and evaluated its pharmacological profile. JTP-103237 selectively inhibited MGAT2 without remarkable species differences and reduced absorbed lipids in circulation. After lipid administration, JTP-103237 slightly but significantly decreased triglyceride content in proximal small intestine and significantly increased the lipids content in the distal small intestine. In addition, JTP-103237 significantly increased MGAT substrate (monoacylglycerol and fatty acid) content in the small intestine. JTP-103237 increased plasma peptide YY levels after lipid loading and reduced food intake in a dietary fat-dependent manner. After chronic treatment, JTP-103237 significantly decreased body weight and increased O2 consumption in the early dark phase in high fat diet induced obese (DIO) mice. Moreover, JTP-103237 improved glucose tolerance and decreased fat weight and hepatic triglyceride content in DIO mice. Our findings indicate that JTP-103237 prevents diet-induced obesity by inhibiting intestinal MGAT2 and has unique properties as a drug for the treatment of obesity.

Topics: Acyltransferases; Animals; Body Weight; Chlorocebus aethiops; COS Cells; Diet, High-Fat; Eating; Glucose Tolerance Test; Humans; Intestinal Absorption; Lipid Metabolism; Male; Mice; Obesity; Oxygen Consumption; Peptide YY; Piperazines; Rats; Triazoles

The hydrophilic peptide YY (PYY) is a promising hormone-based antiobesity drug. We present a new concept for the delivery of PYY from pH-responsive chitosan-based nanocarriers. To overcome the drawbacks while retaining the merits of the polyelectrolyte complex (PEC) method, we propose a one-pot approach for the encapsulation of a hydrophilic peptide drug in cross-linked PEC nanocarriers. First, the hydrophilic peptide is encapsulated via polyelectrolyte complexation within water-in-oil miniemulsion droplets. In a second step, the PEC surface is reinforced by controlled interfacial cross-linking. PYY is efficiently encapsulated and released upon pH change. Such nanocarriers are promising candidates for the fight against obesity and, in general, for the oral delivery of protein drugs.

Topics: Alginates; Chitosan; Drug Carriers; Electrolytes; Hexuronic Acids; Humans; Hydrophobic and Hydrophilic Interactions; Obesity; Peptide YY; Polymers

Free fatty acid receptor 2 (FFA2) is expressed on enteroendocrine L cells that release glucagon-like peptide 1 (GLP-1) and peptide YY (PYY) when activated by short-chain fatty acids (SCFAs). Functionally GLP-1 and PYY inhibit gut transit, increase glucose tolerance, and suppress appetite; thus, FFA2 has therapeutic potential for type 2 diabetes and obesity. However, FFA2-selective agonists have not been characterized in vivo. Compound 1 (Cpd 1), a potent FFA2 agonist, was tested for its activity on the following: GLP-1 release, modulation of intestinal mucosal ion transport and transit in wild-type (WT) and FFA2(-/-) tissue, and food intake and glucose tolerance in lean and diet-induced obese (DIO) mice. Cpd 1 stimulated GLP-1 secretion in vivo, but this effect was only detected with dipeptidyl peptidase IV inhibition, while mucosal responses were PYY, not GLP-1, mediated. Gut transit was faster in FFA2(-/-) mice, while Cpd 1 slowed WT transit and reduced food intake and body weight in DIO mice. Cpd 1 decreased glucose tolerance and suppressed plasma insulin in lean and DIO mice, despite FFA2(-/-) mice displaying impaired glucose tolerance. These results suggest that FFA2 inhibits intestinal functions and suppresses food intake via PYY pathways, with limited GLP-1 contribution. Thus, FFA2 may be an effective therapeutic target for obesity but not for type 2 diabetes.

Topics: Animals; Appetite; Cells, Cultured; Eating; Gastrointestinal Transit; Glucagon-Like Peptide 1; Glucose Intolerance; Intestinal Mucosa; Intestines; Mice; Mice, Obese; Obesity; Peptide YY; Receptors, Cell Surface

Unlike rats and mice, hamsters develop hypercholesterolemia, and hypertriglyceridemia when fed a cholesterol-rich diet. Because hyperlipidemia is a hallmark of human obesity, we aimed to develop and characterize a novel diet-induced obesity (DIO) and hypercholesterolemia Golden Syrian hamster model.. Hamsters fed a highly palatable fat- and sugar-rich diet (HPFS) for 12 weeks showed significant body weight gain, body fat accumulation and impaired glucose tolerance. Cholesterol supplementation to the diet evoked additional hypercholesterolemia. Chronic treatment with the GLP-1 analogue, liraglutide (0.2 mg/kg, SC, BID, 27 days), normalized body weight and glucose tolerance, and lowered blood lipids in the DIO-hamster. The dipeptidyl peptidase-4 (DPP-4) inhibitor, linagliptin (3.0 mg/kg, PO, QD) also improved glucose tolerance. Treatment with peptide YY3-36 (PYY3-36, 1.0 mg/kg/day) or neuromedin U (NMU, 1.5 mg/kg/day), continuously infused via a subcutaneous osmotic minipump for 14 days, reduced body weight and energy intake and changed food preference from HPFS diet towards chow. Co-treatment with liraglutide and PYY3-36 evoked a pronounced synergistic decrease in body weight and food intake with no lower plateau established. Treatment with the cholesterol uptake inhibitor ezetimibe (10 mg/kg, PO, QD) for 14 days lowered plasma total cholesterol with a more marked reduction of LDL levels, as compared to HDL, indicating additional sensitivity to cholesterol modulating drugs in the hyperlipidemic DIO-hamster. In conclusion, the features of combined obesity, impaired glucose tolerance and hypercholesterolemia in the DIO-hamster make this animal model useful for preclinical evaluation of novel anti-obesity, anti-diabetic and lipid modulating agents.

Topics: Animals; Anti-Obesity Agents; Anticholesteremic Agents; Blood Glucose; Cholesterol; Cricetinae; Diet, High-Fat; Eating; Ezetimibe; Hypoglycemic Agents; Hypolipidemic Agents; Linagliptin; Male; Mesocricetus; Neuropeptides; Obesity; Peptide Fragments; Peptide YY

This study aimed to characterise lean and obese phenotypes according to diet and body composition, and to compare fasting and postprandial appetite and metabolic profiles following a high-fat test meal. A total of ten lean (BMI40 and 30 kg/m2) high-fat consumers (OHF; >40 % energy from fat) were recruited. Before and following the test meal (4727 kJ (1130 kcal), 77 % fat, 20 % carbohydrate (CHO) and 3 % protein), fasting plasma glucose, insulin, leptin, ghrelin, peptide YY (PYY), RER, RMR and subjective appetite ratings (AR) were measured for 6 h. Thereafter, subjects consumed a self-selected portion of a standardised post-test meal (40 % fat, 45 % CHO and 15 % protein) and reported AR. Fasting (P=0·01) and postprandial (P<0·001) fat oxidation was significantly higher in LHF than in LLF but was not different between LHF and OHF. Although similar between the lean groups, fasting and postprandial energy expenditures were significantly higher in OHF compared with LHF (P<0·01). Despite similar AR across groups, LLF consumed a relatively greater quantity of the post-test meal than did LHF (7·87 (sd 2·96) v. 7·23 (sd 2·67) g/kg, P=0·013). The lean groups showed appropriate changes in plasma ghrelin and PYY following the test meal, whereas the OHF group showed a blunted response. In conclusion, the LHF phenotype had a greater capacity for fat oxidation, which may be protective against weight gain. OHF individuals had a blunted appetite hormone response to the high-fat test meal, which may subsequently increase energy intake, driving further weight gain.

Topics: Adult; Appetite; Basal Metabolism; Body Composition; Body Mass Index; Diet; Diet, High-Fat; Dietary Fats; Energy Intake; Fasting; Female; Ghrelin; Humans; Obesity; Oxidation-Reduction; Peptide YY; Phenotype; Postprandial Period; Satiation; Surveys and Questionnaires; Thinness; Weight Gain

To elucidate the specific role of gastric vs. intestinal manipulations in the regulation of body weight and glucose homeostasis.. The effects of intestinal bypass alone (duodenal-jejunal bypass -DJB) and gastric resection alone (SG) in Zucker Diabetic Fatty (ZDF) rats were compared. Additional animals underwent a combination procedure (SG + DJB). Outcome measures included changes in weight, food intake (FI), oral glucose tolerance (GT) and gut hormones.. DJB did not substantially affect weight and FI, whereas SG significantly reduced weight gain and food consumption. DJB rats showed weight-independent improvement in GT, which improved less after SG. Furthermore, SG significantly suppressed plasma ghrelin and increased insulin, glucagon like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide and peptide YY response to oral glucose whereas DJB had no effects on postprandial levels of these hormones. DJB restored postprandial glucagon suppression in diabetic rats whereas SG did not affect glucagon response. The combination procedure (SG + DJB) induced greater weight loss and better GT than SG alone without reducing food intake further.. These findings reveal a dominant role of the stomach in the regulation of body weight and incretin response to oral glucose whereas intestinal bypass primarily affects glucose homeostasis by a weight-, insulin- and incretin-independent mechanism.

Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Duodenum; Gastrectomy; Gastric Inhibitory Polypeptide; Ghrelin; Glucagon-Like Peptide 1; Glucose Tolerance Test; Homeostasis; Insulin; Jejunoileal Bypass; Jejunum; Male; Obesity; Peptide YY; Postoperative Care; Rats

Obesity is a health concern. Resistant starch (RS) type 2 from high-amylose maize (HAM-RS2) and dietary sodium butyrate (SB) reduce abdominal fat in rodents. RS treatment is associated with increased gut hormones peptide YY (PYY) and glucagon-like peptide 1 (GLP-1), but it is not known if SB increases these hormones.. This was investigated in a 2 × 2 rat study with HAM-RS2 (0 or 28% weight) and dietary sodium butyrate (0 and 3.2%) resulting in isocaloric treatments: energy control (EC), sodium butyrate (SB), HAM-RS2 (RS), and the combination (SBRS).. RS and SB reduced abdominal fat and the combination reduced abdominal fat compared to SB and RS. RS was associated with increased fermentation in the cecum. Serum PYY and GLP-1 total were increased with RS treatment. RS treatment was associated with increased cecal butyrate produced from fermentation of RS, but there was no cecal increase for dietary SB.. SB after its absorption into the blood appears to not affect production of PYY and GLP-1, while butyrate from fermentation in the cecum promotes increased PYY and GLP-1. Future studies with lower doses of RS and SB are warranted and the combination may be beneficial for human health.

Topics: Abdominal Fat; Adiposity; Amylose; Animals; Anti-Obesity Agents; Bifidobacterium; Butyric Acid; Cecum; Fermentation; Glucagon-Like Peptide 1; Intestinal Mucosa; Lactobacillales; Male; Obesity; Peptide YY; Plant Proteins; Plants, Genetically Modified; Prebiotics; Rats; Rats, Sprague-Dawley; Seeds; Starch; Zea mays

Crude extracts from ginseng demonstrated anti-obesity properties. Ginsenoside Rb1 is the main component of ginseng, however, there are only few studies examining its effects in obesity. In the present study, we evaluated its potential anti-obesity effects in the murine model of diet-induced obesity. Seventy male C57BL/6 mice were randomly divided to consume for 12 weeks either chow diet (N = 8) or high-fat (HF) diet (N = 62). The latter mice were then divided into four groups: diet-induced obesity group (DIO; N = 10), obesity-resistant group (OR; N = 10), HF group (N = 5), and the group whose diet was changed from HF to normal diet (DC; N = 5). Intraperitoneal injections of Rb-1 were administered daily to mice in the DIO and OR groups for 3 weeks. Body weight and energy intake were monitored, and fasting blood glucose, lipids, neuropeptide Y, Y2 receptor, and peptide YY were quantified. Compared with HF group, weight gain and food intake of DIO mice with Rb-1 injection was significantly decreased (p < 0.05). Further, levels of blood glucose and some lipids were also decreased in DIO-Rb1 group compared with HF group. Furthermore, Rb1 was also found to modulate serum levels of PYY and NPY, and mRNA expression of NPY, Y2 receptor and PYY in tissue samples of DIO mice. Taken together, ginsenoside Rb1 may be useful in the treatment of obesity via modifying the serum content and mRNA expression of NPY, Y2 receptor and PYY.

Topics: Animals; Blood Glucose; Body Weight; Diet; Diet, High-Fat; Drug Administration Schedule; Ginsenosides; Injections, Intraperitoneal; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Neuropeptide Y; Obesity; Panax; Peptide YY; Receptors, Neuropeptide Y

Short-term exercise training improves glycemic control, but the effect of short-term training on postprandial satiety peptide responses or perceived satiety remains unknown. We tested the hypothesis that short-term aerobic exercise training (15 days) would alter postprandial pancreatic and gut peptide (pancreatic polypeptide (PP) and peptide YY (PYY)) responses and perceived appetite and satiety in obese individuals.. Thirteen healthy obese men and women (age: 42±2 years; body mass index: 30-45 kg m(-2)).. Subjects were studied before and after 15 days of training (walking 1 h at 70-75% VO(2peak)). On the study day, subjects consumed 1500 kcal as six meals (250 kcal: 9 g protein, 40 g carbohydrate, 6 g fat), while blood samples and satiety measurements were taken at baseline and every 20 min for 12 h. Blood was analyzed for PP, PYY, glucose and insulin levels. Appetite and satiety was assessed with a visual analog scale throughout the day.. Incremental area under the curve (iAUC) for PP increased significantly with training (pre: 2788±753; post: 3845±830 pg ml(-1)·per min for 12 h; P<0.001), but there was no difference in the PP response to each meal. The initial PP response to the first meal increased (ΔPP(min 20-0): pre 86±25; post 140±36 pg ml(-1); P<0.05) with training. PYY iAUC showed no significant changes with training but showed a significant main effect of time across meals, with the largest response being to the first meal (P<0.005). There were no changes in satiety, glucose or insulin levels with training.. Short-term exercise training increases postprandial PP concentrations in obese individuals; however, PYY levels and glycemic control remain unaffected. Both PP and PYY show meal-induced increases at all meals, but PYY has a greater response at the first meal with reduced responses at subsequent meals.

Topics: Adult; Appetite; Area Under Curve; Blood Glucose; Body Mass Index; Energy Intake; Exercise; Female; Humans; Insulin; Male; Obesity; Pancreatic Polypeptide; Peptide YY; Postprandial Period; Satiation; Time Factors

To evaluate the foregut and hindgut hypotheses for metabolic surgery in obese rats with diabetes.. Otsuka Long-Evans Tokushima fatty rats were divided into a sham operation group, a partial duodeno-jejunal bypass (P-DJB) group, and a complete DJB (C-DJB) group. P-DJB is a model to test foregut hypothesis, whereas C-DJB is a model to test both hypotheses. We performed oral glucose tolerance tests (OGTT) on all groups at baseline, and then 4 and 8 weeks postoperatively. The rats were killed thereafter and the plasma levels of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) were measured. A separate sub-group of C-DJB rats underwent OGTT after treatment with the GLP-1 antagonist, the PYY antagonist, or saline.. Marked improvement of the blood glucose control during the OGTT was noted 8 weeks after C-DJB, but not 8 weeks after P-DJB or the sham operation. The serum GLP-1 and PYY levels were higher in the C-DJB group than in the other two groups. Pretreatment with the GLP-1 antagonist increased the blood glucose levels 30 min after the OGTT in the C-DJB rats.. Improvement in glucose metabolism after DJB was associated with the inflow of bile and pancreatic juice into the ileum, supporting validity of the hindgut hypothesis. GLP-1 appears to play a role in this improvement.

Topics: Animals; Bariatric Surgery; Bile; Blood Glucose; Diabetes Mellitus, Type 2; Duodenum; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; Ileum; Jejunum; Male; Obesity; Pancreatic Juice; Peptide YY; Rats; Rats, Inbred OLETF

The significant weight loss observed with combination naltrexone-sustained release (SR) 32 mg and bupropion SR 360 mg (NB32) therapy is thought to be due, in part, to bupropion stimulation of hypothalamic pro-opiomelanocortin (POMC) neurons, and naltrexone blockade of opioid receptor-mediated POMC autoinhibition, but the neurobiological mechanisms are not fully understood. We assessed changes in brain reactivity to food cues before and after NB32 treatment.. Forty women (31.1±8.1 years; body mass index: 32.5±3.9) received 4 weeks of NB32 or placebo, and were instructed to maintain their dietary and exercise habits. Functional magnetic resonance imaging responses (analyzed using SPM2 and clusters (>100 pixels)) to a 5-min food video (preparation of the subject's favorite food) and a 5-min neutral video (manipulation of neutral objects) under conditions of mild food deprivation (∼14 h) were assessed before and after treatment.. The food cues video induced positive brain activation in visual and prefrontal cortices, insula and subcortical brain regions. The group-by-treatment interaction on regional brain activation was significant and showed that whereas NB32 attenuated the activation in the hypothalamus in response to food cues (P<0.01), it enhanced activation in regions involved in inhibitory control (anterior cingulate), internal awareness (superior frontal, insula, superior parietal) and memory (hippocampal) regions (whole-brain analysis; P<0.05).. Blunting the hypothalamic reactivity to food cues while enhancing the activation of regions involved with self-control and internal awareness by NB32 might underlie its therapeutic benefits in obesity.

Topics: Adolescent; Adult; Appetite; Bupropion; Cues; Diet; Dopamine Uptake Inhibitors; Drug Therapy, Combination; Female; Ghrelin; Humans; Hypothalamus; Leptin; Magnetic Resonance Imaging; Meals; Naltrexone; Obesity; Peptide YY; Treatment Outcome; Weight Loss

Roux-en-Y gastric bypass (RYGB) has greater efficacy for weight loss in obese patients than gastric banding (BAND) surgery. We hypothesise that this may result from different effects on food hedonics via physiological changes secondary to distinct gut anatomy manipulations.. We used functional MRI, eating behaviour and hormonal phenotyping to compare body mass index (BMI)-matched unoperated controls and patients after RYGB and BAND surgery for obesity.. Obese patients after RYGB had lower brain-hedonic responses to food than patients after BAND surgery. RYGB patients had lower activation than BAND patients in brain reward systems, particularly to high-calorie foods, including the orbitofrontal cortex, amygdala, caudate nucleus, nucleus accumbens and hippocampus. This was associated with lower palatability and appeal of high-calorie foods and healthier eating behaviour, including less fat intake, in RYGB compared with BAND patients and/or BMI-matched unoperated controls. These differences were not explicable by differences in hunger or psychological traits between the surgical groups, but anorexigenic plasma gut hormones (GLP-1 and PYY), plasma bile acids and symptoms of dumping syndrome were increased in RYGB patients.. The identification of these differences in food hedonic responses as a result of altered gut anatomy/physiology provides a novel explanation for the more favourable long-term weight loss seen after RYGB than after BAND surgery, highlighting the importance of the gut-brain axis in the control of reward-based eating behaviour.

Topics: Adult; Appetite Regulation; Bile Acids and Salts; Body Mass Index; Brain; Diet Records; Dumping Syndrome; Feeding Behavior; Female; Food; Gastric Bypass; Gastroplasty; Glucagon-Like Peptide 1; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Obesity; Peptide YY; Pleasure; Young Adult

Intestinal nutrient infusions result in variable decreases in food intake and body weight based on the nutrient type and the specific intestinal infusion site. We previously found that intrajejunal infusions of a fatty acid and glucose, but not casein hydrolysate, decreases food intake and body weight in lean chow-fed laboratory rats. To test whether obese, high fat-fed animals would show similar decreases in food intake and body weight in response to intrajejunal infusions of the same nutrients, equal kilocalorie loads of these nutrients (11.4 kcal) or vehicle were infused into the jejunum of obese, high fat-fed male Sprague-Dawley rats over 7 h/day for 5 consecutive days. Food intake was continuously monitored, and body weight was measured daily. After the infusion on the final day, rats were killed and plasma was collected. Similar to lean chow-fed rats, intrajejunal infusions of linoleic acid (LA) and glucose (Glu), but not casein hydrolysate (Cas), suppressed food intake with no compensatory increase in food intake after the infusion period. In contrast to lean chow-fed rats, only the LA, and not the Glu or Cas, produced decreases in body weight in the obese high fat-fed rat. There also were no differences in plasma glucagon-like peptide-1 levels in any of the nutrient infusion groups compared with saline infusion. These results suggest that there is a differential response to the same nutrients in lean vs. obese animals.

Topics: Animals; Body Weight; Caseins; Eating; Endocrine System; Enteral Nutrition; Glucagon-Like Peptide 1; Glucose; Jejunum; Linoleic Acid; Male; Obesity; Peptide YY; Rats; Rats, Sprague-Dawley; Satiation

Patients with craniopharyngioma (CP) have disturbances of the hypothalamic-pituitary axis and serious comorbidities such as obesity. We hypothesized that the secretion of hormones regulating the nutritional status is altered in adult patients with CP compared with patients with non-functioning pituitary adenoma (NFPA).. WE INCLUDED 40 CP (50% MALES, MEAN AGE: 49.6±14.3 years) and 40 NFPA (72.5% males, mean age: 63.4±9.8 years) patients. We measured glucose, insulin, leptin, total ghrelin, peptide-YY (PYY) and cholecystokinin (CCK) during oral glucose tolerance test (OGTT). Fat mass (FM) was determined by dual X-ray absorptiometry.. Gender distribution was not significantly different, but CP patients were significantly younger (P<0.001). CP patients had significantly higher BMI and FM than NFPA patients (BMI 32±8 vs 28±4 kg/m(2), P=0.009 and FM 37±9 vs 33±9%, P=0.02). Fasting glucose level (84±12 vs 78±11 mg/dl, P=0.03), leptin (27.9±34.2 vs 11.9±11.6 μg/l, P=0.008) and leptin levels corrected for percentage FM (0.66±0.67 vs 0.32±0.25 μg/l%, P=0.005) were significantly higher in CP than in NFPA patients, whereas ghrelin was significantly lower (131±129 vs 191±119 ng/l, P=0.035). Insulin, PYY and CCK did not differ significantly between groups. After glucose load, leptin decreased significantly in CP patients (P=0.019). In both groups, ghrelin decreased significantly during OGTT (both P<0.001). The percentage decline was significantly smaller for CP. PYY and CCK increased equally after glucose in both groups.. Our patients with CP have more metabolic complications than our patients with NFPA. The levels of leptin and ghrelin at fasting status and after glucose seem to be altered in CP, whereas changes in insulin, PYY and CCK do not seem to be responsible for the metabolic changes in these patients.

Topics: Absorptiometry, Photon; Adenoma; Adult; Aged; Appetite Regulation; Blood Glucose; Body Fat Distribution; Case-Control Studies; Cholecystokinin; Craniopharyngioma; Female; Ghrelin; Glucose Tolerance Test; Humans; Insulin; Leptin; Male; Middle Aged; Obesity; Peptide YY; Pituitary Neoplasms

The combination of peptide YY (PYY) and glucagon-like peptide-1 (GLP-1) has been proposed as a potential treatment for diabetes and obesity. However, the combined effects of these hormones, PYY(3-36) and GLP-1(7-36 amide), on glucose homeostasis are unknown.. This study sought to investigate the acute effects of PYY(3-36) and GLP-1(7-36) amide, individually and in combination, on insulin secretion and sensitivity.. Using a frequently sampled iv glucose tolerance test (FSIVGTT) and minimal modeling, this study measured the effects of PYY(3-36) alone, GLP-1(7-36) amide alone, and a combination of PYY(3-36) and GLP-1(7-36) amide on acute insulin response to glucose (AIRg) and insulin sensitivity index (SI) in 14 overweight human volunteers, studied in a clinical research facility.. PYY(3-36) alone caused a small but nonsignificant increase in AIRg. GLP-1(7-36) amide alone and the combination of PYY(3-36) and GLP-1(7-36) amide did increase AIRg significantly. No significant differences in SI were observed with any intervention.. PYY(3-36) lacks any significant acute effects on first-phase insulin secretion or SI when tested using an FSIVGTT. Both GLP-1(7-36) amide alone and the combination of PYY3-36 and GLP-1(7-36) amide increase first-phase insulin secretion. There does not seem to be any additive or synergistic effect between PYY(3-36) and GLP-1(7-36) amide on first-phase insulin secretion. Neither hormone alone nor the combination had any significant effects on SI.

Topics: Adult; Blood Glucose; Female; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; Homeostasis; Humans; Insulin; Insulin Resistance; Male; Middle Aged; Obesity; Overweight; Peptide Fragments; Peptide YY; Young Adult

Bayliss and Starling first coined the term 'hormone' with reference to secretin, a substance they found that was produced by the gut, but released into the blood stream to act at a distance. The intestine is now known as the largest endocrine organ in the body, and it produces numerous hormones with a wide range of functions. These include controlling appetite and energy homeostasis. Obesity is one of the greatest health threats facing the world today. At present, the only successful treatment is surgery. Bariatric procedures such as the Roux-en-Y bypass work by elevating gut hormones that induce satiety. Significant research has gone into producing versions of these hormones that can be delivered therapeutically to treat obesity. This review looks at the role of gut hormones in obesity, and the development of gut hormone-derived obesity treatments.

Topics: Animals; Appetite; Appetite Regulation; Awards and Prizes; Bariatric Surgery; Energy Metabolism; Female; Gastrointestinal Hormones; Glucagon-Like Peptide 1; Humans; Male; Obesity; Pandemics; Peptide YY; Societies, Scientific

Eating at a time when the internal circadian clock promotes sleep is a novel risk factor for weight gain and obesity, yet little is known about mechanisms by which circadian misalignment leads to metabolic dysregulation in humans. We studied 14 adults in a 6-d inpatient simulated shiftwork protocol and quantified changes in energy expenditure, macronutrient utilization, appetitive hormones, sleep, and circadian phase during day versus nightshift work. We found that total daily energy expenditure increased by ∼4% on the transition day to the first nightshift, which consisted of an afternoon nap and extended wakefulness, whereas total daily energy expenditure decreased by ∼3% on each of the second and third nightshift days, which consisted of daytime sleep followed by afternoon and nighttime wakefulness. Contrary to expectations, energy expenditure decreased by ∼12-16% during scheduled daytime sleep opportunities despite disturbed sleep. The thermic effect of feeding also decreased in response to a late dinner on the first nightshift. Total daily fat utilization increased on the first and second nightshift days, contrary to expectations, and carbohydrate and protein utilization were reduced on the second nightshift day. Ratings of hunger were decreased during nightshift days despite decreases in 24-h levels of the satiety hormones leptin and peptide-YY. Findings suggest that reduced total daily energy expenditure during nightshift schedules and reduced energy expenditure in response to dinner represent contributing mechanisms by which humans working and eating during the biological night, when the circadian clock is promoting sleep, may increase the risk of weight gain and obesity.

Topics: Adult; Analysis of Variance; Circadian Rhythm; Eating; Electromyography; Energy Metabolism; Female; Ghrelin; Humans; Leptin; Male; Melatonin; Obesity; Peptide YY; Risk Factors; Sleep; Sleep Deprivation; Sleep Stages; Time Factors; Wakefulness; Weight Gain; Work Schedule Tolerance

Adiponectin, visfatin, and omentin are adipokines involved in insulin sensitivity. This study aimed to determine interactions between these adipokines in subcutaneous and visceral fat and in serum, and their associations with clinical factors. Adiponectin was present at the highest levels in subcutaneous and visceral fat and serum. Subcutaneous adiponectin showed positive correlations with serum adiponectin and the quantitative insulin sensitivity check index (QUICKI). Serum adiponectin correlated positively with QUICKI and serum omentin-1 but negatively with body weight, BMI, and homeostasis model assessment of insulin resistance (HOMA-IR). Subcutaneous omentin correlated positively with QUICKI but negatively with waist and hip circumferences. Serum omentin-1 correlated positively with QUICKI but negatively with body weight, BMI, waist and hip circumferences, weight gain, and HOMA-IR. Serum visfatin correlated positively with serum omentin-1 and negatively with weight gain. Serum peptide YY (PYY) levels were correlated positively with subcutaneous visfatin but negatively with visceral visfatin. Positive correlations were observed between subcutaneous expression of adiponectin, visfatin, and omentin and visceral expression of these genes. Multiple linear regression analysis showed that serum adiponectin was associated with BMI and QUICKI. Serum omentin-1 could be predicted from BMI, QUICKI, and weight gain. Weight gain, serum adiponectin, omentin-1, and DBP could be used to predict serum visfatin. In conclusion, adiponectin and omentin from subcutaneous fat displayed correlations with decreased obesity and increased insulin sensitivity while visfatin showed an association with serum PYY and weight gain. The expressions of these adipokines were correlated within each type of fat but not between different fat depots.

Topics: Adiponectin; Adult; Body Mass Index; Cytokines; Gene Expression Regulation; GPI-Linked Proteins; Humans; Insulin; Insulin Resistance; Intra-Abdominal Fat; Lectins; Middle Aged; Nicotinamide Phosphoribosyltransferase; Obesity; Peptide YY; Subcutaneous Fat

This study explored the dose-dependent effect of oat cereal β-glucan on improving metabolic indexes of obesity mice. C57-Bl mice were randomized to chow diet (N) group and high fat diet group and other three doses of oat β-glucan groups (low β-glucan, medium β-glucan, and high β-glucan). Energy intake, glucose, lipids, and appetite related hormones were tested. Dose-dependent relation was observed on oat β-glucan doses and body weight change, average energy intake, total cholesterol, HDL cholesterol, plasma neural peptide Y, arcuate neural peptide Y mRNA, and arcuate neural peptide Y receptor 2 mRNA level. Oat β-glucan helped to increase plasma peptide Y-Y and intestine peptide Y-Y expression in obesity mice.

Topics: Animals; Avena; beta-Glucans; Cholesterol, HDL; Cholesterol, LDL; Diet; Energy Intake; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Peptide YY; Satiation

Diet-induced weight loss is accompanied by compensatory changes, which increase appetite and encourage weight regain. There is some evidence that ketogenic diets suppress appetite. The objective is to examine the effect of ketosis on a number of circulating factors involved in appetite regulation, following diet-induced weight loss.. Of 50 non-diabetic overweight or obese subjects who began the study, 39 completed an 8-week ketogenic very-low-energy diet (VLED), followed by 2 weeks of reintroduction of foods. Following weight loss, circulating concentrations of glucose, insulin, non-esterified fatty acids (NEFA), β-hydroxybutyrate (BHB), leptin, gastrointestinal hormones and subjective ratings of appetite were compared when subjects were ketotic, and after refeeding.. During the ketogenic VLED, subjects lost 13% of initial weight and fasting BHB increased from (mean±s.e.m.) 0.07±0.00 to 0.48±0.07 mmol/l (P<0.001). BHB fell to 0.19±0.03 mmol/l after 2 weeks of refeeding (P<0.001 compared with week 8). When participants were ketotic, the weight loss induced increase in ghrelin was suppressed. Glucose and NEFA were higher, and amylin, leptin and subjective ratings of appetite were lower at week 8 than after refeeding.. The circulating concentrations of several hormones and nutrients which influence appetite were altered after weight loss induced by a ketogenic diet, compared with after refeeding. The increase in circulating ghrelin and subjective appetite which accompany dietary weight reduction were mitigated when weight-reduced participants were ketotic.

Topics: 3-Hydroxybutyric Acid; Adult; Aged; Appetite Regulation; Body Mass Index; Caloric Restriction; Diet, Ketogenic; Fasting; Fatty Acids, Nonesterified; Female; Gastrointestinal Hormones; Ghrelin; Humans; Insulin; Islet Amyloid Polypeptide; Ketosis; Leptin; Male; Middle Aged; Obesity; Overweight; Peptide YY; Postmenopause; Weight Loss

Roux-en-Y gastric bypass (RYGB) is effective in controlling blood glucose in obese patients with type 2 diabetes (T2DM). The alterations of gut hormones involving in glucose metabolism may play an important role. Our aim was to explore the short-term effects of Billroth II gastrojejunostomy (a similar type of RYGB) on glucose metabolism and gut hormone modulations in nonobese patients with different levels of blood glucose tolerance.. Twenty one nonobese gastric cancer patients with different levels of blood glucose tolerance were submitted to Billroth II gastrojejunostomy. Among them, seven had T2DM, seven with impaired glucose tolerance (IGT) and the other seven had normal glucose tolerance (NGT). Body weight, glucose parameters, responses of plasma glucagon-like peptide-1 (GLP-1), peptide YY (PYY) and gastric inhibitory polypeptide (GIP) to 75 g glucose were measured at baseline and 3 months after surgery.. Similar weight losses were observed in all groups. Blood glucose was reduced in T2DM and IGT patients. Fasting and 30-min plasma glucose were increased significantly in NGT. GLP-1 showed insignificant alterations in all groups. PYY was evaluated in T2DM and IGT but remained unchanged in the NGT group. Decreased fasting and AUC GIP were observed in patients with T2DM; however, fasting and 30-min GIP were increased in NGT patients.. Billroth II gastrojejunostomy is effective in reducing blood glucose in nonobese patients with T2DM and IGT but could deteriorate early blood glucose in nonobese NGT in a 3-month time period. Variations of glucose and gut hormone changes in the three groups suggest a role of proximal intestine in the pathophysiology of T2DM.

Topics: Adult; Aged; Area Under Curve; Blood Glucose; Diabetes Mellitus, Type 2; Female; Gastric Bypass; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose Intolerance; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Insulin; Male; Middle Aged; Obesity; Peptide YY; Postoperative Period; Stomach Neoplasms; Weight Loss

Relatively little is known about changes in eating behavior or hormonal responses to food after bariatric surgery in adolescents.. This study compared eating behavior and hormones among adolescents in a bariatric surgery program with those in nonoverweight control adolescents and evaluated changes before and after laparoscopic adjustable gastric banding (LAGB).. Fasting leptin, peptide YY (PYY), and ghrelin concentrations were obtained, and postprandial ghrelin and PYY area under the curve (AUC) were assessed after a single-item breakfast. Intake from an ad libitum lunchtime multi-item meal was measured.. Compared with controls (n = 9), all presurgical candidates (n = 20) had significantly greater fasting leptin, lower fasting ghrelin, and lower AUC ghrelin but similar PYY and AUC PYY. Preoperative candidates did not differ from controls in total energy consumed during the test meal. Postoperatively, among the 11 participants with data both before and after surgery, BMI (in kg/m(2)) decreased by 3.5 (P < 0.001), significantly less energy was consumed in the test meal, and a smaller number of foods were selected. AUC ghrelin and PYY did not significantly change before or after LAGB.. Few significant short-term changes were observed in appetitive hormones after LAGB. It is unclear whether objective measures of eating behavior will prove useful in evaluating the impact of bariatric surgery on outcomes. This trial was registered at clinicaltrials.gov as CT00764127.

Topics: Adolescent; Area Under Curve; Bariatric Surgery; Case-Control Studies; Fasting; Feeding Behavior; Female; Ghrelin; Humans; Laparoscopy; Leptin; Male; Meals; Obesity; Peptide YY; Postprandial Period; Prospective Studies; Surveys and Questionnaires

Reducing dietary energy density (ED) promotes weight loss; however, underlying mechanisms are not well understood. The purpose of this study was to determine if low-ED diets facilitate weight loss through actions on ghrelin and peptide YY (PYY), independent of influences of psychosocial measures. Seventy-one obese women (BMI 30-40 kg/m(2)) ages 22-60 years received counseling to reduce ED. Fasting blood samples were analyzed for total ghrelin and total PYY by radioimmunoassay at months 0, 3, 6, and 12. Restraint, disinhibition, and hunger were assessed by the Eating Inventory. Body weight (-7.8 ± 0.5 kg), BMI (-2.9 ± 0.2 kg/m(2)), body fat (-3.0 ± 0.3%), and ED (-0.47 ± 0.05 kcal/g or -1.97 ± 0.21 kJ/g) decreased from months 0 to 6 (p<0.05) after which no change occurred from months 6 to 12. Ghrelin increased in a curvilinear fashion (month 0: 973 ± 39, month 3: 1024 ± 37, month 6: 1109 ± 44, and month 12: 1063 ± 45 pg/ml, p<0.001) and PYY increased linearly (month 0: 74.2 ± 3.1, month 3: 76.4 ± 3.2, month 6: 77.2 ± 3.0, month 12: 82.8 ± 3.2 pg/ml, p<0.001). ED, body weight, and hunger predicted ghrelin, with ED being the strongest predictor (ghrelin = 2674.8+291.6 × ED-19.2 × BW-15 × H; p<0.05). There was a trend toward a significant association between ED and PYY (PYY = 115.0-43.1 × ED; p = 0.05). Reductions in ED may promote weight loss and weight loss maintenance by opposing increases in ghrelin and promoting increases in PYY.

Topics: Adult; Body Mass Index; Energy Metabolism; Female; Ghrelin; Humans; Middle Aged; Obesity; Peptide YY; Weight Loss; Young Adult

To investigate the effect of 12 weeks of aerobic (AER) compared with resistance training (RES) on perceived hunger and fullness, together with appetite-related hormones in both the fasted state and postprandially.. Thirty-three inactive, overweight and obese men (age 49±7 years; BMI 30.8±4.2 kg/m(2)) were allocated to either AER exercise (n=12), RES exercise (n=13) or a control group (CON; n=8). AER and RES completed 12 weeks of training (3 sessions per week), while CON continued their sedentary routine. Perceived hunger and fullness, together with appetite-related hormones (active ghrelin, leptin, insulin, pancreatic polypeptide (PP), and peptide tyrosine tyrosine (PYY)) were assessed pre and post-intervention in the fasted state and in response to oral glucose consumption (1284 kJ; 75 g carbohydrate).. Both AER and RES training elicited a decrease in fat mass (p<0.05), while CON did not. There was no difference in perceived hunger either in the fasted state (p>0.05) or in response to caloric consumption (p>0.05) following the intervention in any group. In contrast, both fasting and postprandial perceived fullness was higher following AER exercise (p<0.05), but not RES exercise or CON. These observations were not associated with alterations in fasting or postprandial active ghrelin, PP or PYY, although fasting and postprandial leptin was reduced following both AER and RES training (p<0.05).. Aerobic exercise training is associated with an increase in satiety, while an equivalent period of resistance training is not.

Topics: Exercise; Fasting; Ghrelin; Glucose Tolerance Test; Humans; Insulin; Leptin; Male; Middle Aged; Obesity; Pancreatic Polypeptide; Peptide YY; Postprandial Period; Resistance Training; Satiation; Sedentary Behavior

Glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), secreted by enteroendocrine L-cells located most densely in the colon and rectum, are of fundamental importance in blood glucose and appetite regulation. In animal models, colonic administration of bile acids can stimulate GLP-1 and PYY by TGR5 receptor activation. We evaluated the effects of taurocholic acid (TCA), administered as an enema, on plasma GLP-1 and PYY, as well as gastrointestinal sensations in 10 healthy male subjects, and observed that rectal administration of TCA promptly stimulated secretion of both GLP-1 and PYY, and increased fullness, in a dose-dependent manner. These observations confirm that topical application of bile acids to the distal gut may have potential for the management of type 2 diabetes and obesity.

Topics: Administration, Rectal; Adult; Appetite Regulation; Blood Glucose; Body Mass Index; Cholagogues and Choleretics; Diabetes Mellitus, Type 2; Enema; Glucagon-Like Peptide 1; Humans; Male; Obesity; Peptide YY; Taurocholic Acid; Treatment Outcome

Eating slowly increases the postprandial responses of some anorexigenic gut hormones in healthy lean subjects. As the rate of food intake is positively associated with obesity, the aim of the study was to determine whether eating the same meal at different rates evokes different postprandial anorexigenic responses in obese adolescent and adult subjects.. Eighteen obese adolescents and adults were enrolled. A test meal was consumed on two different sessions by each subject, meal duration taking either 5  min (fast feeding) or 30  min (slow feeding). Circulating levels of glucagon-like peptide 1 (GLP1), peptide YY (PYY), glucose, insulin, and triglycerides were measured over 210  min. Visual analog scales were used to evaluate the subjective feelings of hunger and satiety.. fast feeding did not stimulate GLP1 release in obese adolescent and adults, whereas slow feeding increased circulating levels of GLP1 only in obese adolescents. Plasma PYY concentrations increased both in obese adolescents and in adults, irrespective of the eating rate, but slow feeding was more effective in stimulating PYY release in obese adolescents than in adults. simultaneously, slow feeding evoked a higher satiety only in obese adolescents compared with fast feeding but not in obese adults. in obese adolescents, slow feeding decreased hunger (only at 210 min). irrespective of the eating rate, postprandial responses of insulin and triglycerides were higher in obese adults than in obese adolescents.. Slow feeding leads to higher concentrations of anorexigenic gut peptides and favors satiety in obese adolescents, but this physiological control of food intake is lost in obese adults.

Topics: Adolescent; Adolescent Behavior; Adolescent Development; Adult; Aging; Body Mass Index; Feeding Behavior; Female; Glucagon-Like Peptide 1; Humans; Ice Cream; Intestinal Mucosa; Italy; Male; Obesity; Peptide YY; Postprandial Period; Reproducibility of Results; Satiety Response; Time Factors

Patients show an elevated postprandial satiety gut hormone release after Roux-en-Y Gastric bypass (gastric bypass). The altered gut hormone response appears to have a prominent role in the reduction of appetite and body weight (BW) after gastric bypass. Patients with insufficient BW loss after gastric bypass have an attenuated postprandial gut hormone response in comparison with patients who lost an adequate amount of BW. The effects of additional gut hormone administration after gastric bypass are unknown.. The effects of peripheral administration of peptide YY3-36 (PYY3-36; 300 nmol kg(-1)), glucagon-like peptide-1 (GLP-1) analogue Exendin-4 (20 nmol kg(-1)) and somatostatin analogue octreotide (10 μg kg(-1)) on feeding and BW were evaluated in rats after gastric bypass.. Gastric bypass rats weighed (P<0.01) and ate less on postoperative day 5 (P<0.001) and thereafter, whereas postprandial plasma PYY and GLP-1 levels were higher compared with sham-operated controls (P<0.001). Administration of both PYY3-36 and Exendin-4 led to a further decrease in food intake in bypass rats compared with saline treatment (P=0.02 and P<0.0001, respectively). Similar reduction in food intake was observed in sham rats (P=0.02 and P<0.001, respectively). Exendin-4 treatment resulted in a significant BW loss in bypass (P=0.03) and sham rats (P=0.04). Subsequent treatment with octreotide led to an increase in food intake in bypass (P=0.007), but not in sham rats (P=0.87).. Peripheral administration of PYY3-36 and Exendin-4 reduces short-term food intake, whereas octreotide increases short-term food intake in rats after gastric bypass. The endogenous gut hormone response after gastric bypass can thus potentially be further enhanced by additional exogenous therapy with pharmacological doses of gut hormones in patients with insufficient weight loss or weight regain after surgery.

Topics: Animals; Appetite Depressants; Appetite Regulation; Appetite Stimulants; Eating; Exenatide; Gastric Bypass; Glucagon-Like Peptide 1; Hypoglycemic Agents; Obesity; Octreotide; Peptide Fragments; Peptide YY; Peptides; Postoperative Period; Rats; Satiation; Venoms

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

Obesity and its associated conditions such as type 2 diabetes mellitus are major causes of morbidity and mortality. The iminosugar N-(5-adamantane-1-yl-methoxy-pentyl)-deoxynojirimycin (AMP-DNM) improves insulin sensitivity in rodent models of insulin resistance and type 2 diabetes mellitus. In the current study, we characterized the impact of AMP-DNM on substrate oxidation patterns, food intake, and body weight gain in obese mice. Eight ob/ob mice treated with 100 mg/(kg d) AMP-DNM mixed in the food and 8 control ob/ob mice were placed in metabolic cages during the first, third, and fifth week of the experiment for measurement of substrate oxidation rates, energy expenditure, activity, and food intake. Mice were killed after 6 weeks of treatment. Initiation of treatment with AMP-DNM resulted in a rapid increase in fat oxidation by 129% (P = .05), a decrease in carbohydrate oxidation by 35% (P = .01), and a reduction in food intake by approximately 26% (P < .01) compared with control mice. Treatment with AMP-DNM decreased hepatic triglyceride content by 66% (P < .01) and, in line with the elevated fat oxidation rates, increased hepatic carnitine palmitoyl transferase 1a expression. Treatment with AMP-DNM increased plasma levels of the appetite-regulating peptide YY compared with control mice. Treatment with AMP-DNM rapidly reduces food intake and increases fat oxidation, resulting in improvement of the obese phenotype. These features of AMP-DNM, together with its insulin-sensitizing capacity, make it an attractive candidate drug for the treatment of obesity and its associated metabolic derangements.

Topics: 1-Deoxynojirimycin; Adamantane; Adipose Tissue; Animals; Body Weight; Carbohydrate Metabolism; Carnitine O-Palmitoyltransferase; Eating; Ghrelin; Glucose; Imino Sugars; Liver; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Oxidation-Reduction; Peptide YY; Triglycerides; Up-Regulation; Weight Gain

The endocannabinoid system is a potential pharmacotherapy target for obesity. However, the role of this system in human food intake regulation is currently unknown.. To test whether circulating endocannabinoids might functionally respond to food intake and verify whether these orexigenic signals are deregulated in obesity alongside with anorexigenic ones, we measured plasma anandamide (AEA), 2-arachidonoylglycerol (2-AG) and peptide YY (PYY) changes in response to a meal in 12 normal-weight and 12 non-diabetic, insulin-resistant obese individuals.. Both normal-weight and obese subjects had a significant preprandial AEA peak. Postprandially, AEA levels significantly decreased in normal-weight, whereas no significant changes were observed in obese subjects. Similarly, PYY levels significantly increased in normal-weight subjects only. No meal-related changes were found for 2-AG. Postprandial AEA and PYY changes inversely correlated with waist circumference, and independently explained 20.7 and 21.3% of waist variance. Multiple regression analysis showed that postprandial AEA and PYY changes explained 34% of waist variance, with 8.2% of the variance commonly explained.. These findings suggest that AEA might be a physiological meal initiator in humans and furthermore show that postprandially AEA and PYY are concomitantly deregulated in obesity.

Topics: Adult; Appetite Regulation; Arachidonic Acids; Body Mass Index; Cannabinoid Receptor Modulators; Eating; Endocannabinoids; Female; Glycerides; Humans; Insulin Resistance; Male; Obesity; Peptide YY; Polyunsaturated Alkamides; Postprandial Period

Skipping breakfast influences cognitive performance. The aim of our study was to investigate the relationship between the variation of hormonal and metabolic postprandial parameters induced by breakfast consumption or fasting and cognitive performance in obese children.. Cross-sectional study for repeated measures. Memory and attention assessment tests, hormones and nutrient oxidation were measured before and after consuming breakfast vs fasting in 10 prepubertal obese children.. Fasting induced a significant (P<0.05) increase of the Overall Index of the Continuous Performance Test II (a global index of inattention) and the Test of Memory and Learning Word Selective Reminding (a test of verbal memory), whereas no changes were found after breakfast. Fasting was associated with a reduction of insulin and an increase in glucagon, with no changes in glucose. The increase in inattention was associated with a reduction of carbohydrate oxidation (ρ=-0.66, P<0.05). We found no difference in the area under the curve of peptide YY and glucagon-like peptide-1 after breakfast or fasting, whereas Ghrelin was significantly lower. No association between postprandial hormone variation and cognitive performance was found.. Attention and visual memory performance in the morning were reduced when the children skipped breakfast. No association was found with hormones or metabolic changes, but we did find an association with a reduction of carbohydrate oxidation. Nevertheless, these preliminary findings need confirmation in larger sample size.

Topics: Area Under Curve; Attention; Blood Glucose; Carbohydrate Metabolism; Child; Cognition; Cross-Sectional Studies; Diet; Fasting; Feeding Behavior; Ghrelin; Glucagon; Glucagon-Like Peptide 1; Humans; Insulin; Memory; Obesity; Oxidation-Reduction; Peptide YY; Postprandial Period; Verbal Learning

Topics: Animals; Appetite Depressants; Chewing Gum; Humans; Obesity; Peptide YY

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

While protein is regarded as the most satiating macronutrient, many studies have employed test meals that had very high and unsustainable protein contents. Furthermore, the comparative responses between lean and obese subjects and the relationships between energy intake suppression and gut hormone release remain unclear. We evaluated the acute effects of meals with modest variations in 1) fat, protein, and carbohydrate content and 2) protein load on gastrointestinal hormones, appetite, and subsequent energy intake in lean and obese subjects. Sixteen lean and sixteen obese men were studied on four occasions. Following a standardized breakfast, they received for lunch: 1) high-fat (HF), 2) high-protein (HP), 3) high-carbohydrate/low-protein (HC/LP), or 4) adequate-protein (AP) isocaloric test meals. Hunger, fullness, and gut hormones were measured throughout, and at t = 180 min energy intake at a buffet meal was quantified. In lean subjects, hunger was less and fullness greater following HF, HP, and AP compared with HC/LP meals, and energy intake was less following HF and HP compared with HC meals (P < 0.05). In the obese subjects, hunger was less following HP compared with HF, HC/LP, and AP meals, and energy intake was less following HP and AP compared with HF and HC meals (P < 0.05). There were no major differences in hormone responses to the meals among subject groups, but the CCK and ghrelin responses to HP and AP were sustained in both groups. In conclusion, HP meals suppress energy intake in lean and obese subjects, an effect potentially mediated by CCK and ghrelin, while obese individuals appear to be less sensitive to the satiating effects of fat.

Topics: Adolescent; Adult; Appetite; Cholecystokinin; Dietary Carbohydrates; Dietary Fats; Dietary Proteins; Energy Intake; Gastrointestinal Hormones; Ghrelin; Humans; Male; Middle Aged; Obesity; Peptide YY; Postprandial Period; Satiety Response; Young Adult

Losing weight can pose a challenge, but how to avoid putting those pounds back on can be a real struggle. A major health problem for obese people is that diseases linked to obesity, such as type 2 diabetes and cardiovascular disease, put their lives at risk, even in young individuals. Although bariatric surgery-a surgical method to reduce or modify the gastrointestinal tract-was originally envisioned for the most severe cases of obesity, evidence suggests that the benefit of this procedure may not be limited to the staggering weight loss it causes. Endogenous factors released from the gut, and modified after surgery, may explain why bariatric surgery can be beneficial for obesity-related diseases and why operated individuals successfully maintain the weight loss. In 'Bedside to Bench,' Rachel Larder and Stephen O'Rahilly peruse a human study with dieters who regained weight despite a successful diet. Appetite-regulating hormones in the gut may be responsible for this relapse in the long term. In 'Bench to Bedside,' Keval Chandarana and Rachel Batterham examine how two different methods of bariatric surgery highlight the relevance of gut-derived hormones not only in inducing sustained weight loss but also in improving glucose homeostasis. These insights may open new avenues to bypass the surgery and obtain the same results with targeted drugs.

Topics: Bariatric Surgery; Cholecystokinin; Glucagon-Like Peptide 1; Glucose; Humans; Obesity; Peptide YY; Weight Loss

Losing weight can pose a challenge, but how to avoid putting those pounds back on can be a real struggle. A major health problem for obese people is that diseases linked to obesity, such as type 2 diabetes and cardiovascular disease, put their lives at risk, even in young individuals. Although bariatric surgery-a surgical method to reduce or modify the gastrointestinal tract-was originally envisioned for the most severe cases of obesity, evidence suggests that the benefit of this procedure may not be limited to the staggering weight loss it causes. Endogenous factors released from the gut, and modified after surgery, may explain why bariatric surgery can be beneficial for obesity-related diseases and why operated individuals successfully maintain the weight loss. In 'Bedside to Bench,' Rachel Larder and Stephen O'Rahilly peruse a human study with dieters who regained weight despite a successful diet. Appetite-regulating hormones in the gut may be responsible for this relapse in the long term. In 'Bench to Bedside,' Keval Chandarana and Rachel Batterham examine how two different methods of bariatric surgery highlight the relevance of gut-derived hormones not only in inducing sustained weight loss but also in improving glucose homeostasis. These insights may open new avenues to bypass the surgery and obtain the same results with targeted drugs.

Topics: Bariatric Surgery; Diabetes Mellitus, Type 2; Gastric Bypass; Humans; Obesity; Peptide YY; Weight Loss

Peptide YY (PYY) is best known for its important role in appetite regulation, but recent pharmacological studies have suggested that PYY is also involved in regulating energy balance and glucose homeostasis. However, the mechanism behind the regulation of these parameters by PYY is less clear. Here, by utilising an inducible transgenic mouse model where PYY overexpression is induced in adult animals (PYYtg) and release of mature PYY peptides is controlled by endogenous machineries, we show that elevating PYY levels leads to reduced food intake after a 24-h fast. Furthermore, PYYtg mice, although not significantly different from WT with respect to body weight, adiposity, lean mass, physical activity or energy expenditure, exhibited a significantly increased respiratory exchange ratio (RER), indicating decreased lipid oxidation and/or increased lipogenesis. Importantly, PYYtg mice showed a 25% reduction in liver protein levels of phosphorylated acetyl-CoA carboxylase (pACC) in the absence of changes in total ACC levels compared to those of WT mice. Moreover, liver protein levels of AMP-activated kinase (AMPK) in PYYtg mice were 25% lower than those of WT mice, consistent with a reduced pACC in these mice. These data suggest that elevation of PYY levels as seen after a meal can increase lipogenic capacity, which is likely a key contributor to the increased RER seen in PYYtg mice. In addition, PYYtg mice exhibited comparable insulin tolerance and oral glucose tolerance to those of WT, but showed a trend towards decreased insulin levels in response to an oral glucose challenge, indicating that PYY could improve insulin action. Taken together, these findings demonstrate that under physiological conditions, PYY reduces food intake while enhancing lipogenic capacity and insulin action, likely contributing to fuel assimilation in the postprandial state.

Topics: Acetyl-CoA Carboxylase; Animals; Animals, Genetically Modified; Body Weight; Eating; Fasting; Glucose Tolerance Test; Homeostasis; Lipid Metabolism; Male; Mice; Obesity; Peptide YY

Glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) are secreted from enteroendocrine L cells in response to numerous stimuli, including bile salts. Both have multiple effects that are potentially useful in treating diabetes and obesity. L cell number and hormone content in the intestine are highest in the rectum in humans. We investigated the effects of intrarectal sodium taurocholate on plasma GLP-1, PYY, insulin and glucose concentrations, and on food intake of a subsequent meal.. Ten obese type 2 diabetic volunteers were each studied on five separate occasions after an overnight fast and oral administration of 100 mg sitagliptin 10 h before the study. They then received an intrarectal infusion of either one of four doses of taurocholate (0.66, 2, 6.66 or 20 mmol, each in 20 ml of vehicle) or vehicle alone (1% carboxymethyl cellulose) single-blind over 1 min. Hormone and glucose measurements were made prior to, and for 1 h following, the infusion. The consumption of a previously selected favourite meal eaten to satiety was measured 75 min after the infusion.. Taurocholate dose-dependently increased GLP-1, PYY and insulin, with 20 mmol doses resulting in peak concentrations 7.2-, 4.2- and 2.6-fold higher, respectively, than those achieved with placebo (p < 0.0001 for each). Plasma glucose decreased by up to 3.8 mmol/l (p < 0.001). Energy intake was decreased dose-dependently by up to 47% (p < 0.0001). The ED(50) values for effects on integrated GLP-1, insulin, PYY, food intake and glucose-lowering responses were 8.1, 10.5, 18.5, 24.2 and 25.1 mmol, respectively.. Therapies that increase bile salts (or their mimics) in the distal bowel may be valuable in the treatment of type 2 diabetes and obesity.

Topics: Adult; Blood Glucose; Body Mass Index; Cholagogues and Choleretics; Diabetes Mellitus, Type 2; Eating; Enteroendocrine Cells; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Secretion; Male; Middle Aged; Obesity; Peptide YY; Rectum; Taurocholic Acid; United Arab Emirates

PYY is a gut-derived putative satiety signal released in response to nutrient ingestion and is implicated in the regulation of energy homeostasis. Pyy-expressing neurons have been identified in the hindbrain of river lamprey, rodents, and primates. Despite this high evolutionary conservation, little is known about central PYY neurons. Using in situ hybridization, PYY-Cre;ROSA-EYFP mice, and immunohistochemistry, we identified PYY cell bodies in the gigantocellular reticular nucleus region of the hindbrain. PYY projections were present in the dorsal vagal complex and hypoglossal nucleus. In the hindbrain, Pyy mRNA was present at E9.5, and expression peaked at P2 and then decreased significantly by 70% at adulthood. We found that, in contrast to the circulation, PYY-(1-36) is the predominant isoform in mouse brainstem extracts in the ad libitum-fed state. However, following a 24-h fast, the relative amounts of PYY-(1-36) and PYY-(3-36) isoforms were similar. Interestingly, central Pyy expression showed nutritional regulation and decreased significantly by acute starvation, prolonged caloric restriction, and bariatric surgery (enterogastroanastomosis). Central Pyy expression correlated with body weight loss and circulating leptin and PYY concentrations. Central regulation of energy metabolism is not limited to the hypothalamus but also includes the midbrain and the brainstem. Our findings suggest a role for hindbrain PYY in the regulation of energy homeostasis and provide a starting point for further research on gigantocellular reticular nucleus PYY neurons, which will increase our understanding of the brain stem pathways in the integrated control of appetite and energy metabolism.

Topics: Animals; Bariatric Surgery; Brain Stem; Caloric Restriction; Food Deprivation; Gene Expression Regulation; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nerve Tissue Proteins; Neurons; Obesity; Organ Specificity; Peptide Fragments; Peptide YY; Random Allocation; Rhombencephalon; RNA, Messenger

Decisions about what, when and how much to eat are made by the brain, though these choices can be strongly influenced by the hedonic and rewarding properties of sweet or fatty foods. The rumbling before and the fullness after eating tells us that the gut also has an important role in the initiation and termination of feeding. Gut-derived peptides continually convey homeostatic information to the brain to guide feeding. These circulating signals can also modify the pleasure and reward associated with food.

Topics: Animals; Bariatric Surgery; Brain; Eating; Feeding Behavior; Glucagon-Like Peptide 1; Homeostasis; Humans; Molecular Targeted Therapy; Obesity; Peptide Fragments; Peptide YY; Reward

Obesity is rising at an alarming rate globally. Different fermentable carbohydrates have been shown to reduce obesity. The aim of the present study was to investigate if two different fermentable carbohydrates (inulin and β-glucan) exert similar effects on body composition and central appetite regulation in high fat fed mice.. Thirty six C57BL/6 male mice were randomized and maintained for 8 weeks on a high fat diet containing 0% (w/w) fermentable carbohydrate, 10% (w/w) inulin or 10% (w/w) β-glucan individually. Fecal and cecal microbial changes were measured using fluorescent in situ hybridization, fecal metabolic profiling was obtained by proton nuclear magnetic resonance ((1)H NMR), colonic short chain fatty acids were measured by gas chromatography, body composition and hypothalamic neuronal activation were measured using magnetic resonance imaging (MRI) and manganese enhanced MRI (MEMRI), respectively, PYY (peptide YY) concentration was determined by radioimmunoassay, adipocyte cell size and number were also measured. Both inulin and β-glucan fed groups revealed significantly lower cumulative body weight gain compared with high fat controls. Energy intake was significantly lower in β-glucan than inulin fed mice, with the latter having the greatest effect on total adipose tissue content. Both groups also showed an increase in the numbers of Bifidobacterium and Lactobacillus-Enterococcus in cecal contents as well as feces. β-Glucan appeared to have marked effects on suppressing MEMRI associated neuronal signals in the arcuate nucleus, ventromedial hypothalamus, paraventricular nucleus, periventricular nucleus and the nucleus of the tractus solitarius, suggesting a satiated state.. Although both fermentable carbohydrates are protective against increased body weight gain, the lower body fat content induced by inulin may be metabolically advantageous. β-Glucan appears to suppress neuronal activity in the hypothalamic appetite centers. Differential effects of fermentable carbohydrates open new possibilities for nutritionally targeting appetite regulation and body composition.

Topics: Adipocytes; Animals; Appetite Regulation; beta-Glucans; Bifidobacterium; Body Composition; Brain Mapping; Carbohydrates; Chromatography, Gas; Enterococcus; Fermentation; In Situ Hybridization, Fluorescence; Inulin; Lactobacillus; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Male; Mice; Mice, Inbred C57BL; Obesity; Peptide YY; Radioimmunoassay

Enteroendocrine cells such as duodenal cholecystokinin (CCK cells) are generally thought to be confined to certain segments of the gastrointestinal (GI) tract and to store and release peptides derived from only a single peptide precursor. In the current study, however, transgenic mice expressing enhanced green fluorescent protein (eGFP) under the control of the CCK promoter demonstrated a distribution pattern of CCK-eGFP positive cells that extended throughout the intestine. Quantitative PCR and liquid chromatography-mass spectrometry proteomic analyses of isolated, FACS-purified CCK-eGFP-positive cells demonstrated expression of not only CCK but also glucagon-like peptide 1 (GLP-1), gastric inhibitory peptide (GIP), peptide YY (PYY), neurotensin, and secretin, but not somatostatin. Immunohistochemistry confirmed this expression pattern. The broad coexpression phenomenon was observed both in crypts and villi as demonstrated by immunohistochemistry and FACS analysis of separated cell populations. Single-cell quantitative PCR indicated that approximately half of the duodenal CCK-eGFP cells express one peptide precursor in addition to CCK, whereas an additional smaller fraction expresses two peptide precursors in addition to CCK. The coexpression pattern was further confirmed through a cell ablation study based on expression of the human diphtheria toxin receptor under the control of the proglucagon promoter, in which activation of the receptor resulted in a marked reduction not only in GLP-1 cells, but also PYY, neurotensin, GIP, CCK, and secretin cells, whereas somatostatin cells were spared. Key elements of the coexpression pattern were confirmed by immunohistochemical double staining in human small intestine. It is concluded that a lineage of mature enteroendocrine cells have the ability to coexpress members of a group of functionally related peptides: CCK, secretin, GIP, GLP-1, PYY, and neurotensin, suggesting a potential therapeutic target for the treatment and prevention of diabetes and obesity.

Topics: Animals; Cell Lineage; Cell Separation; Cholecystokinin; Diabetes Mellitus; Enteroendocrine Cells; Flow Cytometry; Gastric Inhibitory Polypeptide; Gene Expression Regulation; Ghrelin; Glucagon-Like Peptide 1; Green Fluorescent Proteins; Humans; Immunohistochemistry; Intestinal Mucosa; Mice; Mice, Transgenic; Neurotensin; Obesity; Peptide YY; Promoter Regions, Genetic

Significant weight loss following Roux-en-Y gastric bypass surgery (RYGB) in obese humans correlates with enhanced secretion of anorexigenic gut hormones glucagon-like peptide-1 (GLP-1) and peptide YY(3-36) (PYY(3-36)). Our aim here was to identify a dosing strategy for intraperitoneal (IP) infusion of GLP-1 homologue exendin-4 alone and with PYY(3-36) that produces a sustained reduction in daily food intake and body weight in diet-induced obese (DIO) rats. We tested 12 exendin-4 strategies over 10 weeks. Exendin-4 infused during the first and last 3 h of the dark period at 15-20 pmol/h (0.15 nmol/kg/day) produced a sustained 24 ± 1% reduction in daily food intake for 17 days, and decreased body weight by 7%. In a separate group of DIO rats, none of seven dosing strategies combining exendin-4 and PYY(3-36) produced a similar reduction in daily food intake for >10 days. The subsequent decline in efficacies of exendin-4 alone and with PYY(3-36) on food intake and body weight in each experiment suggested possible receptor downregulation and tolerance to treatments. However, when treatments were discontinued for 1 day following losses in efficacies, daily food intake significantly increased. Together, these results demonstrate that (i) intermittent IP infusion of a low dose of exendin-4 can produce a relatively prolonged reduction in daily food intake and body weight in DIO rats, (ii) co-infusion of exendin-4 and PYY(3-36) does not further prolong this response, and (iii) activation of an orexigenic mechanism gradually occurs to counteract the inhibitory effects of exendin-4 alone and with PYY(3-36) on food intake and body weight.

Topics: Animals; Body Weight; Diet; Dose-Response Relationship, Drug; Drug Combinations; Drug Evaluation, Preclinical; Eating; Exenatide; Hypoglycemic Agents; Male; Obesity; Peptide Fragments; Peptide YY; Peptides; Rats; Rats, Sprague-Dawley; Venoms; 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

Eating rate has recently been shown to influence energy intake and appetite during an ad libitum meal, and alter postprandial secretion of glucagon-like peptide-1 (GLP-1) and peptide-YY (PYY) following a fixed-portion meal. Whether these effects influence satiety, as measured by energy intake at the subsequent meal, is unclear. We manipulated eating rate during a fixed-portion meal in order to examine how eating behavior and associated periprandial and postprandial responses of putative endocrine mediators of appetite would affect energy intake at the following meal in fifteen non-obese (BMI<25 kg/m²) and ten obese (BMI ≥ 30 kg/m²) healthy adult men and women. In random order, each participant consumed a standardized, fixed-portion meal in 7 (FM), 14 (MM) or 28 (SM) minutes. Fullness, measured by the Satiety Labeled Intensity Magnitude (SLIM) scale, serum insulin, glucose, leptin, pancreatic polypeptide (PP), PYY, GLP-1, neuropeptide-Y, and plasma cholecystokinin (CCK) were measured for 3h following the fixed-portion meal. Ad libitum energy intake at the next meal was then measured. Eating slowly delayed time to peak fullness (P ≤ 0.05), but did not alter peak fullness. Peak PP concentrations were attenuated during FM compared to MM and SM (P ≤ 0.05) and were reached earlier during MM compared to SM (P ≤ 0.05). A meal-by-time interaction (P ≤ 0.05), but no differences in AUC, peak, or time to peak were observed for CCK. No additional between meal differences in AUC, peak or time to peak for any endocrine mediator of appetite was observed. Ad libitum energy intake was not different between trials. In conclusion, the rate at which a fixed-portion meal is consumed does not appear to alter satiety despite a small effect on PP and CCK responses.

Topics: Adolescent; Adult; Appetite; Blood Glucose; Cholecystokinin; Eating; Energy Intake; Feeding Behavior; Female; Glucagon-Like Peptide 1; Humans; Insulin; Leptin; Male; Middle Aged; Neuropeptide Y; Obesity; Pancreatic Polypeptide; Peptide YY; Postprandial Period; Satiation; Time Factors

Microsomal triglyceride transfer protein (MTP) takes part in the mobilization and secretion of triglyceride-rich lipoproteins from enterocytes and hepatocytes. We investigated the effects of JTT-130, a novel intestine-specific MTP inhibitor, on high fat diet-induced obesity and glucose intolerance.. Male Sprague-Dawley rats were fed a 3.1% fat diet or a 35% fat diet with or without JTT-130 as a food admixture (0.029%). Food intake, body weight, abdominal fat, hepatic triglyceride, faecal free fatty acids and plasma levels of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) were assessed. Plasma levels of glucose and insulin were measured during intraperitoneal glucose tolerance tests. In addition, indirect calorimetry was performed on rats fed with a 35% fat diet.. JTT-130 treatment decreased body weights, abdominal fat and hepatic triglyceride with suppression of food intake and elevation of faecal free fatty acids and plasma GLP-1 and PYY levels in rats fed with the 35% fat diet, whereas no significant effects on these parameters except for increased faecal free fatty acids were observed in rats fed with the 3.1% fat diet. JTT-130 treatment decreased plasma levels of glucose and insulin during intraperitoneal glucose tolerance tests on rats fed with the 35% fat diet, but not on rats fed with the 3.1% fat diet. JTT-130-treated rats showed increased O(2) consumption and CO(2) production on a 35% fat diet.. JTT-130 suppresses high fat diet-induced obesity and glucose intolerance with suppression of food intake and fat absorption and could be useful for prevention and treatment of obesity and obesity-related insulin resistance.

Topics: Animals; Benzamides; Biomarkers; Blood Glucose; Carrier Proteins; Diet, High-Fat; Dietary Fats; Eating; Fatty Acids; Feces; Glucagon-Like Peptide 1; Glucose Intolerance; Glucose Tolerance Test; Hypoglycemic Agents; Insulin; Insulin Resistance; Liver; Male; Malonates; Obesity; Peptide YY; Rats; Rats, Sprague-Dawley; Triglycerides

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.. 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 postoperatively. 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.. 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.. 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.

Topics: Analysis of Variance; Animals; Colon; Diet, Fat-Restricted; Diet, Reducing; Enzyme-Linked Immunosorbent Assay; Gastric Bypass; Gastric Mucosa; Ghrelin; Glucagon; Glucagon-Like Peptide 1; Leptin; Male; Mice; Obesity; Peptide YY; Radioimmunoassay; Random Allocation; Reverse Transcriptase Polymerase Chain Reaction; Weight Loss

Weight-loss independent mechanisms may play an important role in the improvement of glucose homeostasis after Roux-en-Y gastric bypass (RYGB). The objective of this analysis was to determine whether RYGB causes greater improvement in glucostatic parameters as compared with laparoscopic adjustable gastric banding (LAGB) or low calorie diet (LCD) after equivalent weight loss and independent of enteral nutrient passage. Study 1 recruited participants without type 2 diabetes mellitus (T2DM) who underwent LAGB (n = 8) or RYGB (n = 9). Study 2 recruited subjects with T2DM who underwent LCD (n = 7) or RYGB (n = 7). Insulin-supplemented frequently-sampled intravenous glucose tolerance test (fsIVGTT) was performed before and after equivalent weight reduction. MINMOD analysis of insulin sensitivity (Si), acute insulin response to glucose (AIRg) and C-peptide (ACPRg) response to glucose, and insulin secretion normalized to the degree of insulin resistance (disposition index (DI)) were analyzed. Weight loss was comparable in all groups (7.8 ± 0.4%). In Study 1, significant improvement of Si, ACPRg, and DI were observed only after LAGB. In Study 2, Si, ACPRg, and plasma adiponectin increased significantly in the RYGB-DM group but not in LCD. DI improved in both T2DM groups, but the absolute increase was greater after RYGB (258.2 ± 86.6 vs. 55.9 ± 19.9; P < 0.05). Antidiabetic medications were discontinued after RYGB contrasting with 55% reduction in the number of medications after LCD. No intervention affected fasting glucagon-like peptide (GLP)-1, peptide YY (PYY) or ghrelin levels. In conclusion, RYGB produced greater improvement in Si and DI compared with diet at equivalent weight loss in T2DM subjects. Such a beneficial effect was not observed in nondiabetic subjects at this early time-point.

Topics: Adiponectin; Adult; Blood Glucose; C-Peptide; Caloric Restriction; Diabetes Mellitus, Type 2; Diet, Reducing; Female; Gastric Bypass; Ghrelin; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Insulin Secretion; Laparoscopy; Male; Middle Aged; Obesity; Peptide YY; Weight Loss

We investigated the effects of the EVASYON program on body fatness, cardiometabolic risk factors, gut appetite-controlling hormones and serum levels of cytokines in adolescents with overweight or obesity (OW/OB).. This study comprised 13 boys (10 obese) and 12 girls (8 obese), aged 13-16 years, from a Madrid Hospital. The EVASYON program was based on a calorie-restricted diet (10-40%), increased physical activity (at least 60 min/day 5 days a week), psychological therapy and nutritional education for 13 months. Anthropometric and blood pressure measurements were measured before and after intervention. Serum glucose, total cholesterol, high-density lipoprotein cholesterol, triglycerides, leptin, total peptide YY and insulin levels were determined before and after intervention. Serum levels of cytokines IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, and TNF-α were also assessed before and after intervention.. A decrease in body mass index (BMI), BMI z-score, skinfolds (triceps, biceps, subscapular, thigh, and calf), sum of six skinfolds and body circumferences (arm relaxed and flexed, waist, hip, and proximal thigh) values were observed after the intervention program (all p < 0.05). In addition, diastolic blood pressure also decreased (p < 0.05). A decrease in serum leptin levels (-48.4%, p < 0.001) was observed after intervention without changes in total peptide YY and insulin levels. Levels of IL-8, IL-10, and TNF-α also decreased (all p < 0.05) after the intervention program.. These preliminary results evidence that the EVASYON program may improve body fat, leptin, and some pro-inflammatory cytokines in adolescents with OW/OB.

Topics: Adiponectin; Adipose Tissue; Adolescent; Cardiovascular Diseases; Cytokines; Female; Humans; Insulin; Leptin; Male; Obesity; Overweight; Peptide YY; Risk Factors

We studied whether serum fasting levels of active form of peptide YY (PYY), PYY(3-36), are associated with obesity and related phenotypes. The study population consisted of 428 patients with coronary artery disease and diagnosed type 2 diabetes and 440 patients with coronary artery disease but without evidence of diabetes from the ARTEMIS study. The patients were recruited from the consecutive series of patients undergoing coronary angiography in the Oulu University Hospital. The patients without diabetes underwent a 2-hour oral glucose tolerance test. PYY(3-36) levels were analyzed by human PYY(3-36) specific radioimmunoassay. Result suggested that when PYY(3-36) tertiles were considered, high serum fasting PYY(3-36) concentration was associated with high body mass index, waist circumference, hemoglobin A1c, fasting blood glucose, leptin, triglyceride (p for all p ≤ 0.001), serum insulin (p=0.013) and with a low high-density lipoprotein cholesterol (p=0.004) concentrations in the analyses adjusted for age, sex and study group. The link high PYY(3-36)-high insulin level was evident in subjects with normal glucose tolerance (p<0.05). The prevalence of diabetes was 72%, 46% and 30% in the highest, medium and lowest PYY(3-36) tertile (p<0.001). The PYY(3-36) concentrations (after adjustment for age, sex and body mass index) were higher in type 2 diabetics compared to subjects with impaired fasting glucose, impaired glucose tolerance and normal glucose tolerance (p<0.001 for trend). In conclusion, fasting PYY(3-36) concentrations in type 2 diabetic subjects are high. Although high PYY(3-36) is strongly linked to obesity and associated insulin resistance, the relation between PYY(3-36) and type 2 diabetes is independent of body fatness.

Topics: Aged; Blood Glucose; Blood Pressure; Body Mass Index; Cholesterol; Coronary Artery Disease; Diabetes Mellitus, Type 2; Fasting; Humans; Insulin; Insulin Resistance; Obesity; Peptide YY

This study tested the effects of (1→3),(1→4) β-D-glucan from oats, on activation of the gut-hypothalamic (PYY₃₋₃₆-NPY) axis, satiety, and weight loss in diet-induced obesity (DIO) mice. DIO mice were fed standard lab chow diets or varied doses of β-glucan for 6 weeks. Energy intake, satiety, body weight changes and peptide Y-Y₃₋₃₆ (PYY₃₋₃₆) were measured together with a satiety test and measurement of neuropeptide Y (NPY) mRNA expression in the hypothalamic arcuate nucleus (Arc). The average energy intake (-13%, p<0.05) and body weight gain was lower with increasing β-glucan over 6 wk with acute suppression of energy intake over 4 h. The highest β-glucan diet significantly increased plasma PYY₃₋₃₆, with suppression of Arc NPY mRNA.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Avena; beta-Glucans; Body Weight; Diet; Dose-Response Relationship, Drug; Energy Intake; Gastrointestinal Tract; Male; Mice; Mice, Inbred C57BL; Neuropeptide Y; Obesity; Peptide Fragments; Peptide YY; RNA, Messenger; Satiety Response

Unknown hormonal and neural satiety signals are thought to drive sustainable weight loss following laparoscopic adjustable gastric banding (LAGB). The objective of this study was to investigate whether the structurally related satiety hormones pancreatic polypeptide (PP) and peptide YY (PYY) influence total percentage weight loss after LAGB.. A cross-sectional study examined 17 postoperative individuals who had already achieved a mean of 28% LAGB-induced weight loss (range, 10-38%). A prospective study assessed plasma PP and PYY meal responses in 16 obese individuals prior to LAGB.. In the cross-sectional study, individuals with higher weight loss had lower PP meal responses (2-h AUC, R = -0.60, p = 0.01) and lower fasting PYY levels (R = -0.55, p = 0.02). In the prospective study, subsequent mean weight loss was 20% (range, 5-50%) after a mean of 53 months. Low preoperative PP meal response (2-h AUC) predicted significantly higher subsequent weight loss after LAGB (R = -0.56, p = 0.024). The eight individuals with the lowest PP meal response lost more weight than the eight with the highest PP meal response (median 25% vs. 14%, p = 0.004). When compared across all three groups, mean PP meal responses did not differ. Fasting PYY levels, however, were significantly lower in the postoperative group compared to the group tested pre-operatively, or the BMI-matched controls (-30%, p = 0.03).. PYY appears reduced in proportion to weight loss following LAGB, possibly representing attempted orexigenic homeostatic compensation. Although PP responses appear unchanged by weight loss status, low PP meal response may predict higher weight loss. PP meal response may be a biological marker that could predict an individual's susceptibility to the mechanism underlying LAGB-induced weight loss.

Topics: Adult; Cross-Sectional Studies; Female; Gastroplasty; Humans; Male; Obesity; Pancreatic Polypeptide; Peptide YY; Postprandial Period; Prospective Studies; Weight Loss

Prader-Willi syndrome (PWS) is a leading genetic cause of obesity, characterized by hyperphagia, endocrine and developmental disorders. It is suggested that the intense hyperphagia could stem, in part, from impaired gut hormone signaling. Previous studies produced conflicting results, being confounded by differences in body composition between PWS and control subjects.. Fasting and postprandial gut hormone responses were investigated in a cross-sectional cohort study including 10 adult PWS, 12 obese subjects matched for percentage body fat and central abdominal fat, and 10 healthy normal weight subjects.. PYY[total], PYY[3-36], GLP-1[active] and ghrelin[total] were measured by ELISA or radioimmunoassay. Body composition was assessed by dual energy X-ray absorptiometry. Visual analog scales were used to assess hunger and satiety.. In contrast to lean subjects (p<0.05), PWS and obese subjects were similarly insulin resistant and had similar insulin levels. Ghrelin[total] levels were significantly higher in PWS compared to obese subjects before and during the meal (p<0.05). PYY[3-36] meal responses were higher in PWS than in lean subjects (p=0.01), but not significantly different to obese (p=0.08), with an additional non-significant trend in PYY[total] levels. There were no significant differences in self-reported satiety between groups, however PWS subjects reported more hunger throughout (p=0.003), and exhibited a markedly reduced meal-induced suppression of hunger (p=0.01) compared to lean or obese subjects.. Compared to adiposity-matched control subjects, hyperphagia in PWS is not related to a lower postprandial GLP-1 or PYY response. Elevated ghrelin levels in PWS are consistent with increased hunger and are unrelated to insulin levels.

Topics: Adult; Blood Glucose; Body Composition; Cohort Studies; Cross-Sectional Studies; Fasting; Female; Ghrelin; Glucagon-Like Peptide 1; Humans; Hunger; Hyperphagia; Insulin; Male; Obesity; Peptide YY; Postprandial Period; Prader-Willi Syndrome; Signal Transduction; Young Adult

Topics: Biliopancreatic Diversion; Esophageal Motility Disorders; Female; Gastrectomy; Gastric Emptying; Gastric Fundus; Gastrointestinal Motility; Gastrointestinal Transit; Humans; Laparoscopy; Magnetic Resonance Imaging, Cine; Male; Obesity; Obesity, Morbid; Peptide YY; Radiography; Radionuclide Imaging; Stomach

Bariatric surgery is currently the most effective and durable treatment option for extreme obesity. Restrictive procedures, such as AGB and SG, limit gastric capacity and, thus, food intake while leaving the gastrointestinal tract intact. Malabsorptive procedures, such as BPD, shorten the length of the intestine to decrease nutrient absorption. Combined procedures, such as RYGB, include restriction and gastrointestinal rearrangement. Procedures that bypass segments of the gut are associated with greater weight loss and greater improvements in comorbid conditions than is gastric banding. This may be due, in part, to the differential effects of gastrointestinal rearrangement on the secretion of orexigenic and anorexigenic gut peptides that regulate appetite, glucose homeostasis, and body weight. Bariatric surgery is generally associated with low rates of perioperative and postoperative morbidity and mortality, although rigorous comparative safety data are lacking. High-quality, long-term, randomized, controlled trials are needed to compare the efficacy, safety, and cost effectiveness of the various bariatric surgery procedures with each other, as well as with intensive nonsurgical weight loss interventions.

Topics: Anastomosis, Roux-en-Y; Bariatric Surgery; Biliopancreatic Diversion; Endoscopy, Digestive System; Ghrelin; Glucagon-Like Peptide 1; Humans; Obesity; Peptide YY; Treatment Outcome; Weight Loss

Hypertension is a major health problem and is usually associated with common conditions such as obesity, which contribute to clinical cardiac dysfunction. The role of energy homeostasis hormones such as ghrelin and PYY 3-36 in cardiovascular function remains incompletely understood. Therefore, the aim of our study was to explore the potential differences in concentrations of ghrelin forms and PYY 3-36 circulating in obese patients with grade 1 and grade 2 hypertension, with higher and lower BMI and without and with insulin resistance as well as to determine whether these hormones may be associated with left ventricular hypertrophy.. A total of 142 adult subjects were studied in three subgroups: lean (BMI < 25 kg/m(2)) normotensive subjects and obese subjects (BMI 30.0-34.9 kg/m(2)), and obese subjects (BMI 35.0-39.9 kg/m(2)) under hypertensive treatment for at least 9 years. Fasting blood glucose, insulin, high-sensitivity C-reactive protein (hs-CRP), lipid profile, urinic acid, acylated ghrelin (A-Ghr), total ghrelin (T-Ghr), and PYY 3-36 were measured. Insulin resistance was determined by the homeostasis model assessment of insulin resistance (HOMA-IR). We also echocardiographically assessed left ventricular mass (LVM) index (LVMI = LVM/height(2.7)). We evaluated the association between plasma T-Ghr, A-Ghr, PYY 3-36 levels with LVMI and other measured factors using univariate and multivariate analysis.. There were significant differences between BMI, waist circumference (WC), LVMI, hs-CRP and A-Ghr/nonacylated ghrelin (NA-Ghr) ratio (in the two obese subgroups. There was no significant difference between T-Ghr, A-Ghr and PYY 3-36 levels between obese subgroups. T-Ghr and PYY 3-36 were significantly lower in obese patients than in the control group, whereas A-Ghr levels did not differ between obese and controls. A-Ghr/NA-Ghr ratio was significantly higher in patients with second-degree hypertension and BMI 35.0-39.9 kg/m(2) than in patients with first-degree hypertension and BMI 30.0-34.9 kg/m(2). There were negative associations between T-Ghr, NA-Ghr or PYY 3-36 and LVMI (r = -0.49, p = 0.0001; r = -0.47, p = 0.0001; or r = -0.18, p = 0.029, respectively) and positive association between A-Ghr/NA-Ghr ratio and LVMI (r = 0.3, p = 0.0003). T-Ghr and NA-Ghr, were associated negatively with fasting insulin (r = -0.31, p = 0.0025; and r = -0.36, p = 0.001, repectively), while A-Ghr/NA-Ghr ratio was positively associated with BMI and fasting insulin (r = 0.23, p = 0.041; r = 0.3, p = 0.0045, respectively). T-Ghr, A-Ghr, and NAGhr were also inversely related to HOMA-IR indices in obese patients (r = -0.43, p = 0.001; r = -0.32, p = 0.0359; r = -0.35, p = 0.001, respectively). In insulin-resistant obese subjects T-Ghr and NA-Ghr correlated negatively with HOMA-IR (r = -0.34, p = 0.0015; r = -0.28, p = 0.0116, respectively). LVMI was associated negatively with T-Ghr, NA-Ghr and PYY 3-36 (r = -0.49, p = 0.0001; r = -0.47, p = 0.0001; r = -0.18, p = 0.029, respectively). In addition, LVMI was positively associated with A-Ghr/NA-Ghr ratio (r = 0.30, p = 0.0003).. Plasma ghrelin forms and PYY 3-36 levels are associated with LVMI. These associations indicate a possible interaction between gut peptides and the cardiovascular system in hypertension and obesity.

Topics: Acylation; Adult; Body Mass Index; C-Reactive Protein; Female; Ghrelin; Heart Ventricles; Humans; Hypertension; Hypertrophy, Left Ventricular; Insulin; Insulin Resistance; Male; Middle Aged; Multivariate Analysis; Obesity; Peptide YY; Reference Values; Waist Circumference

Peptide Tyrosine-Tyrosine (PYY) is a 36-amino acid peptide hormone released post-prandially from the endocrine cells in the intestinal tract to suppress pancreatic secretions and eventually reduce appetite. The R72T variant in the PYY gene (rs1058046) has been associated with increased susceptibility to obesity. Therefore, the objective of this study was to investigate the association of this variant with obesity and its related anthropometric measurements among the Kampar Health Clinic cohort, Malaysia.. A total of 197 (78 males, 119 females; 98 non-obese, 99 obese) subjects were recruited by convenience sampling and anthropometric measurements were taken. Genotyping was performed using StuI Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP), revealing 61 RR, 94 RT and 42 TT subjects.. Most of the obese subjects had the RT genotype (50.5%), while only 18.2% were TT. PYY R72T genotypes and alleles had no association with obesity (p = 0.535; 0.074, respectively), gender (p = 0.767; p = 0.100, respectively) but were associated with ethnicity (p = 0.003; p = 0.002, respectively). Among the 13 anthropometric measurements taken, significant difference was only found in Waist Circumference (WC) and Visceral Fat Level (VFL) among the alleles, suggesting that subjects with T allele will have an increment of 1.82 cm in WC and 1.32% in VFL.. The R72T variant in PYY gene was not associated with obesity and most of its related anthropometric measurements. This suggests that other genes and/or environmental factors like dietary habits and lifestyle factors may be the contributors of obesity.

Topics: Adult; Aged; Aged, 80 and over; Body Mass Index; Cohort Studies; DNA; DNA Primers; Female; Genotype; Humans; Malaysia; Male; Middle Aged; Obesity; Peptide YY; Polymerase Chain Reaction; Polymorphism, Restriction Fragment Length; Surveys and Questionnaires; Young Adult

Black women suffer a disproportionately higher rate of obesity than their white counterparts. Reasons for this racial disparity may reflect underlying differences in the appetite suppressing peptide-YY (PYY). The PYY response to food is differentially influenced by macronutrient content but the effect of glycemic load on PYY response is unknown. This study examined whether glycemic load influences fasting and postprandial PYY levels and whether fasting and postprandial PYY levels are lower in obese black women compared to normal weight black women and to white women. Data were collected from 40 women (20 black, 20 white; 10 each normal weight vs. obese) at the University of North Carolina Clinical and Translational Research Center (CTRC). Participants completed in counterbalanced order two 4(1/2)-day weight-maintenance, mixed macronutrient high vs. low glycemic load diets followed by a test meal of identical composition. Total PYY levels were assessed before and after each test meal. Results show no differences in fasting PYY levels but significantly less postprandial PYY area under the curve (PYY(AUC)) in the group of obese black women compared to each other group (race x obesity interaction, P < 0.04). PYY(AUC) was positively related to insulin sensitivity (P < 0.004) but was not affected by glycemic load (main and interactive effects, P > 0.27). These findings indicate that postprandial PYY secretion is not affected by glycemic load but is blunted in obese black women compared with normal weight black women and with white women; additionally, they begin to address whether blunted PYY secretion contributes uniquely to the pathogenesis of obesity in black women.

Topics: Adult; Black People; Body Weight; Eating; Fasting; Female; Humans; Hyperglycemia; Insulin Resistance; Obesity; Peptide YY; Prevalence; United States; White People; Young Adult

Ghrelin is an orexigenic 28-amino acid peptide produced by the stomach. Circulating ghrelin levels rise shortly before and fall shortly after every meal. Peptide YY (PYY), an anorexigenic 36-amino acid peptide, is secreted primarily from the intestinal mucosa of the ileum and large intestine. Plasma PYY levels begin to rise within 15 min after starting to eat and plateau within approximately 90 min, remaining elevated for up to 6 h. Recently, some studies have tried to evaluate the potential role of ghrelin and PYY in the hyperphagia of patients with Prader-Willi syndrome (PWS). While hyperghrelinemia is well characterized in PWS, conflicting results have been reported for PYY. The aim of the study was to investigate ghrelin and PYY responses to a standard liquid high-fat meal in children with PWS.. Circulating levels of total ghrelin and PYY levels were assayed by RIA after overnight fasting and 45, 60, 90, and 180 min following a standard meal (Ensure 6 ml/kg) in 16 patients with PWS (11 boys and five girls, aged 4.6-10.7 years, including ten receiving 0.02 mg/kg per day rhGH for 2-18 months; body mass index (BMI) z-score: 0.6+/-0.2 and 1.6+/-0.5 for children treated or not treated with rhGH respectively), ten obese (eight boys and two girls, aged 9.2-15.6 years; BMI z-score: 2.4+/-0.2, i.e. BMI >97th centile for chronological age and sex) subjects, and 16 normal-weight controls (five boys and 11 girls, aged 5.8-17.3 years; BMI z-score: 0.6+/-0.2).. PWS children showed higher fasting levels of ghrelin than obese and lean controls. Postprandial ghrelin drop was more pronounced in PWS than in the other study groups. No significant difference on fasting levels of PYY was found among groups. PWS showed a higher postprandial PYY rise than obese and lean controls. PWS patients treated and not treated with GH showed similar fasting and postprandial levels of ghrelin and PYY. Fasting PYY levels correlated negatively (P<0.05; r=-0.68) with those of ghrelin only in PWS.. The results of this study confirm fasting hyperghrelinemia in PWS. Since in PWS adults an impaired postprandial suppression of plasma ghrelin was previously reported to be associated with a blunted postprandial PYY response, the finding of a meal-induced decrease and increase in ghrelin and PYY levels respectively in PWS children would imply that the regulation of appetite/satiety of these peptides is operative during childhood, and it progressively deteriorates and vanishes in adulthood when hyperphagia and obesity worsen.

Topics: Adolescent; Analysis of Variance; Blood Glucose; Body Mass Index; Child; Child, Preschool; Eating; Fasting; Female; Ghrelin; Human Growth Hormone; Humans; Insulin; Male; Obesity; Peptide YY; Postprandial Period; Prader-Willi Syndrome; Radioimmunoassay; Recombinant Proteins; Time Factors

The increasing prevalence of obesity worldwide calls for safe and highly efficacious satiety drugs. PYY3-36 has been implicated in food intake regulation, and novel peptide analogues with high Y2 receptor-subtype selectivity and potency have potential as drugs for the treatment of obesity. It has been hypothesized that PYY3-36 associates with the plasma membrane prior to receptor activation such that the amphipathic alpha-helix of PYY3-36 possibly guides the C-terminal pentapeptide into the correct conformation for receptor activation. Ala-scans are used routinely to study the effect of individual amino acids in a given peptide sequence. Here we report the glyco-scan of the peptide hormone PYY3-36, in which hydroxyl side-chain functionalities were glycosylated; in addition new glycosylation sites were introduced. An array of novel PYY3-36 analogues with a glycan positioned in the water-membrane interface or in the N terminal were screened for Y-receptor affinity and selectivity as well as metabolic stability. Interestingly, in contrast to the Y1 and Y4 receptors, the Y2 receptor readily accommodated glycosylations. Especially glycosylations in the alpha-helical region of PYY3-36 were favorable both in terms of Y-receptor selectivity and endopeptidase resistance. We thus report several PYY3-36 analogues with enhanced Y-receptor selectivity. Our results can be used in the design of novel PYY analogues for the treatment of obesity. The glyco-scan concept, as systematically demonstrated here, has the potential for a wider applicability.

Topics: Animals; Circular Dichroism; Glycosylation; Humans; Mice; Obesity; Peptide Fragments; Peptide YY; Protein Structure, Secondary; Receptors, Neuropeptide Y; Structure-Activity Relationship

Ghrelin and peptide YY (PYY) stimulate hunger and satiety, respectively. The physiology of these hormones during normal meal intake remains unclear. This study was designed to compare the responses of these two hormones to meal intake between lean and obese Hispanic adolescents. A total of 10 obese and 7 lean Hispanic youth, aged 11-14 years, consumed two mixed meals, one small and one large, during which plasma measurements of active and total ghrelin and total PYY were obtained. Obese subjects tended to consume more calories during the small meal than lean subjects, although this did not reach statistical significance. Intake of the small meal significantly suppressed active ghrelin and stimulated PYY levels in the lean subjects, and these changes were further accentuated by the large meals. In obese subjects, the suppression of active ghrelin and stimulation of PYY by caloric intake were blunted. Interestingly, a paradoxical stimulation of active ghrelin levels was noted during the small meals in both lean and obese subjects. This stimulation was not seen during the larger meals in lean subjects, but remained present in the obese subjects. Thus, meal-related changes in active ghrelin and PYY are blunted in obese as compared to lean Hispanic subjects. This blunting could contribute to the development or worsening of obesity.

Topics: Adolescent; Appetite; Area Under Curve; Blood Glucose; Child; Eating; Female; Ghrelin; Humans; Insulin; Male; Obesity; Peptide YY; Postprandial Period; Satiety Response

The effects of medical and surgical treatments for obesity on peptide YY (PYY) levels, in patients with similar weight loss, remain unclear.. The objective of the study was to assess PYY and appetite before and after Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (SG), and medical treatment (MED).. This was a prospective, controlled, nonrandomized study.. The study was conducted at the Departments of Nutrition and Digestive Surgery at a university hospital.. PARTICIPANTS included three groups of eight patients with similar body mass indexes (RYGB 37.8 +/- 0.8, SG 35.3 +/- 0.7, and MED 39.1 +/- 1.7 kg/m(2), P = NS) and eight lean controls (body mass index 21.7 +/- 0.7 kg/m(2)).. Total plasma PYY, hunger, and satiety visual analog scales in fasting and after ingestion of a standard test meal were measured.. At baseline there were no differences in the area under the curve (AUC) of PYY, hunger, or satiety in obese groups. Two months after the interventions, RYGB, SG, and MED groups achieved similar weight loss (17.7 +/- 3, 14.9 +/- 2.4, 16.6 +/- 4%, respectively, P = NS). PYY AUC increased in RYGB (P < 0.001) and SG (P < 0.05) and did not change in MED. PYY levels decreased at fasting, 30 min, and 180 min after a standard test meal in MED (P < 0.05). Hunger AUC decreased in RYGB (P < 0.05). Satiety AUC increased in RYGB (P < 0.05) and SG (P < 0.05). Appetite did not change in MED. PYY AUC correlated with satiety AUC (r = 0.35, P < 0.05).. RYGB and SG increased PYY and reduced appetite. MED failed to produce changes. Different effects occur despite similar weight loss. This suggests that the weight-loss effects of these procedures are enhanced by an increase in PYY and satiety.

Topics: Adult; Analysis of Variance; Area Under Curve; Body Mass Index; Diet Therapy; Exercise; Female; Gastrectomy; Gastric Bypass; Humans; Hunger; Male; Middle Aged; Obesity; Patient Selection; Peptide YY; Prospective Studies; Radioimmunoassay; Regression Analysis; Satiation; Time Factors; Weight Loss

Roux-en-Y gastric bypass (RYGB) surgery is the most effective treatment for morbid obesity and remission of associated type 2 diabetes, but the mechanisms involved are poorly understood. The aim of the present study was to develop and validate a rat model for RYGB surgery that allows repeated measurement of meal-induced changes in gut and pancreatic hormones via chronic venous catheters. Male Sprague Dawley rats made obese on a palatable high-fat diet were subjected to RYGB or sham surgery and compared with chow-fed, lean controls. Hormonal responses to a mixed-liquid test meal were examined by frequent blood sampling through chronically implanted jugular catheters in freely behaving rats, 3-4 months after surgery, when RYGB rats had significantly reduced body weight and fat mass compared with sham-operated rats. Hyperleptinemia, basal hyperinsulinemia, and hyperglycemia as well as postprandial glucose intolerance seen in sham-operated, obese rats were completely reversed by RYGB and no longer different from lean controls. Postprandial increases in glucagon-like peptide-1, peptide YY, and amylin as well as suppression of ghrelin levels were all significantly augmented in RYGB rats compared with both sham-operated obese and lean control rats. Thus, our rat model replicates most of the salient hormonal and glycemic changes reported in obese patients after RYGB, with the addition of amylin to the list of potential candidate hormones involved in hypophagia, weight loss, and remission of diabetes. The model will be useful for elucidating the specific peripheral and central mechanisms involved in the suppression of appetite, loss of body weight, and remission of type 2 diabetes.

Topics: Amyloid; Analysis of Variance; Animals; Body Weight; Eating; Gastric Bypass; Ghrelin; Glucagon-Like Peptide 1; Insulin; Islet Amyloid Polypeptide; Leptin; Male; Obesity; Peptide YY; Postprandial Period; Rats; Rats, Sprague-Dawley; Time Factors

To compare the effects of weight loss by an energy-restricted low-fat diet vs low-carbohydrate diet on serum peptide YY (PYY) levels.. 8-Week prospective study of 30 obese adults (mean age: 42.8+/-2.0 years, mean body mass index 35.5+/-0.6 kg m(-2)).. After 8 weeks, subjects on the low-carbohydrate diet lost substantially more weight than those on the low-fat diet (5.8 vs 0.99 kg, P<0.001). Weight loss by either diet resulted in a 9% reduction in both mean fasting serum PYY levels (baseline: 103.5+/-8.8 pg ml(-1), after weight loss: 94.1+/-6.5 pg ml(-1), P<0.01) and postprandial area under the curve (AUC) PYY (baseline: (20.5+/-1.5) x 10(3) pg h(-1) ml(-1), after weight loss: mean AUC PYY (18.8+/-1.4) x 10(3) pg h(-1) ml(-1), P<0.001). There was a trend towards lower levels of PYY with greater degrees of weight loss.. Reduced PYY levels after weight loss by an energy-restricted low-fat or low-carbohydrate diet likely represents a compensatory response to maintain energy homeostasis and contributes to difficulty in weight loss during energy-restricted diets.

Topics: Adult; Body Mass Index; Diet, Carbohydrate-Restricted; Diet, Fat-Restricted; Diet, Reducing; Female; Humans; Male; Obesity; Peptide YY; Postprandial Period; Prospective Studies; Weight Loss

Bile acid sequestrants (BAS) have shown antidiabetic effects in both humans and animals but the underlying mechanism is not clear. In the present study, we evaluated cholestyramine in Zucker diabetic fatty (ZDF) rats. Although control ZDF rats had continuous increases in blood glucose and hemoglobin A1c (HbA1c) and serum glucose and a decrease in serum insulin throughout a 5-week study, the cholestyramine-treated ZDF rats showed a dose-dependent decrease and normalization in serum glucose and HbA1c. An oral glucose tolerance test showed a significant increase in glucose-stimulated glucagon-like peptide 1 (GLP-1), peptide YY (PYY), and insulin release in rats treated with cholestyramine. Quantitative analysis of gene expression indicated that cholestyramine treatment decreased farnesoid X receptor (FXR) activity in the liver and the intestine without liver X receptor (LXR) activation in the liver. Moreover, a combination of an FXR agonist with cholestyramine did not reduce the antihyperglycemic effect over cholestyramine alone, suggesting that the FXR-small heterodimer partner-LXR pathway was not required for the glycemic effects of cholestyramine. In summary, our results demonstrated that cholestyramine could completely reverse hyperglycemia in ZDF rats through improvements in insulin sensitivity and pancreatic beta-cell function. Enhancement in GLP-1 and PYY secretion is an important mechanism for BAS-mediated antidiabetic efficacy.

Topics: Animals; Blood Glucose; Cholestyramine Resin; Diabetes Mellitus, Experimental; Gene Expression; Glucagon-Like Peptide 1; Glucose Tolerance Test; Glycated Hemoglobin; Hypoglycemic Agents; Insulin; Insulin Resistance; Intestinal Mucosa; Liver; Liver X Receptors; Male; Obesity; Orphan Nuclear Receptors; Peptide YY; Rats; Rats, Zucker; Receptors, Cytoplasmic and Nuclear

To study the effects of rapid i.v. glucose bolus on insulin, leptin, ghrelin, peptide YY (PYY), free fatty acids (FFA), glucagon and glucagon-like peptide-1 (GLP-1) concentrations together with self-reported satiety ratings in lean and obese human subjects.. Twenty-five healthy subjects were recruited, 12 were lean (mean age = 26 years, BMI range = 19.8-23.9 kg/m(2)) and 13 were obese (mean age = 27 years, BMI range = 27.7-42.2 kg/m(2)). In two separate 55 min counter-balanced blinded sessions (separate days), subjects were administered an i.v. dose of 300 mg/kg glucose or saline. Blood concentrations of several feeding-related hormones were recorded at multiple time points, together with ratings of satiety and euphoria.. Greater increases in glucose concentrations were observed in the obese group compared to the lean group (p < 0.0001). In both lean and obese subjects, glucose injection induced a clear fall in the concentrations of FFA, ghrelin, glucagon and PYY (p < 0.0001) but not in the concentrations of leptin or GLP-1. Obese subjects showed positive correlations between satiety and glucose, but only at time points 30 min (r = 0.73, p = 0.005) and 55 min (r = 0.82, p = 0.0005).. The directions and the magnitudes of short-term hormonal changes after i.v. glucose challenge are the same in lean and moderately obese subjects. Possible short-term regulatory effects of leptin and GLP-1 can not be induced by acute energy load bypassing the GI-tract.

Topics: Adult; Blood Glucose; Fatty Acids, Nonesterified; Female; Ghrelin; Glucagon; Glucose; Glucose Tolerance Test; Hormones; Humans; Injections, Intravenous; Insulin; Leptin; Male; Obesity; Peptide YY; Thinness; Young Adult

The aim of this study was to investigate the appetite hormones and metabolic responses of hyperinsulinemic subjects to high-protein (HP) meals as compared to high-carbohydrate (HC) and high-fat (HF) meals.. Fifteen hyperinsulinemic normoglycemic men received, on 3 separate occasions, HP, HC, or HF meals in a randomized crossover design. Blood samples were collected before and after the ingestion of each meal. Postprandially, acylated ghrelin, PYY(3-36), insulin, glucose, and triglycerides were measured.. While the HC meal induced an acutely greater postprandial ghrelin decrease below baseline, the HP meal maintained this decline significantly more than the HF meal at 240 min. Postprandial PYY(3-36) responses did not significantly vary with time and meal composition. Postprandial insulin and glucose peaks were significantly lower following the HP and HF meals in comparison to the HC meal, whereas triglyceride responses were significantly higher following the HF meal. Significant correlations, negative between acylated ghrelin and insulin and positive between PYY(3-36) and insulin, were observed.. In hyperinsulinemic normoglycemic men, HP meals ensure a longer-lasting suppression of circulating ghrelin levels and result in more favorable metabolic responses, characterized by a lower surge of postprandial insulin and glucose and a reduced postprandial triglyceride response, as compared to both HC and HF meals.

Topics: Adolescent; Adult; Appetite Regulation; Blood Glucose; Dietary Carbohydrates; Dietary Fats; Dietary Proteins; Ghrelin; Humans; Hyperinsulinism; Insulin; Male; Obesity; Peptide YY; Postprandial Period; Triglycerides; Young Adult

The prevalence of obesity is increasing with an alarming rate worldwide and there is a need for efficacious satiety drugs. PYY3-36 has been shown to play a role in hypothalamic appetite regulation and novel analogs targeting the Y2 receptor have potential as drugs for the treatment of obesity. We have designed a series of novel PYY3-36 isoforms, by first adding the dipeptide Ile-Lys N-terminal to the N(α) of Ser-13 in PYY13-36 and then anchoring the N-terminal segment, e.g. PYY3-12, to the new Lys N(ε)-amine. We hypothesized that such modifications would alter the folding of PYY, due to changes in the turn motif, which could change the binding mode to the Y receptor sub-types and possibly also alter metabolic stability. In structure-affinity/activity relationship experiments, one series of PYY isoforms displayed equipotency towards the Y receptors. However, an increased Y2 receptor potency for the second series of PYY isoforms resulted in enhanced Y receptor selectivity compared to PYY3-36. Additionally, acute as well as chronic mice studies showed body-weight-lowering effects for one of the PYY isoforms, which was also reflected in a reduction of circulating leptin levels. Interestingly, while the stability and pharmacokinetic profile of PYY3-36 and the N-terminally modified PYY3-36 analogue were identical, only mice treated with the branched analogue showed marked increases in adiponectin levels as well as reductions in non-esterified free fatty acids and triglycerides.

Topics: Amino Acid Sequence; Animals; Appetite Regulation; Humans; Mice; Mice, Obese; Obesity; Peptide Hormones; Peptide YY; Protein Isoforms; Receptors, Neuropeptide Y; Structure-Activity Relationship

Topics: Adult; Energy Metabolism; Female; Homeostasis; Humans; Hypothalamo-Hypophyseal System; Male; Middle Aged; Obesity; Peptide Fragments; Peptide YY; Pituitary-Adrenal System

Topics: Appetite Regulation; Biomedical Research; Diabetes Mellitus, Type 2; Drug Design; Energy Metabolism; Forecasting; Gastrointestinal Motility; Ghrelin; Glucagon-Like Peptide 1; Humans; Obesity; Pancreatic Polypeptide; Peptide YY

Disturbed satiety and hunger perception in obese individuals has been reported, however data on the dynamic changes of hormonal mediators are sparse.. To evaluate the secretion pattern of insulin, ghrelin, peptide-YY (PYY), and amylin via 0 to 180 min oral glucose tolerance testing in obese and lean children.. A prospective clinical study was conducted on lean (n=9) and obese (n=20) Caucasian children of comparable age, gender, and pubertal stage. Serial blood samples were collected.. Compared to baseline, levels of acylated ghrelin showed a significant decrease in lean (p<0.05) but not in obese children. PYY increase was blunted and of shorter duration (60 min) in obese children. Amylin levels increased in both groups, and attained significantly higher levels in obese children (p<0.05).. Glucose stimulated gut hormone secretion differed between obese and lean children, and may explain the disturbed satiety observed in obese children.

Topics: Adolescent; Child; Energy Metabolism; Female; Gastrointestinal Hormones; Ghrelin; Humans; Insulin; Insulin Resistance; Islet Amyloid Polypeptide; Male; Obesity; Peptide YY

The last decade has witnessed a marked increase in our understanding of the importance of gut hormones in the regulation of energy homeostasis. In particular, the discovery that the gut hormone peptide YY 3-36 (PYY3-36) reduced feeding in obese rodents and humans fuelled interest in the role of PYY3-36 in body weight regulation. Pharmacological and genetic approaches have revealed that the Y2-receptor mediates the anorectic effects of PYY3-36 whilst mechanistic studies in rodents identified the hypothalamus, vagus and brainstem regions as potential sites of action. More recently, using functional brain imaging techniques in humans, PYY3-36 was found to modulate neuronal activity within hypothalamic and brainstem, and brain regions involved in reward processing. Several lines of evidence suggest that low circulating PYY concentrations predispose towards the development and or maintenance of obesity. Subjects with reduced postprandial PYY release exhibit lower satiety and circulating PYY levels that correlate negatively with markers of adiposity. In addition, mice lacking PYY are hyperphagic and become obese. Conversely, chronic PYY3-36 administration to obese rodents reduces adiposity, and transgenic mice with increased circulating PYY are resistant to diet-induced obesity. Moreover, there is emerging evidence that PYY3-36 may partly mediate the reduced appetite and weight loss benefits observed post-gastric bypass surgery. Taken together these findings, coupled with the retained responsiveness of obese subjects to the effects of PYY3-36, suggest that targeting the PYY system may offer a therapeutic strategy to help treat obesity.

Topics: Animals; Appetite Regulation; Eating; Energy Metabolism; Gastric Bypass; Humans; Obesity; Peptide Fragments; Peptide YY; Receptors, Gastrointestinal Hormone; Weight Loss

Topics: Animals; Appetite Depressants; Appetite Regulation; Central Nervous System; Feeding Behavior; Glucagon-Like Peptide 1; Humans; Hypothalamus; Neurosecretory Systems; Obesity; Peptide YY

Obtaining a fuller understanding of gut hormones as mediators of appetite regulation and energy homeostasis has never been so important with obesity rates increasing at pandemic proportions. The role of the gut hormone peptide YY 3-36 (PYY3-36) in particular has sparked interest since the discovery of its anorectic effect in obese rodents and humans. Fasting circulating PYY concentrations correlate negatively with BMI and waist circumference in humans, whilst postprandial PYY levels predict subsequent changes in weight over a period of at least 6 months. Furthermore, Pyy null mice demonstrate increased adiposity and hyperphagia, which is reversed by exogenous PYY3-36. Chronic administration of PYY3-36 to diet-induced obese rodents has shown a dose-dependent reduction in adiposity. Taken in concert, these findings suggest that the PYY system may hold significant potential in the treatment and prevention of obesity.

Topics: Animals; Appetite Regulation; Energy Metabolism; Humans; Mice; Obesity; Peptide YY

The Study of the Effects of Diet on Metabolism and Nutrition (STEDMAN) Project uses comprehensive metabolic profiling to probe biochemical mechanisms of weight loss in humans. Measurements at baseline, 2 and 4 weeks, 6 and 12 months included diet, body composition, metabolic rate, hormones, and 80 intermediary metabolites measured by mass spectrometry. In 27 obese adults in a behavioral weight loss intervention, median weight decreased 13.9 lb over the first 6 months, then reverted towards baseline by 12 months. Insulin resistance (HOMA) was partially ameliorated in the first 6 months and showed sustained improvement at 12 months despite weight regain. Ghrelin increased with weight loss and reverted to baseline, whereas leptin and PYY fell at 6 months and remained persistently low. NPY levels did not change. Factors possibly contributing to sustained improvement in insulin sensitivity despite weight regain include adiponectin (increased by 12 months), IGF-1 (increased during weight loss and continued to increase during weight regain), and visceral fat (fell at 6 months but did not change thereafter). We observed a persistent reduction in free fatty acids, branched chain amino acids, and related metabolites that may contribute to improved insulin action. These findings provide evidence for sustained benefits of weight loss in obese humans and insights into mechanisms.

Topics: Adiponectin; Adult; Behavior Therapy; Biomarkers; Body Weight; Diet; Energy Metabolism; Female; Ghrelin; Humans; Insulin Resistance; Insulin-Like Growth Factor I; Leptin; Middle Aged; Neuropeptide Y; Obesity; Peptide YY; Weight Gain; Weight Loss

Neuropeptide Y (NPY) and its family of peptides are thought to have a major role in the physiological control of energy homeostasis. Among five NPY receptors described, stimulation of the Y2 receptor (Y2R) or inhibition of the Y5 receptor (Y5R) has recently been shown to produce weight-lowering effects in obese rodents. The present study examined and compared the effects of a Y2R agonist, PYY(3-36), and a Y5R antagonist, alone and in combination, on food intake and body weight in diet-induced obese (DIO) mice. Acute intraperitoneal injection of PYY(3-36) dose-dependently reduced spontaneous feeding in lean and DIO mice. In contrast, acute oral administration of the Y5R antagonist had no effect on spontaneous feeding or the anorexigenic effects of PYY(3-36). In a chronic study, subcutaneous infusion of PYY(3-36) (1 mg/kg/day for 14 days) significantly reduced food intake and body weight in DIO mice. The Y5R antagonist (10 mg/kg/day for 14 days, orally) reduced body weight to the same extent as PYY(3-36) without a significant feeding reduction. Combined administration of PYY(3-36) and the Y5R antagonist resulted in a greater body weight reduction than treatment with either agent alone. The combined effects on food intake, body weight, and adiposity are almost the same as a hypothetical sum of the effects of each drug alone. These results illustrate that the combination of a Y2R agonist, PYY(3-36), and a Y5R antagonist resulted in additive effects on body weight and adiposity in DIO mice, suggesting that Y2R stimulation signal and Y5R blockade signal act by distinct pathways.

Topics: Adiposity; Animals; Anti-Obesity Agents; Body Weight; Dietary Fats; Eating; Male; Mice; Mice, Inbred C57BL; Obesity; Peptide YY; Receptors, Neuropeptide Y

Several abnormalities of peripheral neuropeptide release in obese and obese patients with binge eating disorder (BED) compared to controls have been reported: lower baseline, meal-induced, and post-meal ghrelin concentrations, decreased baseline PYY, and a blunted PYY response to meals. In contrast, obese BED individuals show comparable CCK releases. We aimed at clarifying the role of peripheral hormones in BED, to assess the impact of a cognitive behavioral treatment (CBT) for BED on neuropeptides and to investigate the predictive value of neuropeptide concentrations on binge eating status after treatment.. Blood samples of 14 female and 4 male overweight to obese participants with BED were collected repeatedly for CCK, PYY, and ghrelin analysis in the morning after an 8-h fasting period. BED participants and 19 controls matched for age and body mass index (BMI) were served a standardized breakfast. The release of neuropeptides was compared to corresponding measures of controls.. Fasting baseline values of all three peptides were comparable between BED participants and controls. BED participants revealed a higher meal-induced increase in CCK and PYY compared to controls, whereas ghrelin was not affected. Following a short-term CBT the neuropeptide concentration of the BED participants was comparable to before CBT. The hormone release prior to treatment had no predictive value on binge eating status after the treatment.. With respect to CCK and PYY our results point to a combined conditioned response from the central nervous system and the gut to initiate the release of satiety hormones in order to prevent further bingeing after initial food intake. The release of neuropeptides does not predict short-term treatment outcome. Future prospective studies should investigate whether neuropeptide secretion influences the course of BED in the long term.

Topics: Bulimia Nervosa; Case-Control Studies; Cholecystokinin; Cognitive Behavioral Therapy; Eating; Female; Ghrelin; Humans; Male; Middle Aged; Obesity; Peptide YY; Severity of Illness Index

Topics: Animals; Bariatric Surgery; Energy Intake; Fasting; Ghrelin; Humans; Insulin Resistance; Mice; Obesity; Peptide Fragments; Peptide YY; Postprandial Period; Rats; Receptors, Gastrointestinal Hormone; Satiation

Obesity is a heritable trait that contributes to hypertension and subsequent cardiorenal disease risk; thus, the investigation of genetic variation that predisposes individuals to obesity is an important goal. Circulating peptide YY (PYY) is known for its appetite and energy expenditure-regulating properties; linkage and association studies have suggested that PYY genetic variation contributes to susceptibility for obesity, rendering PYY an attractive candidate for study of disease risk.. To explore whether common genetic variation at the human PYY locus influences plasma PYY or metabolic traits, we systematically resequenced the gene for polymorphism discovery and then genotyped common single-nucleotide polymorphisms across the locus in an extensively phenotyped twin sample to determine associations. Finally, we experimentally validated the marker-on-trait associations using PYY 3'-untranslated region (UTR)/reporter and promoter/reporter analyses in neuroendocrine cells.. Four common genetic variants were discovered across the locus, and three were typed in phenotyped twins. Plasma PYY was highly heritable (P < 0.0001), and genetic pleiotropy was noted between plasma PYY and body mass index (BMI) (P = 0.03). A PYY haplotype extending from the proximal promoter (A-23G, rs2070592) to the 3'-UTR (C+1134A, rs162431) predicted not only plasma PYY (P = 0.009) but also other metabolic syndrome traits. Functional studies with transfected luciferase reporters confirmed regulatory roles in altering gene expression for both 3'-UTR C+1134A (P < 0.001) and promoter A-23G (P = 0.0016).. Functional genetic variation at the PYY locus influences multiple heritable metabolic syndrome traits, likely conferring susceptibility to obesity and subsequent cardiorenal disease.

Topics: 3' Untranslated Regions; Diseases in Twins; Exons; Gene Expression Regulation; Genetic Predisposition to Disease; Genetic Variation; Heart Diseases; Humans; Introns; Kidney Diseases; Metabolic Syndrome; Obesity; Peptide YY; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Twins

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

The aim of the study were to answer the question 1.) Whether circulating pro-inflammatory markers of endothelial dysfunction and due to chronic low-grade inflammation of obesity, are altered in untreated lean, young relatively healthy polycystic ovary syndrome (PCOS) patients in comparison with healthy controls; 2.) Whether postprandial plasma concentration pattern of ghrelin and PYY can be predictable as risk factors for atherosclerosis and depend of obesity. Forty young women with PCOS were divided in two groups: 19 lean and 21 obese. The control group included 20 lean, healthy volunteers. Plasma total and active ghrelin, total PYY and PYY(3-36), serum adiponectin and insulin were measured using RIA technique, serum sCD40L, visfatin, sP-, sE-selectins, resistin by EIA. Composition of test meal was: 527 kcal total and consisted of 24.1% fat, 54.4% carbohydrate and 21.5% protein. Total and active ghrelin and total PYY were significantly lower in obese PCOS women, whereas active ghrelin was also significantly lower in lean PCOS women compared to controls. Postprandial plasma total ghrelin levels decrease were blunted in lean and obese compared to controls (12.8 % and 18.2% vs 28.2 %). Postprandial plasma active ghrelin decreased in lean and obese PCOS groups (49.9 % and 44.1 %) and controls (63.8 %). PCOS subjects exhibited smaller rises in postprandial levels of total PYY. Postprandial plasma PYY(3-36) levels increased in obese PCOS women (30.9 %) and controls (41%), whereas lean PCOS women exhibited blunted increase (11.5%). sCD40L levels increased, whereas adiponectin decreased in PCOS groups independently, whereas rise in visfatin, sE- and sP-selectin and the fall in adiponectin was associated with obesity. sP- and sE -selectins correlated positively with obesity. In summary, our study provides the first evidence that lean untreated young PCOS women contribute to the so called "pancreatic islet adaptation to insulin resistance" because of ghrelin and PYY profiles. We confirmed existing of low-grade chronic inflammation in early stage of visceral obesity in lean PCOS patients. The lost endogenous "islet adaptation to insulin resistance" may lead to endothelial dysfunction and promote acceleration of atherosclerosis.

Topics: Adiponectin; Atherosclerosis; Biomarkers; Body Mass Index; Chronic Disease; Endothelium, Vascular; Female; Ghrelin; Humans; Inflammation; Insulin; Obesity; Peptide YY; Polycystic Ovary Syndrome; Postprandial Period; Risk Factors; Young Adult

To investigate the response of serum ghrelin and PYY to oral glucose and steamed-bread load and their relationships to insulin and glucose in nonobese and obese patients with type 2 diabetes.. Ten obese subjects (Male: waist > or =90 cm, Female: waist > or =80 cm) and eleven nonobese subjects with type 2 diabetes were given oral glucose load and steamed-bread challenge in 2 consecutive days after blood glucose was controlled. The serum levels of ghrelin, PYY, insulin and glucose were measured with routine methods.. (1) Either in oral glucose or steamed-bread load tests, both fasting serum PYY and ghrelin levels of obese subjects were significantly lower than those of nonobese subjects. After taking glucose or steamed-bread, all subjects were observed the increase of PYY and ghrelin levels, which reached the peak at 30 min and 60 min respectively. However, there were no significant difference found between nonobese and obese group at 30 min, 60 min and 120 min (P=NS). (2) In all subjects, fasting serum PYY, ghrelin concentrations were inversely associated with waist circumferences and BMI but not WHR. (3) No correlations were observed between serum PYY and insulin, glucose at any time points. The ghrelin and insulin levels showed a correlation at 0 min (r = -0.591, P = 0.005), however, no correlations were found at any other time points. When comparing PYY, ghrelin AUC with the AUC of insulin and glucose, no correlations were found. (4) Ghrelin level was positively correlated with QUICKI, however, no correlation between PYY concentrations and QUICKI was noted.. In the subjects with type 2 diabetes, both PYY and ghrelin respond differently to glucose and bread, athough the calories are similar. PYY and ghrelin levels are inversely related to waist and BMI but not WHR. It is fasting ghrelin not PYY negatively associated with fasting insulin and positively with QUICKI.

Topics: Adult; Aged; Diabetes Mellitus, Type 2; Female; Ghrelin; Glucose Tolerance Test; Humans; Insulin Resistance; Male; Middle Aged; Obesity; Peptide YY

SR141716 has been shown to significantly inhibit food intake and reduce body weight by antagonizing CB(1) receptors. The gut hormones peptide YY(3-36) (PYY(3-36)) and oxyntomodulin (OXM) inhibit food intake through Y(2) and Glucagon-Like-Peptide (GLP)-1 receptors respectively.. To determine the effects of co-administration of SR141716 with either PYY(3-36) or OXM in mice on food intake.. Mice (n = 14 per group) were fasted for 16 h prior to study days and given two intraperitoneal injections: study 1, vehicle-saline, SR141716-saline, vehicle-PYY3-36 or SR141716-PYY3-36; study 2: vehicle-saline, SR141716-saline, vehicle-OXM or SR141716-OXM. Food was returned and measured following injections.. Co-administration of SR141716-PYY(3-36) or SR141716-OXM showed greater inhibition in food intake when compared with administration of SR141716, PYY(3-36) or OXM alone.. Our data show that SR141716 in combination with PYY(3-36) or OXM reduces food intake additively in mice.

Topics: Animals; Dose-Response Relationship, Drug; Drug Therapy, Combination; Eating; Fasting; Mice; Obesity; Oxyntomodulin; Peptide Fragments; Peptide YY; Piperidines; Pyrazoles; Rimonabant; Treatment Outcome

The gut-derived hormone, peptide YY (PYY) reduces food intake and enhances satiety in both humans and animals. Obese individuals also have a deficiency in circulating peptide YY, although whether this is a cause or a consequence of obesity is unclear. Our aims were to determine whether peptide YY (PYY) over-expression may have therapeutic effects for the treatment of obesity by altering energy balance and glucose homeostasis. We generated PYY transgenic mice and measured body weight, food intake, temperature, adiposity, glucose tolerance, circulating hormone and lipid concentrations and hypothalamic neuropeptide levels (neuropeptide Y; proopiomelanocortin, and thyrotropin-releasing hormone) under chow and high-fat feeding and after crossing these mice onto the genetically obese leptin-deficient ob/ob mouse background. PYY transgenic mice were protected against diet-induced obesity in association with increased body temperature (indicative of increased thermogenesis) and sustained expression of thyrotropin-releasing hormone in the paraventricular nucleus of the hypothalamus. Moreover, PYY transgenic mice crossed onto the genetically obese ob/ob background had significantly decreased weight gain and adiposity, reduced serum triglyceride levels and improved glucose tolerance compared to ob/ob controls. There was no effect of PYY transgenic over expression on basal or fasting-induced food intake measured at 11-12 weeks of age. Together, these findings suggest that long-term administration of PYY, PYY-like compounds or agents that stimulate PYY synthesis in vivo can reduce excess adiposity and improve glucose tolerance, possibly via effects on the hypothalamo-pituitary-thyroid axis and thermogenesis.

Topics: Adiposity; Animals; Body Weight; Diet; Eating; Energy Metabolism; Glucose; Glucose Tolerance Test; Homeostasis; Hypothalamo-Hypophyseal System; In Situ Hybridization; Leptin; Mice; Mice, Inbred C57BL; Mice, Transgenic; Obesity; Paraventricular Hypothalamic Nucleus; Peptide YY; Reverse Transcriptase Polymerase Chain Reaction; Thermogenesis; Thyroid Gland; Thyrotropin

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

Gut-derived hormone peptide YY (PYY) is low in subjects with obesity and type 2 diabetes (T2D). However, it is unknown whether this is a primary defect or a consequence of metabolic disturbances. In this study, we aimed to assess whether low fasting and postprandial PYY secretion is an early defect, potentially promoting the development of obesity and T2D, and whether it is modified by macronutrient content.. Prospective cross-sectional cohort study.. Nine individuals with a strong family history of T2D (REL) and seven age and adiposity matched individuals with no family history of T2D (CON).. Metabolic studies including hyperinsulinemic-euglycemic clamp, dual X-ray absorptiometry and two meal tests containing 1000 kcal with an either high fat (76%) or high carbohydrate (76%) content.. Fasting and postprandial PYY levels were measured and analyzed for potential correlations with markers for adiposity and insulin resistance.. Insulin sensitivity was not different between REL and CON. Fasting glucose, insulin, triglycerides and PYY were also not different between groups. However, the postprandial incremental area under curve (AUC) of PYY was significantly lower in REL after the high carbohydrate (HCHO) meal (+27.3 vs +60.6% increase from baseline, P=0.038). The AUC of insulin during HCHO meal correlated negatively with both AUC and fasting level of PYY (r=-0.58 and -0.60, respectively, P<0.05).. A blunted postprandial PYY secretion is observed in a very early stage in the development of T2D in genetically susceptible individuals. This defect precedes the presence of insulin resistance and adiposity, and could therefore predispose to the development of T2D.

Topics: Adult; Area Under Curve; Blood Glucose; Diabetes Mellitus, Type 2; Dietary Carbohydrates; Dietary Fats; Disease Progression; Enteroendocrine Cells; Epidemiologic Studies; Family Health; Female; Genetic Predisposition to Disease; Glucose Clamp Technique; Humans; Insulin; Insulin Resistance; Male; Middle Aged; Obesity; Peptide YY; Postprandial Period; Triglycerides

Gut hormones [ghrelin, peptide YY (PYY) and glucagon-like peptide-1 (GLP-1)] are an important group of hormones that target appetite control. They are released from endocrine L cells of the small bowel in proportion to the volume, components and calories in a meal. In the current study, 20 g of gelatin (flavored and sweetened) were given to obese patients (n=12) and lean subjects (n=10). Subsequently, plasma samples were collected at-30- minute intervals up to 180 minutes and glucose, insulin, PYY, GLP-1 and ghrelin were assayed using specific and sensitive immunofluorometric and radioimmunoassays. As expected, obese patients had normal serum glucose levels, higher serum insulin, and lower plasma concentration of ghrelin at all times compared to lean subjects. GLP-1 plasma levels were significantly elevated at 60 minutes, peaking at 120 minutes in obese patients and lean subjects. As a consequence, there was a significant rise in serum insulin levels with a significantly higher peak level at 60 min (obese) and 30 min (lean). There were no significant changes in PYY plasma concentrations and no correlation was found between body mass index and concentrations of ghrelin, PYY and GLP-1 in the group of obese patients. In conclusion, a single gelatin meal induces a rise in plasma GLP-1 followed by an increase in serum levels of insulin. These findings may be applied to maximize satiety in obese patients as a means of improving adherence to calorie-controlled diets as well as provide better control of diabetic patients.

Topics: Adult; Blood Glucose; Body Mass Index; Case-Control Studies; Female; Gelatin; Ghrelin; Glucagon-Like Peptide 1; Humans; Insulin; Male; Middle Aged; Obesity; Peptide YY; Postprandial Period; Thinness

Ghrelin and polipeptide YY (PYY) are involved in the regulation of food intake. We evaluated these two peptides and their possible relationship in adult patients with Prader-Willi syndrome (PWS).. Seven patients with PWS, 16 age-sex-BMI matched obese and 42 age-sex matched lean subjects.. Fasting plasma PYY and ghrelin levels were measured in all subjects and, postprandially until 6 h, in seven matched subjects of each group.. Fasting ghrelin levels were higher in PWS than in the other two groups. Fasting PYY levels were lower in patients with PWS than in lean subjects but similar to those in obese subjects. The postprandial decrease in ghrelin concentrations was lower in PWS as compared to the other two groups and therefore the 6-h-postprandial area under the curve (AUC) for ghrelin was higher in PWS than in obese subjects. PYY response after the meal was blunted in patients with PWS, but not in the other two groups that showed a peak at 60 min The AUC for PYY was lower in PWS as compared to the other two groups. Fasting PYY levels correlated negatively with fasting ghrelin levels and with ghrelin AUC and they were the only predictor for ghrelin AUC (beta = -0.464, P = 0.034). The increase in PYY correlated negatively with the decrease in ghrelin at times 60 min and 120 min in PWS.. In PWS, the low decrease in postprandial ghrelin levels could be related to the low fasting PYY concentrations and their blunted postprandial response.

Topics: Adult; Analysis of Variance; Area Under Curve; Case-Control Studies; Fasting; Female; Ghrelin; Humans; Insulin; Insulin-Like Growth Factor I; Male; Obesity; Peptide Hormones; Peptide YY; Postprandial Period; Prader-Willi Syndrome

Peptide YY(3-36) [PYY(3-36)] is a gut-brain peptide that decreases food intake when administered by intravenous infusion to lean and obese humans and rats. However, chronic administration of PYY(3-36) by osmotic minipump to lean and obese rodents produces only a transient reduction in daily food intake and weight gain. It has recently been shown that 1-h intravenous infusions of PYY(3-36) every other hour for 10 days produced a sustained reduction in daily food intake, body weight, and adiposity in lean rats. Here, we determined whether intermittent delivery of PYY(3-36) can produce a similar response in diet-induced obese rats. During a 21-day period, obese rats (body fat >25%) received twice daily intraperitoneal infusion of vehicle (n = 18) or PYY(3-36) (n = 24) during hours 1-3 and 7-9 of the dark period. Rats had free access to both a 45% fat solid diet and a 29% fat liquid diet; intakes were determined from continuous computer recording of changes in food container weights. To sustain a 15-25% reduction in daily caloric intake, the initial PYY(3-36) dose of 30 pmol.kg(-1).min(-1) was reduced to 10 pmol.kg(-1).min(-1) on day 10 and then increased to 17 pmol.kg(-1).min(-1) on day 13. This dosing strategy produced a sustained reduction in daily caloric intake of 11-32% and prevented body weight gain (8 +/- 6 vs. 51 +/- 11 g) and fat deposition (4.4 +/- 7.6 vs. 41.0 +/- 12.8 g). These results indicate that intermittent intraperitoneal infusion of PYY(3-36) can produce a sustained reduction in food intake and adiposity in diet-induced obese rodents consuming palatable high-fat foods.

Topics: Adiposity; Animals; Body Weight; Diet; Dose-Response Relationship, Drug; Eating; Energy Intake; Infusions, Intravenous; Infusions, Parenteral; Male; Obesity; Peptide Fragments; Peptide YY; Rats; Rats, Sprague-Dawley; Weight Gain

Metabolic syndrome (MS), defined as central obesity, hyperinsulinemia, insulin resistance, hypertension, dyslipidemia and glucose intolerance, has been associated with inflammatory biomarkers and cardiovascular diseases. This study was carried out on three groups of women; lean controls, moderately obese with MS (OB-MS) and morbidly obese with MS (MOB-MS). The main objectives were: 1. to analyze the plasma levels of total and acylated ghrelin, peptide YY(3-36) (PYY(3-36)), cholecystokinin (CCK), gastrin and insulin levels under basal conditions and in response to a standard mixed meal, and 2. to elucidate the relationship between the plasma levels of these gut peptides and metabolic syndrome parameters. Plasma levels of the gut hormones were measured by radioimmunoassays at time 0 just before the meal and at 30, 60 and 120 min after a meal ingestion. Traditional lipid profile and high-sensitivity C reactive protein (hs-CRP), the strongest biomarker of inflammation were also determined in OB-MS and MOB-MS. When compared to OB-MS, MOB-MS exhibited much higher anthropometric parameters such as waist circumference, higher fat mass and higher plasma levels of low density lipoprotein-cholesterol (LDL-C) and hs-CRP. Both these obese groups revealed significantly higher values of body mass index (BMI), fat mass, total cholesterol (TC), LDL-C, fasting glucose, fasting insulin, insulin resistance (IR) calculated from homeostatic model assessment (HOMA) and hs-CRP compared to the values recorded in lean subjects. Fasting PYY(3-36) level was lower, while fasting acylated ghrelin was higher in MOB-MS than in OB-MS. Plasma total and acylated ghrelin levels were significantly lower in OB-MS compared to lean women. In MOB-MS women the fasting PYY(3-36) levels were lower compared to lean controls and OB-MS, whilst postprandially in both OB-MS and MOB-MS, it was much lower than in lean women. The fasting plasma levels of total and acylated ghrelin and their postprandial decrease were significantly smaller in both obese groups compared to lean subjects. Plasma hs-CRP levels correlated positively with BMI, waist circumference, fat mass, fasting glucose, HOMA IR and fasting active ghrelin, whilst it negatively correlated with plasma fasting and total ghrelin. Moreover, plasma fasting acylated ghrelin correlated positively with fat mass. Fasting total ghrelin correlated positively with BMI, HDL-C and negatively with HOMA IR. We conclude that MS features of obesity are closely

Topics: Acylation; Adult; Blood Glucose; Body Mass Index; C-Reactive Protein; Cholecystokinin; Cholesterol, LDL; Fasting; Female; Gastrins; Gastrointestinal Hormones; Ghrelin; Humans; Insulin; Insulin Resistance; Metabolic Syndrome; Obesity; Obesity, Morbid; Peptide Hormones; Peptide YY; Poland; Postprandial Period

Maternal obesity has been reported as a risk factor for various maternal and fetal complications. The aim of the present study was to examine the patterns of basal and postprandial plasma concentrations of certain gut hormones affecting food intake such as acylated ghrelin, peptide YY(3-36) (PYY(3-36)), cholecystokinin (CCK), insulin and glucose in pregnant women with varying body mass gain during physiological pregnancy. The study included 34 women with singleton pregnancies in the 2(nd) trimester of gestation. The examined pregnant women were divided into 4 groups; I. control pregnancy (CP) with weight gain below 0.5 kg/week; II. overweight low weight gain <1 kg/week (OLWG), III. overweight high weight gain >1 kg/week (OHWG); morbidly obese pregnant with weight gain >1.5 kg/week (MOP). The basal acylated-ghrelin levels in MOP subjects were significantly higher than those in CP and no usual suppression of acylated ghrelin after the meal observed in CP as well as in OLWG and OHWG was found in MOP women. Basal PYY(3-36) plasma levels were similar in CP, OLWG and OHWG but in MOP was significantly reduced and no significant increase in hormone level, typically observed in CP, was detected after a meal in overweight or obese women studied. The fasting CCK and C-reactive protein (CRP) levels in MOP subjects were significantly higher than those in CP and other overweight women. In conclusion, we found that pregnant women with overweight and obesity exhibit significant changes in fasting and postprandial gut hormones affecting food intake such as acylated ghrelin, PYY(3-36) and CCK as well as in CRP and these changes might contribute, at least in part, the development of obesity in pregnancy.

Topics: Acylation; Adult; Appetite; Blood Glucose; Body Mass Index; C-Reactive Protein; Cholecystokinin; Fasting; Female; Gastrins; Gastrointestinal Hormones; Ghrelin; Homeostasis; Humans; Insulin; Obesity; Obesity, Morbid; Peptide Hormones; Peptide YY; Poland; Postprandial Period; Pregnancy; Pregnancy Complications; Weight Gain

Peptide YY (PYY) is a gastrointestinal hormone, localized in enteroendocrine L-cells. Its hydrolyzed form PYY(3-36) is a satiety factor. The aim of this study was to identify if intestinal PYY enteroendocrine cells or content correlate with the diet-induced obese (DIO) or diet-resistant (DR) phenotypes. We also examined intestinal sensitivity to PYY and PYY(3-36) in DIO and DR rats. Animals were maintained on a medium-high fat diet and split into DIO and DR groups based on weight gain. PYY immunoreactive cells were unaltered in DIO intestine and stomach compared to DR rats. PYY content and circulating levels were also unchanged in DIO rats. Intestinal PYY and PYY(3-36) responses were enhanced in fasted rats, and equipotent in both DIO and DR jejunum. We conclude that PYY cell number, tissue content and peripheral sensitivity are maintained in DIO rats. Our data suggests that neither PYY nor PYY(3-36) contribute to the maintenance of either the DIO or DR phenotype, and that peripheral resistance to PYY and PYY(3-36) does not accompany DIO.

Topics: Adipose Tissue; Animals; Body Weight; Diet; Dietary Fats; Eating; Enteroendocrine Cells; Fasting; Feeding Behavior; Male; Obesity; Peptide YY; Rats; Rats, Sprague-Dawley; Weight Gain

Prader-Willi syndrome (PWS) is a contiguous gene syndrome characterized by uncontrollable eating or hyperphagia. Several studies have confirmed that plasma ghrelin levels are markedly elevated in PWS adults and children. The study of anorexigenic hormones is of interest because of their regulation of appetite by negative signals. To study the pattern and response of the anorexigenic hormones such as cholecystokinin (CCK) and peptide YY (PYY) to a meal in PWS, we measured the plasma CCK, PYY, ghrelin and serum insulin levels in PWS patients (n=4) and in controls (n=4) hourly for a day, and analyzed hormone levels and hormonal responses to meals. Repeated measures of ANOVA of hormone levels demonstrated that only insulin levels decreased (p=0.013) and CCK (p=0.005) and ghrelin (p=0.0007) increased in PWS over 24 hr. However, no significant group x time interactions (ghrelin: p=0.89, CCK: p=0.93, PYY: p=0.68 and insulin: p=0.85) were observed; in addition, there were no differences in an assessment of a three-hour area under the curve after breakfast. These results suggest that the response pattern of hormones to meals in PWS patients parallels that of normal controls. In addition, the decrease of insulin levels over 24 hr, in spite of obesity and elevated ghrelin levels, suggests that the baseline insulin level, not the insulin response to meals, may be abnormal in patients with PWS.

Topics: Adolescent; Area Under Curve; Biopsy; Body Mass Index; Body Weight; Child; Cholecystokinin; Ghrelin; Humans; Insulin; Male; Obesity; Peptide Hormones; Peptide YY; Prader-Willi Syndrome; Time Factors

It is well known that the peripheral peptide YY (PYY)-central neuropeptide Y (NPY) Y2 receptor axis plays an important role in promoting negative energy balance regulation. Both the hypothalamus and medulla oblongata express a high level of Y2 receptors; however, the functional role of this receptor in chronic high-fat diet-induced obesity has not been fully examined. Using quantitative autoradiography, this study measured binding densities of total [(125)I]PYY and Y2 receptors in the hypothalamus and medulla of chronic high-fat diet-induced obese (DIO), obese-resistant, and low-fat-fed mice. Plasma PYY was also measured using RIA after 22 wk of dietary intervention. The results revealed that body weight gain was significantly higher in the obese mice, compared with the lean mice. Furthermore, PYY and NPY Y2 receptor binding densities in the medulla of the obese mice were significantly higher, compared with the lean mice, whereas the level of plasma PYY was significantly lower in the DIO mice than the low-fat-fed mice. In conclusion, this study showed that the DIO mice had low plasma PYY, which may have caused a compensatory up-regulation of PYY and Y2 receptor densities in the medulla. A low-level response of PYY-medullary regulation to positive energy balance may have contributed to the development of high-fat diet-induced obesity in DIO mice; conversely, a normal response of this regulatory axis in the obese-resistant mice may have contributed to the maintenance of body weight while on a high-fat diet.

Topics: Adipose Tissue; Animals; Autoradiography; Body Weight; Diet, Fat-Restricted; Dietary Fats; Disease Susceptibility; Energy Intake; Hypothalamus; Medulla Oblongata; Mice; Mice, Inbred C57BL; Obesity; Organ Size; Peptide YY; Receptors, Neuropeptide Y

Circulating levels of the pancreatic beta-cell peptide hormone amylin and the gut peptide PYY[3-36] increase after nutrient ingestion. Both have been implicated as short-term signals of meal termination with anorexigenic and weight-reducing effects. However, their combined effects are unknown. We report that the combination of amylin and PYY[3-36] elicited greater anorexigenic and weight-reducing effects than either peptide alone. In high-fat-fed rats, a single ip injection of amylin (10 microg/kg) plus PYY[3-36] (1000 microg/kg) reduced food intake for 24 h (P < 0.05 vs. vehicle), whereas the anorexigenic effects of either PYY[3-36] or amylin alone began to diminish 6 h after injection. These anorexigenic effects were dissociable from changes in locomotor activity. Subcutaneous infusion of amylin plus PYY[3-36] for 14 d suppressed food intake and body weight to a greater extent than either agent alone in both rat and mouse diet-induced obesity (DIO) models (P < 0.05). In DIO-prone rats, 24-h metabolic rate was maintained despite weight loss, and amylin plus PYY[3-36] (but not monotherapy) increased 24-h fat oxidation (P < 0.05 vs. vehicle). Finally, a 4 x 3 factorial design was used to formally describe the interaction between amylin and PYY[3-36]. DIO-prone rats were treated with amylin (0, 4, 20, and 100 microg/kg.d) and PYY[3-36] (0, 200, 400 microg/kg.d) alone and in combination for 14 d. Statistical analyses revealed that food intake suppression with amylin plus PYY[3-36] treatment was synergistic, whereas body weight reduction was additive. Collectively, these observations highlight the importance of studying peptide hormones in combination and suggest that integrated neurohormonal approaches may hold promise as treatments for obesity.

Topics: Amyloid; Animals; Anti-Obesity Agents; Dietary Fats; Drug Synergism; Drug Therapy, Combination; Eating; Humans; Islet Amyloid Polypeptide; Male; Mice; Obesity; Peptide Fragments; Peptide YY; Rats; Weight Loss

Topics: Animals; Anti-Obesity Agents; Eating; Humans; Male; Mice; Obesity; Peptide YY

Glucose-dependent insulinotropic polypeptide (GIP) and peptide YY (PYY) are secreted from the intestinal K- and L-cells, respectively, following a meal. Both peptides are believed to play a key role in glucose homeostasis and energy expenditure. This study investigated the effects of daily administration of the stable and specific GIP-R antagonist, (Pro(3))GIP (25 nmol/kg) and the endogenous truncated form of PYY, PYY(3-36) (50 nmol/kg), in mice fed with a high fat diet. Daily i.p. injection of (Pro(3))GIP, PYY(3-36) or combined peptide administration over 24 days significantly (P<0.05-0.01) decreased body weight compared with saline-treated controls without change in food intake. Plasma glucose levels and glucose tolerance were significantly (P<0.05) lowered by (Pro(3))GIP treatment alone, and in combination with PYY(3-36). These changes were accompanied by a slight improvement of insulin sensitivity in all of the treatment groups. (Pro(3))GIP treatment significantly reduced plasma corticosterone (P<0.05), while combined administration with PYY(3-36) significantly lowered serum glucagon (P<0.05). No appreciable changes were observed in either circulating or glucose-stimulated insulin secretion in all treatment groups. (Pro(3))GIP-treated mice had significantly (P<0.01) lowered fasting glucose levels and an improved (P<0.05) glycemic response to feeding. These comparative data indicate that chemical ablation of GIP receptor action using (Pro(3))GIP provides an especially effective means of countering obesity and related abnormalities induced by consumption of high fat energy rich diet.

Topics: Animals; Blood Glucose; Corticosterone; Dietary Fats; Gastric Inhibitory Polypeptide; Glucagon; Glucose Tolerance Test; Insulin; Male; Mice; Obesity; Peptide Fragments; Peptide YY; Receptors, Gastrointestinal Hormone

Topics: Administration, Oral; Appetite; Appetite Depressants; Cholecystokinin; Energy Intake; Fatty Acids, Nonesterified; Gastric Emptying; Gastrointestinal Hormones; Gastrointestinal Tract; Gastrointestinal Transit; Humans; Obesity; Peptide YY; Triglycerides

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

Animal studies have revealed brain regions that control homeostatic feeding, but the rampant overeating contributing to the obesity epidemic suggests the participation of "nonhomeostatic" control centers. Recent papers by Batterham et al. (2007) and Farooqi et al. (2007) link peptide YY(3-36) and leptin to the activation of nonhomeostatic brain regions.

Topics: Animals; Brain; Eating; Food; Homeostasis; Humans; Leptin; Magnetic Resonance Imaging; Models, Neurological; Obesity; Peptide Fragments; Peptide YY; Reward

The responses of the gut hormone peptide YY (PYY) to food were investigated in 20 normal-weight and 20 obese humans in response to six test meals of varying calorie content. Human volunteers had a graded rise in plasma PYY (R2 = 0.96; P < 0.001) during increasing calorific meals, but the obese subjects had a lower endogenous PYY response at each meal size (P < 0.05 at all levels). The ratio of plasma PYY(1-36) to PYY(3-36) was similar in normal-weight and obese subjects. The effect on food intake and satiety of graded doses of exogenous PYY(3-36) was also evaluated in 12 human volunteers. Stepwise increasing doses of exogenous PYY(3-36) in humans caused a graded reduction in food intake (R2 = 0.38; P < 0.001). In high-fat-fed (HF) mice that became obese and low-fat-fed mice that remained normal weight, we measured plasma PYY, tissue PYY, and PYY mRNA levels and assessed the effect of exogenous administered PYY(3-36) on food intake in HF mice. HF mice remained sensitive to the anorectic effects of exogenous ip PYY(3-36). Compared with low-fat-fed fed mice, the HF mice had lower endogenous plasma PYY and higher tissue PYY but similar PYY mRNA levels, suggesting a possible reduction of PYY release. Thus, fasting and postprandial endogenous plasma PYY levels were attenuated in obese humans and rodents. The PYY(3-36) infusion study showed that the degree of plasma PYY reduction in obese subjects were likely associated with decreased satiety and relatively increased food intake. We conclude that obese subjects have a PYY deficiency that would reduce satiety and could thus reinforce their obesity.

Topics: Animals; Body Weight; Eating; Energy Intake; Humans; Mice; Models, Animal; Obesity; Peptide YY; Postprandial Period; Reference Values; Satiety Response

Endogenous peptide YY(3-36) (PYY(3-36)) is associated with postprandial regulation of appetite. We investigated the safety and effectiveness of peripherally administered synthetic human PYY(3-36) for 14 days in New Zealand white rabbits. Weight gain and food consumption were assessed and pharmacokinetics and toxicity characterized.. In all, 24 animals were randomized to one of four intravenous treatment groups - control (0.9% saline) or PYY(3-36) bolus at 4.1, 41.0, or 205 microg/kg/day. Body weight and consumption of fixed food allotment were measured daily. Hematology and serum chemistries were profiled at baseline and Day 15, and pharmacokinetics measured following dose 14. Histopathologic examination of designated tissues and organs in control and PYY(3-36) 205 mug/kg animals was conducted. All animals were subject to clinical and macroscopic observation.. The trend effect of higher dose PYY(3-36) on lower average weight was significant (P = 0.01; Day 14 compared to baseline) and its effect on reduced food consumption was suggested (P = 0.065; number of days < or =75% food eaten, compared with control). Hematology and clinical chemistries were within normal limits pretest and at Day 15. No clinical, macroscopic, histologic, or microscopic changes related to the test article were observed over the course of study.. Lower average weight occurs in rabbits treated once daily with intravenous injection PYY(3-36) (205 microg/kg/day) over 14 days. No clinical or histologic signs of toxicity were observed. Further research is warranted to describe alternate routes of peripheral administration for optimizing weight control.

Topics: Animals; Appetite Depressants; Appetite Regulation; Body Weight; Dose-Response Relationship, Drug; Eating; Female; Infusions, Intravenous; Male; Obesity; Peptide Fragments; Peptide YY; Rabbits; Satiety Response; Weight Gain

Gut hormones and their receptors are considered important in the control of feeding behavior. The gut hormone peptide-YY (PYY) has anorexic effects via the inhibitory neuropeptide Y2 receptor (Y2R) highly expressed in orexigenic NPY/AGRP neurons within the arcuate nucleus, a major integrator of appetite control in the hypothalamus.. Genetic case-control association study of single nucleotide polymorphisms (SNPs) in Y2R and PYY.. Swedish Caucasians comprising 148 lean, 129 overweight/obese and 226 morbidly obese men.. Genotypes of the common, silent and conserved SNP Y2R 585T>C and the common SNP PYY Arg72Thr, as well as various obesity-related clinical parameters.. Obese men had a lower allele and homozygosity frequency of the common allele 585T>C:T which was particularly evident comparing morbidly obese with lean men (P = 0.002), and analyzing dependence between continuous body mass index (BMI) and genotype (P = 0.002). In agreement, systolic blood pressure tended to be lower in those homozygous for allele T, which was not explained by the BMI - genotype dependence. We found no association to obesity for the PYY Arg72Thr polymorphism, which is located nearby the essential carboxy terminal.. A common and conserved variant of the PYY and NPY receptor Y2R is less prevalent among obese compared to among lean Swedish men. This suggests that the common Y2R variant is protective against obesity. Our findings further implicate Y2R in food intake regulation.

Topics: Adolescent; Adult; Aged; Appetite Regulation; Body Mass Index; Case-Control Studies; Gene Frequency; Genetic Predisposition to Disease; Genotype; Humans; Male; Middle Aged; Obesity; Obesity, Morbid; Overweight; Peptide YY; Polymorphism, Single Nucleotide; Receptors, Neuropeptide Y

In rodents, weight reduction after peptide YY[3-36] (PYY[3-36]) administration may be due largely to decreased food consumption. Effects on other processes affecting energy balance (energy expenditure, fuel partitioning, gut nutrient uptake) remain poorly understood. We examined whether s.c. infusion of 1 mg/(kg x d) PYY[3-36] (for up to 7 d) increased metabolic rate, fat combustion, and/or fecal energy loss in obese mice fed a high-fat diet. PYY[3-36] transiently reduced food intake (e.g., 25-43% lower at d 2 relative to pretreatment baseline) and decreased body weight (e.g., 9-10% reduction at d 2 vs. baseline) in 3 separate studies. Mass-specific metabolic rate in kJ/(kg x h) in PYY[3-36]-treated mice did not differ from controls. The dark cycle respiratory quotient (RQ) was transiently decreased. On d 2, it was 0.747 +/- 0.008 compared with 0.786 +/- 0.004 for controls (P < 0.001); light cycle RQ was reduced throughout the study in PYY[3-36]-treated mice (0.730 +/- 0.006) compared with controls (0.750 +/- 0.009; P < 0.001). Epididymal fat pad weight in PYY[3-36]-treated mice was approximately 50% lower than in controls (P < 0.01). Fat pad lipolysis ex vivo was not stimulated by PYY[3-36]. PYY[3-36] decreased basal gallbladder emptying in nonobese mice. Fecal energy loss was negligible ( approximately 2% of ingested energy) and did not differ between PYY[3-36]-treated mice and controls. Thus, negative energy balance after PYY[3-36] administration in diet-induced obese mice results from reduced food intake with a relative maintenance of mass-specific energy expenditure. Fat loss and reduced RQ highlight the potential for PYY[3-36] to drive increased mobilization of fat stores to help meet energy requirements in this model.

Topics: Adipose Tissue; Animals; Body Weight; Calorimetry; Dietary Fats; Energy Metabolism; Male; Mice; Mice, Inbred C57BL; Obesity; Peptide Fragments; Peptide YY

Topics: Drug Resistance; Humans; Obesity; Peptide YY; Satiety Response

Peptide YY (PYY) has been implicated in the control of food intake through functional studies in rodents and humans. To investigate whether genetic alterations within this gene result in abnormal weight in humans, we sequenced its coding exons and splice sites in a large cohort of extremely obese [n = 379; average body mass index (BMI), 49.0 kg/m2] and lean (n = 378; average BMI, 19.5 kg/m2) individuals. In total, three rare non-synonymous variants were identified, only one of which, PYY Q62P, exhibited familial segregation with body mass. Through serendipity, previous studies based on cell culture revealed this precise variant to have altered receptor-binding selectivity in vitro. We further show, using mouse peptide injection experiments, that while the wild-type PYY peptide reduces food intake, the mutant PYY 62P had an insignificant effect in reducing food intake in vivo. Taken together, these results are the first to support that rare sequence variants within PYY can influence human susceptibility to obesity.

Topics: Amino Acid Sequence; Animals; Case-Control Studies; Eating; Fasting; Genetic Predisposition to Disease; Humans; Male; Mice; Molecular Sequence Data; Mutation, Missense; Obesity; Pedigree; Peptide YY; Postprandial Period; Sequence Alignment; Sequence Analysis, DNA

To study the effect of bariatric surgery on the entero-hypothalamic endocrine axis of humans and rodents.. Bariatric surgery is the most effective obesity treatment as it achieves substantial and sustained weight loss. Glycemic control and enhanced satiation improve before substantial weight loss occurs. Gut peptides, acting both peripherally and centrally, contribute to glycemic control and regulate food intake.. We examined meal-stimulated responses of insulin, ghrelin, peptide YY (PYY), glucagon-like-peptide-1 (GLP-1), and pancreatic polypeptide (PP) in humans and rodents following different bariatric surgical techniques.. Compared with lean and obese controls, patients following Roux-en-Y gastric bypass (RYGB) had increased postprandial plasma PYY and GLP-1 favoring enhanced satiety. Furthermore, RYGB patients had early and exaggerated insulin responses, potentially mediating improved glycemic control. None of these effects were observed in patients losing equivalent weight through gastric banding. Leptin, ghrelin, and PP were similar in both the surgical groups. Using a rodent model of jejuno-intestinal bypass (JIB), we showed elevated PYY and GLP-1 in JIB rats compared with sham-operated rats. Moreover, exogenous PYY reduced food intake and blockade of endogenous PYY increased food intake. Thus, higher plasma PYY following JIB may contribute to reduced food intake and contribute to weight loss.. Following RYGB and JIB, a pleiotropic endocrine response may contribute to the improved glycemic control, appetite reduction, and long-term changes in body weight.

Topics: Adult; Animals; Appetite; Bariatric Surgery; Cross-Sectional Studies; Female; Gastrointestinal Hormones; Ghrelin; Glucagon-Like Peptide 1; Humans; Insulin; Male; Models, Animal; Obesity; Pancreatic Polypeptide; Peptide Hormones; Peptide YY; Rats; Rats, Wistar; Weight Loss

To study the plasma concentration of peptide YY3 - 36 (PYY3-36) and the expression levels of PYY mRNA of ileum and colon in dietary induced obesity (DIO) and dietary induced obesity resistant (DIO-R) rats and the relation between PYY3-36 and DIO-R rats.. Thirty-six female SD rats were randomly divided into high-fat diet group (n = 27) and chow fed control group (n = 9), after 13 weeks of either a high-fat diet or chew fed diet, the high-fat diet group was subdivided into DIO and DIO-R group according to the final body weight. Weight gain, caloric intake, the concentration of PYY3-36 and the expression levels of PYY mRNA were measured and compared.. The total caloric intake of DIO-R rats was lower than DIO rats (P < 0.01), while no significant difference was found between DIO-R and control rats (P > 0.05). The concentration of PYY3-36 and the expressions of PYY mRNA of ileum and colon in DIO-R rats were higher significantly than that of the DIO and control rats (P < 0.01), while no significant difference was found between DIO and control group (P > 0.05), except that PYY mRNA of ileum was advanced in DIO group (P < 0.01).. On the High-fat diet, SD rats showed different susceptibility to obese and energy intake, increased levels of PYY3-36 and PYY mRNA might be related to dietary induced obesity resistant.

Topics: Animals; Dietary Fats; Female; Genetic Predisposition to Disease; Intestinal Mucosa; Obesity; Peptide Fragments; Peptide YY; Random Allocation; Rats; Rats, Sprague-Dawley; RNA, Messenger

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.. 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.. 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.. 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.

Topics: Adipose Tissue; Animals; Body Weight; Chromosomes, Artificial, Bacterial; Cloning, Molecular; DNA Primers; Energy Intake; Female; Glucose Tolerance Test; Hyperinsulinism; Male; Mice; Mice, Knockout; Obesity; Organ Size; Peptide YY; Polymerase Chain Reaction; Restriction Mapping; Sex Characteristics

Obesity prevalence is higher in African-American (AA) vs. American white (AW) youth. Ghrelin is a "hunger" peptide that is high preprandially and decreases postprandially, and peptide YY (PYY) is a "satiety" hormone increasing after meals. Impaired regulation of ghrelin/PYY may be conducive to obesity. We hypothesized that racial differences in childhood obesity could partly be explained by differences in ghrelin/PYY dynamics.. We investigated: 1) ghrelin suppression/PYY elevation in response to an oral glucose tolerance test (OGTT) in AA vs. AW, and 2) the relationship of ghrelin and PYY dynamics to insulin sensitivity. Thirty-three AA and 54 AW prepubertal children underwent an OGTT measuring ghrelin, PYY, glucose, and insulin. Fasting glucose to insulin ratio (G(F)/I(F)) was used to assess the relationship of insulin sensitivity to fasting and post-OGTT ghrelin and PYY levels.. OGTT-induced suppression in ghrelin (Delta ghrelin) was lower in AA youth. Delta ghrelin correlated with G(F)/I(F) (r = 0.47, P < 0.001) and Delta insulin at 30 min (r = -0.47, P < 0.001). In multiple regression analysis, race (P = 0.013) and G(F)/I(F) (P = 0.004) contributed independently to the variance in Delta ghrelin (R(2) = 0.28, P < 0.001). Fasting and post-OGTT PYY levels were lower in AAs and were not related to insulin sensitivity.. The lower suppression of ghrelin in AA, but not the lower PYY levels, correlates with insulinemia and insulin resistance. Less ghrelin suppression and PYY elevation after a meal in black youth could be a potential mechanism of race-related differences in hunger/satiety predisposing to risk of obesity.

Topics: Black or African American; Blood Glucose; Body Composition; Body Mass Index; Child; Fasting; Female; Ghrelin; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Male; Obesity; Peptide Hormones; Peptide YY; Racial Groups; Regression Analysis; White People

Topics: Adolescent; Appetite Regulation; Black or African American; Child; Ghrelin; Hormones; Humans; Obesity; Peptide Fragments; Peptide Hormones; Peptide YY; White People

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

To assess the effects of energy dilution with non-fermentable and fermentable fibers on abdominal fat and gut peptide YY (PYY) and glucagon-like peptide (GLP)-1 expressions, three rat studies were conducted to: determine the effects of energy dilution with a non-fermentable fiber, compare similar fiber levels of fermentable and non-fermentable fibers, and compare similar metabolizable energy dilutions with fermentable and non-fermentable fibers.. In Study 1, rats were fed one of three diets with different metabolizable energy densities. In Study 2, rats were fed diets with similar fiber levels using high amylose-resistant cornstarch (RS) or methylcellulose. In Study 3, rats were fed diets with a similar dilution of metabolizable energy using cellulose or RS. Measurements included food intake, body weight, abdominal fat, plasma PYY and GLP-1, gastrointestinal tract weights, and gene transcription of PYY and proglucagon.. Energy dilution resulted in decreased abdominal fat in all studies. In Study 2, rats fed fermentable RS had increased cecal weights and plasma PYY and GLP-1, and increased gene transcription of PYY and proglucagon. In Study 3, RS-fed rats had increased short-chain fatty acids in cecal contents, plasma PYY (GLP-1 not measured), and gene transcription for PYY and proglucagon.. Inclusion of RS in the diet may affect energy balance through its effect as a fiber or a stimulator of PYY and GLP-1 expression. Increasing gut hormone signaling with a bioactive functional food such as RS may be an effective natural approach to the treatment of obesity.

Topics: Adipose Tissue; Animals; Cecum; Dietary Fiber; Energy Intake; Energy Metabolism; Fatty Acids, Volatile; Female; Fermentation; Glucagon-Like Peptide 1; Humans; Obesity; Organ Size; Peptide YY; Proglucagon; Random Allocation; Rats; Rats, Sprague-Dawley; Starch

To explore the potential role of the endogenous peptide YY (PYY) in the long-term regulation of body weight and energy homeostasis.. Fasting and postprandial plasma PYY concentrations were measured after an overnight fast and 30 to 180 minutes after a standardized meal in 29 (21 men/8 women) non-diabetic subjects, 16 of whom had a follow-up visit 10.8 +/- 1.4 months later. Ratings of hunger and satiety were collected using visual analog scales. Resting metabolic rate (RMR) (15-hour RMR) and respiratory quotient (RQ) were assessed using a respiratory chamber.. Fasting PYY concentrations were negatively correlated with various markers of adiposity and negatively associated with 15-hour RMR (r = -0.46, p = 0.01). Postprandial changes in PYY (area under the curve) were positively associated with postprandial changes in ratings of satiety (r = 0.47, p = 0.01). The maximal PYY concentrations achieved after the meal (peak PYY) were negatively associated with 24-hour RQ (r = -0.41, p = 0.03). Prospectively, the peak PYY concentrations were negatively associated with changes in body weight (r = -0.58, p = 0.01).. Our data indicate that the endogenous PYY may be involved in the long-term regulation of body weight. It seems that this long-term effect was not exclusively driven by the modulation of food intake but also by the control of energy expenditure and lipid metabolism.

Topics: Adolescent; Adult; Area Under Curve; Basal Metabolism; Blood Glucose; Body Weight; Energy Metabolism; Fasting; Female; Glucose Tolerance Test; Humans; Hunger; Insulin; Lipid Metabolism; Male; Middle Aged; Obesity; Oxygen Consumption; Peptide YY; Postprandial Period; Satiety Response

Peptide YY (PYY) levels are reported to be decreased in obesity. The relation between gastric functions, satiation, and gut hormones in obesity is incompletely understood. The aim of this study was to compare gastric volumes, emptying, maximum tolerated volumes, postchallenge symptoms, and selected gut hormones in normal, overweight, or obese healthy volunteers.. In 73 nonbulimic normal, overweight, or obese participants weighing less than 137 kg, we measured gastric emptying of solids and liquids by scintigraphy (gastric emptying half-time [GE t(1/2)]); gastric volumes by single-photon emission computed tomography; maximum tolerated volumes and symptoms by satiation test; and plasma leptin, ghrelin, insulin, glucagon-like peptide 1, and PYY levels. Groups were compared using 1-way analysis of covariance adjusted for sex. Univariate associations among measured responses were assessed using Spearman correlations. Multiple linear regression models, adjusting for weight and sex, assessed the independent ability of gastric functions and hormones to predict satiation volume.. Obese and overweight subjects had significantly lower postprandial gastric volumes, higher fasting and postprandial insulin and leptin levels, and lower fasting ghrelin and lower postprandial reduction in ghrelin levels. PYY levels were not different in obese or overweight subjects compared with controls. The GE t(1/2) was correlated inversely with postprandial PYY; increased body weight was associated with faster GE t(1/2) of solids (r(s) = 0.33, P = .005) and liquids (r(s) = 0.24, P = .04). Postprandial changes in gastric volume and PYY were independent predictors of satiation (both P = .01).. Overweight or obesity are associated with lower postprandial gastric volumes and normal PYY levels. Gastric emptying influences postprandial PYY levels. Postprandial PYY and gastric volume independently predict satiation volume in nonbulimic people across a wide body mass index range.

Topics: Adolescent; Adult; Aged; Female; Gastric Emptying; Gastrointestinal Hormones; Ghrelin; Glucagon-Like Peptide 1; Humans; Insulin; Leptin; Male; Middle Aged; Motor Neurons; Neurons, Afferent; Obesity; Overweight; Peptide Hormones; Peptide YY; Regression Analysis; Satiation; Stomach

To determine whether peptide YY (PYY), ghrelin, glucose-dependent insulinotropic polypeptide (GIP), and satiety responses to food intake are impaired in anorexia or obesity, we studied 30 female adolescents with anorexia nervosa [body mass index (BMI) 16.3 kg/m2], obesity (BMI 34.3 kg/m2), or normal weight (BMI 20.2 kg/m2). PYY, ghrelin, GIP, insulin, and glucose concentrations and four markers of satiety were measured for 240 min after a mixed meal. The area under the curve for glucose was similar in obese (OB) and normal-weight control (C) subjects but was 15% lower in anorexic (AN) subjects. The area under the curve for insulin was 47% lower in AN and 87% higher in OB subjects, compared with C subjects. After the meal, PYY increased significantly in C (+41%, P < 0.05) but not in AN or OB adolescents. Ghrelin concentrations were highest in AN subjects and lowest in the OB group, compared with C subjects and fell significantly by 25% in all three groups. GIP concentrations were lower in AN subjects throughout the test and increased in all three groups after the mixed meal. AN adolescents reported being less hungry than OB and C adolescents. There was a negative correlation between fasting ghrelin (but not PYY or GIP) and BMI and insulin (r2= 0.33) and a positive correlation between the decrease in hunger 15 min after the meal and PYY concentrations at 15 min (r2= 0.20). In conclusion, the blunted PYY response to a meal in OB adolescents suggests that PYY plays a role in the pathophysiology of obesity. Ghrelin is unlikely to play a causal role in anorexia nervosa or obesity. The lower GIP observed in AN subjects despite a similar caloric intake may appropriately prevent an excessive insulin response in these patients.

Topics: Adolescent; Anorexia Nervosa; Appetite; Blood Glucose; Child; Female; Gastric Inhibitory Polypeptide; Ghrelin; Humans; Hunger; Insulin; Obesity; Peptide Hormones; Peptide YY; Prospective Studies

Ghrelin and peptide YY (PYY) are peptides generally produced by the gastrointestinal organs which are involved in appetite regulation via highly specialized centers in the brain. Abnormal plasma ghrelin and PYY levels compared with controls have been reported for subjects with Prader-Willi syndrome (PWS) which is characterized by infantile hypotonia, poor suck reflex and failure to thrive followed by hyperphagia and marked obesity in early childhood. We studied gene expression of ghrelin, peptide YY, and their receptors (i.e., GHS-R1a, GHS-R1b, and NPY2R) in six different brain regions (frontal cortex, temporal cortex, visual cortex, pons, medulla, and hypothalamus) obtained from three subjects with PWS, two individuals with Angelman syndrome, and six controls to determine if expression of these genes is detectable in different regions of the brain in subjects with and without PWS. In general, expression of these genes using RT-PCR was detected in all subjects and no obvious differences were seen in their pattern of expression between subjects with or without PWS. Additional studies including quantitative gene expression measurements will be required to further evaluate the role of these genes in the eating disorder seen in PWS.

Topics: Adult; Aged; Brain; Child, Preschool; Feeding Behavior; Female; Ghrelin; Humans; Hyperphagia; Infant; Male; Middle Aged; Obesity; Peptide Hormones; Peptide YY; Prader-Willi Syndrome; Receptors, G-Protein-Coupled; Receptors, Gastrointestinal Hormone; Receptors, Ghrelin; Reverse Transcriptase Polymerase Chain Reaction

Glucagon-like peptide-1(7-36NH2) (GLP-1) and peptide YY(3-36NH2) (PYY(3-36NH2)) are cosecreted from the intestine in response to nutrient ingestion. Peripheral administration of GLP-1 or PYY(3-36NH2) decreases food intake (FI) in rodents and humans; however, the exact mechanisms by which these peptides regulate FI remain unclear. Male C57BL/6 mice were injected (ip) with exendin-4(1-39) (Ex4, a GLP-1 receptor agonist) and/or PYY(3-36NH2) (0.03-3 microg), and FI was determined for up to 24 h. Ex4 and PYY(3-36NH2) alone decreased FI by up to 83 and 26%, respectively (P < 0.05-0.001), whereas a combination of the two peptides (0.06 microg Ex4 plus 3 microg PYY(3-36NH2)) further reduced FI for up to 8 h in a synergistic manner (P < 0.05-0.001). Ex4 and/or PYY(3-36NH2) delayed gastric emptying by a maximum of 19% (P < 0.01-0.001); however, there was no significant effect on locomotor activity nor was there induction of taste aversion. Capsaicin pretreatment prevented the inhibitory effect of Ex4 on FI (P < 0.05), but had no effect on the anorexigenic actions of PYY(3-36NH2). Similarly, exendin-4(9-39) (a GLP-1 receptor antagonist) partially abolished Ex4-induced anorexia (P < 0.05), but did not affect the satiation produced by PYY(3-36NH2). Conversely, BIIE0246 (a Y2 receptor antagonist) completely blocked the anorexigenic effects of PYY(3-36NH2) (P < 0.001), but had no effect on Ex4-induced satiety. Thus, Ex4 and PYY(3-36NH2) suppress FI via independent mechanisms involving a GLP-1 receptor-dependent, sensory afferent pathway (Ex4) and a Y2-receptor mediated pathway (PYY(3-36NH2)). These findings suggest that administration of low doses of Ex4 together with PYY(3-36NH2) may increase the suppression of FI without inducing significant side effects.

Topics: Animals; Dose-Response Relationship, Drug; Drug Synergism; Eating; Exenatide; Gastric Emptying; Injections, Intraperitoneal; Male; Mice; Mice, Inbred C57BL; Obesity; Peptide Fragments; Peptide YY; Peptides; Satiety Response; Venoms

Obesity is a common sequel to hypothalamic tumors and their treatment, but the underlying mechanisms are not fully established.. Our objective was to evaluate the role of ghrelin and peptide-YY (PYY) in human hypothalamic obesity.. The study took place at a University Medical Center.. Subjects included 14 adult patients (six male, eight female) with tumors of the hypothalamic region and 15 healthy controls (six male and nine female) matched for age, body mass index, and percentage of body fat.. Plasma ghrelin and total PYY were measured using RIAs after an overnight fast and 15, 30, 60, 120, and 180 min after a mixed meal.. We assessed ghrelin, PYY, and appetite ratings.. The fall in ghrelin levels after the test meal was similar in the two groups. There was no statistically significant change postprandially in circulating PYY in the patients with hypothalamic damage. Fasting leptin levels and postprandial insulin responses were also similar in the two groups. Patients with hypothalamic damage reported higher hunger ratings at 3 h after the meal (P = 0.01) and a stronger desire to eat at 2 h (P = 0.01) and 3 h (P = 0.02) compared with the control group.. Adult patients with structural hypothalamic damage show impaired satiety, but the changes observed in circulating ghrelin and PYY concentrations in response to a test meal do not indicate a central role for these gut hormones in the control of appetite and the pathogenesis of obesity in these patients.

Topics: Aged; Case-Control Studies; Fasting; Female; Ghrelin; Humans; Hypothalamic Neoplasms; Insulin; Male; Middle Aged; Obesity; Peptide Hormones; Peptide YY; Postprandial Period; Satiety Response

We determined whether Roux-en-Y gastric bypass (RYGB)-induced protracted weight loss is associated with an increase in anorectic peptide YY (PYY) and decreased gastrointestinal (GI) motility.. RYGB and control sham-operated GI intact obese (SO Obese) and sham-operated GI intact pair-fed (PF) rats were studied. Postoperatively, body weight (BW) and food intake were measured for 90 days. Rats were killed to measure PYY, ghrelin, cholecystokinin (CCK), and glucagonlike peptide-1 (GLP-1). Ninety-day food intake trends were examined by quadratic trend analysis. On the basis of a 28-day weight loss rate, PYY also was measured at 14 and 28 days. Peak 28-day PYY results corresponded with peak BW loss rate; thus, gastric emptying (GE) and intestinal transit time were measured. Data were analyzed by analysis of variance and Tukey's pairwise multiple comparison.. At 90 days, BW in SO Obese versus PF versus RYGB rats was 801 +/- 15 g versus 661 +/- 24 g versus 538 +/- 32 g respectively (P < .05). Concentrations of plasma PYY were increased, while plasma ghrelin was decreased in RYGB versus SO Obese and PF (P < .05). CCK and GLP-1 were unchanged. In RYGB versus controls, PYY was increased at 14 and 28 days but was most elevated at 28 days. In RYGB versus controls, GE was delayed (P < .05) and intestinal transit time was longer (P < .05).. After RYGB, an increase in PYY and a decrease in ghrelin occurred, probably explaining the decrease in food intake, the slower GE and transit time, which contributed to weight loss. Longitudinal studies can be performed with the use of our RYGB model, providing insight into weight loss mechanisms by generating long-term follow-up data currently not available in human studies.

Topics: Anastomosis, Roux-en-Y; Animals; Body Weight; Eating; Gastric Bypass; Gastric Emptying; Gastrointestinal Motility; Ghrelin; Male; Obesity; Peptide Hormones; Peptide YY; Postoperative Period; Rats; Rats, Sprague-Dawley

The interaction of high-fat diet and the peptide YY (PYY) gene expression in diet-induced obesity and the mechanisms which predisposed some individuals to become obese on high-fat diet were explored. Thirty-six male SD rats were randomly divided into high-fat diet group (n=27) and chow fed control group (n=9). After 15 weeks of either a high-fat diet or chew fed diet, the high-fat diet group was subdivided into dietary induced obesity (DIO) and dietary induced obesity resistant (DIR) group according to the final body weight. Then the DIO rats were subdivided into two groups for a 8-week secondary dietary intervention. One of the group was switched to chew fed diet, whereas the other DIO and DIR rats continued on the initial high-fat diet. Weight gain and food intake were measured, food efficiency was calculated, and the concentrations of plasma neuropeptide Y (NPY) and PYY were assayed. Hypothalamic NPY mRNA expression and PYY mRNA expression in ileum and colon was detected by RT-PCR. The results showed that at the end of 15th week, the levels of body weight and caloric intake were significantly higher in DIO group than in DIR or control group (P<0. 01), while no significant difference was found between DIR and control group (P>0.05). The concentration of plasma PYY was significantly higher in DIR group than in DIO and CF group, while no significant difference was found between DIO and CF group (P <0.01). After switching the DIO rats to chow fed diet, their body weight gains were significantly lower than that of the DIO-HF group. The expression of PYY mRNA was increased in DIO-HF/ CF rats than in DIO-HF rats, and the expression of hypothalamic NPY mRNA was decreased in DIO-HF/CF rats than in DIO-HF group. It was concluded that both dietary composition and PYY gene expression could potently alter the hypothalamic NPY expression and result in different susceptibility to obese and overeating. The decreased PYY was associated with the increased NPY expression and their predisposal to obese and overeating in rats.

Topics: Animals; Dietary Fats; Eating; Energy Metabolism; Genetic Predisposition to Disease; Male; Neuropeptide Y; Obesity; Peptide YY; Random Allocation; Rats; Rats, Sprague-Dawley; RNA, Messenger

The gut hormone peptide YY(3-36) (PYY) reduces food intake via hypothalamic Y2 receptors in the brain. There is not much known about PYY in obese children.. The objective of this study was to investigate the role of PYY in the metabolic changes in obese children and its change during weight loss.. The study was performed at a university medical center.. We studied 73 obese children and 45 age-matched normal-weight children.. We determined fasting serum total PYY and leptin by RIA in obese and normal-weight children. Fasting PYY was also measured in 28 obese children before and after completion of a 1-yr outpatient weight reduction program.. PYY, insulin, and body mass index were the main outcome measures.. Obese children demonstrated significantly lower PYY levels than lean children (median, 67 vs. 124 pg/ml; P < 0.001). Fasting PYY correlated negatively to the degree of overweight. PYY levels did not differ significantly between boys and girls, nor between prepubertal and pubertal children. The group of patients participating in the outpatient weight reduction program was divided into four quartiles according to their changes in body mass index SD score over a 1-yr period. PYY increased significantly in patients with the most effective weight loss, but decreased in the subgroup of children with weight gain.. PYY is negatively correlated to the degree of overweight, with reduced values in obese compared with normal-weight children. Decreased PYY levels could predispose subjects to develop obesity. Our results indicate that low pretreatment PYY levels that increase during weight loss may be a predictor of maintained weight loss.

Topics: Case-Control Studies; Child; Energy Metabolism; Fasting; Female; Homeostasis; Humans; Leptin; Male; Obesity; Peptide YY; Radioimmunoassay; Weight Loss

To observe changes of plasma peptide YY (PYY) in acupuncture for slimming.. Thirty-four cases of simple obesity were treated with acupuncture for 3 courses. Body mass index (BMI), and fat percent (F%), and insulin, PYY, blood fat, and blood sugar levels before and after treatment were determined, with 20 normal persons used as controls.. The clinical total effective rate was 88.23%. Acupuncture could increase the decreased insulin sensitive index and PYY level (both P < 0.01), with no correlativity between them (P > 0.05).. Regulation of PYY is possibly one of the mechanisms of acupuncture in slimming, but the relation of PPY with insulin resistance remains to be studied.

Topics: Body Mass Index; Humans; Insulin; Insulin Resistance; Obesity; Peptide YY

To determine whether basal plasma peptide-YY (PYY) levels in overweight, middle-aged black women are different from those of white women of similar BMI and age and ascertain whether there is a difference between the two groups in plasma PYY levels in response to a liquid high fat load.. Using a commercial radioimmunoassay kit, the concentration of PYY was measured at baseline and at 2, 4, 6, and 8 hours after ingesting a fatty liquid meal (86.5% of the calories from fat) in 12 black and 12 white women who were matched for age and BMI.. PYY levels (picograms per milliliter) at baseline and at every other time-point of the test meal were significantly lower in the black than in the white group. In addition, the change in PYY concentration from baseline was lower in the black than in the white group only at 8 hours after the meal.. The lower baseline level and the blunted PYY response of the black women to the fat load indicated that this signal for appetite suppression was reduced, which, in turn, might contribute to the enhanced obesity of the black women.

Topics: Adult; Appetite; Black People; Case-Control Studies; Dietary Fats; Female; Humans; Obesity; Overweight; Peptide YY; Radioimmunoassay; White People

Inactivating mutations of the pro-opiomelanocortin (POMC) gene in both mice and humans leads to hyperphagia and obesity. To further examine the mechanisms whereby POMC-deficiency leads to disordered energy homeostasis, we have generated mice lacking all POMC-derived peptides. Consistent with a previously reported model, Pomc(-/-) mice were obese and hyperphagic. They also showed reduced resting oxygen consumption associated with lowered serum levels of thyroxine. Hypothalami from Pomc(-/-) mice showed markedly increased expression of melanin-concentrating hormone mRNA in the lateral hypothalamus, but expression of neuropeptide Y mRNA in the arcuate nucleus was not altered. Provision of a 45% fat diet increased energy intake and body weight in both Pomc(-/-) and Pomc(+/-) mice. The effects of leptin on food intake and body weight were blunted in obese Pomc(-/-) mice whereas nonobese Pomc(-/-) mice were sensitive to leptin. Surprisingly, we found that Pomc(-/-) mice maintained their acute anorectic response to peptide-YY(3-36) (PYY(3-36)). However, 7 days of PYY(3-36) administration had no effect on cumulative food intake or body weight in wild-type or Pomc(-/-) mice. Thus, POMC peptides seem to be necessary for the normal response of energy balance to high-fat feeding, but not for the acute anorectic effect of PYY(3-36) or full effects of leptin on feeding. The finding that the loss of only one copy of the Pomc gene is sufficient to render mice susceptible to the effects of high fat feeding emphasizes the potential importance of this locus as a site for gene-environment interactions predisposing to obesity.

Topics: Animals; Appetite Depressants; Base Sequence; Body Weight; Dietary Fats; DNA Primers; Energy Intake; Hypothalamic Hormones; Hypothalamus; Kinetics; Leptin; Melanins; Mice; Mice, Knockout; Mutagenesis, Site-Directed; Neuropeptide Y; Obesity; Peptide Fragments; Peptide YY; Phenotype; Pituitary Hormones; Polymerase Chain Reaction; Pro-Opiomelanocortin; Transcription, Genetic

Topics: Animals; Appetite; Body Mass Index; Brain; Central Nervous System; Eating; Humans; Obesity; Peptide Fragments; Peptide YY; Peptides

The role of the melanocortin system in the feeding effects of peripheral peptide YY(3-36) (PYY(3-36)) and ghrelin was investigated using the agouti (A(y)/a) mouse as a model of abnormal melanocortin signalling. Furthermore, we examined whether the ectopic expression of agouti protein in A(y)/a mice results in complete MC4-R inhibition, by studying the effects of peripheral alpha-melanocyte-stimulating hormone (alpha-MSH) and leptin on food intake.. Adult A(y)/a mice were studied in the pre-obese state (7-8 weeks) and obese state (14-15 weeks). Animals received PYY(3-36) (0.02 micromol/kg), NDP-alpha-MSH (0.2 micromol/kg), leptin (2 micromol/kg) (all 24 h fasted state) and ghrelin (0.2 micromol/kg) (fed state) by intraperitoneal (i.p.) injection. Age-matched A(y)/a controls received i.p. saline. A separate cohort of wild-type (WT), age-matched controls received the same peptide dose or saline. Food intake was measured at 1, 2, 4, 8 and 24 h post-injection and compared in all four groups. Plasma leptin-, ghrelin- and PYY-like immunoreactivity (IR) were measured using radioimmunoassay (RIA).. At 2 h post-injection, PYY(3-36) reduced food intake in pre-obese and obese A(y)/a mice, whereas ghrelin had no effect. Plasma ghrelin levels were significantly reduced in pre-obese and obese A(y)/a mice compared to WT controls. Peripheral administration of NDP-alpha-MSH and leptin acutely suppressed feeding (0-2 h) in pre-obese and obese A(y)/a mice.. Responsiveness of pre-obese and obese A(y)/a mice to PYY(3-36) suggests that the melanocortin system may not be essential for the anorectic effects of this peptide. Melanocortinergic antagonism by agouti protein in A(y)/a mice may be sufficient to block the effects of endogenous, but not exogenous PYY(3-36), alpha-MSH and leptin. The mechanism underlying ghrelin resistance in A(y)/a mice may result from antagonism of hypothalamic melanocortin receptors-4 by agouti protein, supporting a role for the melanocortin system in mediating ghrelin's actions.

Topics: Agouti Signaling Protein; alpha-MSH; Animals; Appetite; Drug Resistance; Eating; Fasting; Ghrelin; Intercellular Signaling Peptides and Proteins; Leptin; Melanocyte-Stimulating Hormones; Mice; Mice, Inbred C57BL; Mice, Obese; Mice, Transgenic; Obesity; Peptide Fragments; Peptide Hormones; Peptide YY; Receptor, Melanocortin, Type 4

Peptide YY (PYY) is a 36 amino-acid peptide secreted from ileal L cells following meals. The cleaved subpeptide PYY[3-36] is biologically active and may constitute the majority of circulating PYY-like immunoreactivity. The peptide family that includes PYY, pancreatic peptide and neuropeptide Y is noted for its orexigenic effect following intracerebroventricular administration.. To investigate the effects of peripheral (intraperitoneal and chronic subcutaneous) infusions of PYY[3-36] on food intake, body weight and glycemic indices.. Food intake was measured in normal mice and in several rodent models of obesity and type II diabetes. In marked contrast to the reported central orexigenic effects, in the present study, PYY[3-36] acutely inhibited food intake by up to 45%, with an ED(50) of 12.5 microg/kg in fasted female NIH/Swiss mice. A 4-week infusion reduced weight gain in female ob/ob mice, without affecting the cumulative food intake. In diet-induced obese male mice, PYY[3-36] infusion reduced cumulative food intake, weight gain and epididymal fat weight (as a fraction of carcass) with similar ED(50)'s (466, 297 and 201 microg/kg/day, respectively) and prevented a diet-induced increase in HbA1c. Infusion at 100 microg/kg/day for 8 weeks in male fa/fa rats reduced the weight gain (288+/-11 vs 326+/-12 g in saline-infused controls; P<0.05), similar to effects in a pair-fed group. In female ob/ob and db/db mice, there was no acute effect of PYY[3-36] on plasma glucose concentrations. In male diabetic fatty Zucker rats, PYY[3-36] infused for 4 weeks reduced HbA1c and fructosamine (ED(50)'s 30 and 44 microg/kg/day).. Peripheral PYY[3-36] administration reduced the food intake, body weight gain and glycemic indices in diverse rodent models of metabolic disease of both sexes. These findings justify further exploration of the potential physiologic and therapeutic roles of PYY[3-36].

Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Drug Implants; Eating; Energy Intake; Female; Infusions, Intravenous; Injections, Intraperitoneal; Male; Mice; Mice, Mutant Strains; Models, Animal; Obesity; Peptide Fragments; Peptide YY; Rats; Rats, Inbred Strains; Rats, Zucker

Batterham et al. report that the gut peptide hormone PYY3-36 decreases food intake and body-weight gain in rodents, a discovery that has been heralded as potentially offering a new therapy for obesity. However, we have been unable to replicate their results. Although the reasons for this discrepancy remain undetermined, an effective anti-obesity drug ultimately must produce its effects across a range of situations. The fact that the findings of Batterham et al. cannot easily be replicated calls into question the potential value of an anti-obesity approach that is based on administration of PYY3-36.

Topics: Animals; Animals, Inbred Strains; Appetite; Appetite Depressants; Appetite Regulation; Behavior, Animal; Body Weight; Environment; Feeding Behavior; Humans; Meta-Analysis as Topic; Mice; Obesity; Peptide Fragments; Peptide YY; Rats; Reproducibility of Results; Stress, Physiological

Topics: Drug Industry; Estrone; Humans; Obesity; Oleic Acids; Peptide Fragments; Peptide YY; Satiety Response; United States

Peptide-YY (PYY) is secreted from endocrine L-cells of the gastrointestinal tract in response to caloric ingestion and may mediate postprandial satiety through the hypothalamic neuropeptide Y2 receptor (Y2R). We examined whether variants in the genes encoding PYY and Y2R might be associated with obesity-related phenotypes in humans. Among 101 subjects with severe early-onset obesity and a history of hyperphagia, we found two rare sequence variants-L73P and IVS2 + 32delG-in PYY and three rare missense mutations-L40F, F87I, and A172T-in Y2R. Although none of these were found in 100 normal-weight white control subjects, L73P in PYY and F87I and A172T in Y2R did not segregate with obesity in family studies, and family data were unavailable for IVS2 + 32delG in PYY and L40F in Y2R. Two common single nucleotide polymorphisms (SNPs), R72T and IVS3 + 68C>T, in PYY were in tight linkage disequilibrium but showed no association with BMI in a large white population. In the Y2R, two SNPs, 585T>C and 936T>C, were found and were in tight linkage disequilibrium. Men, homozygous for the rarer variant, had significantly lower BMI (P = 0.017), waist-to-hip ratio (P = 0.013), and, surprisingly, higher nonesterified fatty acid levels (P = 0.01). In conclusion, mutations in PYY and Y2R are not commonly found in humans with severe early-onset obesity. The relationship between common variants in Y2R and obesity-related traits deserves further exploration in other populations.

Topics: Age of Onset; Child; Cohort Studies; Female; Humans; Male; Obesity; Pedigree; Peptide YY; Polymorphism, Single Nucleotide; Receptors, Neuropeptide Y

Topics: Agouti-Related Protein; alpha-MSH; Animals; Anti-Obesity Agents; Appetite; Arcuate Nucleus of Hypothalamus; Body Weight; Brain; Caloric Restriction; Fatty Acids; Ghrelin; Humans; Insulin; Intercellular Signaling Peptides and Proteins; Leptin; Longevity; Mice; Neurons; Neuropeptide Y; Obesity; Peptide Hormones; Peptide YY; Pro-Opiomelanocortin; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Protein Tyrosine Phosphatases; Proteins; Receptor, Insulin; Receptors, Pituitary Hormone; Stearoyl-CoA Desaturase

Topics: Agouti-Related Protein; alpha-MSH; Animals; Anti-Obesity Agents; Appetite; Arcuate Nucleus of Hypothalamus; Ciliary Neurotrophic Factor; Clinical Trials as Topic; Cyclobutanes; Energy Intake; Ghrelin; Humans; Hunger; Intercellular Signaling Peptides and Proteins; Lactones; Leptin; Mice; Nerve Tissue Proteins; Neurons; Neuropeptide Y; Obesity; Orlistat; Peptide Fragments; Peptide Hormones; Peptide YY; Phentermine; Proteins; Receptors, Corticotropin; Receptors, Melanocortin; Weight Loss

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

Topics: Adult; Agouti-Related Protein; alpha-MSH; Animals; Appetite Depressants; Cholecystokinin; Colon; Controlled Clinical Trials as Topic; Ghrelin; Homeostasis; Humans; Hypothalamus; Intercellular Signaling Peptides and Proteins; Intestine, Small; Leptin; Models, Biological; Neuropeptide Y; Obesity; Peptide Fragments; Peptide Hormones; Peptide YY; Pro-Opiomelanocortin; Proteins; Rats; Satiety Response

Topics: Appetite; Eating; Ghrelin; Humans; Insulin; Leptin; Obesity; Peptide Fragments; Peptide Hormones; Peptide YY; Receptor, Melanocortin, Type 4; Receptors, Corticotropin

Topics: Adult; Animals; Appetite; Child; Congresses as Topic; Diabetes Mellitus, Type 2; Glucagon; Glucagon-Like Peptide 1; Humans; Obesity; Peptide Fragments; Peptide YY; Pharmacology, Clinical; Protein Precursors; Receptors, Glucocorticoid

Hypothalamic neuropeptide Y (NPY) is implicated in the regulation of a variety of physiological functions, notably energy homeostasis and reproduction. Chronically elevated NPY levels in the hypothalamus, as in genetically obese ob/ob mice, are associated with obesity, a syndrome of type 2 diabetes, and infertility. However, it is not known which of the five cloned Y receptors mediate these effects. Here, we show that crossing the Y2 receptor knockout mouse (Y2(-/-)) onto the ob/ob background attenuates the increased adiposity, hyperinsulinemia, hyperglycemia, and increased hypothalamo-pituitary-adrenal (HPA) axis activity of ob/ob mice. Compared with lean controls, ob/ob mice had elevated expression of NPY and agouti-related protein (AgRP) mRNA in the arcuate nucleus and decreased expression of proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) mRNA. Y2 deletion in ob/ob mice significantly increased the hypothalamic POMC mRNA expression, with no effect on NPY, AgRP, or CART expression. [Y2(-/-)ob/ob] mice were no different from ob/ob littermates with respect to food intake and body weight, and Y2 receptor deficiency had no beneficial effect on the infertility or the reduced hypothalamo-pituitary-gonadotropic function of ob/ob mice. These data demonstrate that Y2 receptors mediate the obese type 2 diabetes phenotype of ob/ob mice, possibly via alterations in melanocortin tonus in the arcuate nucleus and/or effects on the HPA axis.

Topics: Adipose Tissue; Animals; Blood Glucose; Diabetes Mellitus, Type 2; Female; Gene Deletion; Gonadotropins; Hypothalamo-Hypophyseal System; Insulin; Male; Mice; Mice, Knockout; Neuropeptides; Obesity; Peptide Fragments; Peptide YY; Pituitary-Adrenal System; Receptors, Neuropeptide Y; Syndrome; Thermogenesis; Thyrotropin

Neuropeptide Y (NPY) is involved in the central regulation of appetite, sexual behavior, and reproductive function. We have previously shown that chronic infusion of NPY into the lateral ventricle of normal rats produced an obesity syndrome characterized by hyperphagia, hyperinsulinism and collapse of reproductive function. We further demonstrated that acute inhibition of LH secretion in castrated rats was preferentially mediated by the NPY receptor subtype 5 (Y(5)). In the present study, the effects of chronic, central infusion of NPY, or the mixed Y2-Y5 agonist PYY(3-36), were evaluated both in normal male C57BL/6J mice and Sprague-Dawley rats. After a 7-day infusion to male mice, both NPY and PYY(3-36) at 5 nmol per day, induced marked hyperphagia leading to significant increases in body and fat pad weights. Furthermore, both compounds markedly reduced several markers of the reproductive axis. In the rat study, PYY(3-36) was more active than NPY to inhibit the pituitary-testicular axis, confirming the importance of the Y5 subtype for such effects. In the mouse, chronic NPY infusion induced a sustained increase in corticosterone and insulin secretion. Plasma leptin levels were also markedly increased possibly explaining the observed reduction in gene expression for hypothalamic NPY. Gene expression for hypothalamic POMC was reduced in the NPY- or PYY(3-36)-infused mice, suggesting that NPY exacerbated food intake by both acting through its own receptor(s), and reducing the satiety signal driven by the POMC-derived alpha-MSH. The present study in the mouse suggests in analogy with available rat data, that constant exposure to elevated NPY in the hypothalamic area unabatedly enhances food intake leading to an obesity syndrome including increased adiposity, insulin resistance, hypercorticism, and hypogonadism, reminiscent of the phenotype of the ob/ob mouse, that displays elevated hypothalamic NPY secondary to lack of leptin negative feedback action.

Topics: Animals; Hyperphagia; Hypogonadism; Insulin Resistance; Lateral Ventricles; Leptin; Male; Mice; Mice, Inbred C57BL; Neuropeptide Y; Obesity; Peptide Fragments; Peptide YY; Rats; Rats, Sprague-Dawley; Syndrome

Neuropeptide Y (NPY), a 36-amino-acid neuromodulator abundantly expressed in the brain, has been implicated in the regulation of food intake and body weight. Pharmacological data suggest that NPY's stimulatory effect on appetite is transduced by the G-protein-coupled NPY Y5 receptor (Y5R). We have inactivated the Y5R gene in mice and report that younger Y5R-null mice feed and grow normally; however, they develop mild late-onset obesity characterized by increased body weight, food intake and adiposity. Fasting-induced refeeding is unchanged in younger Y5R-null mice and they exhibit normal sensitivity to leptin. Their response to intracerebroventricular (i.c.v.) administration of NPY and related peptides is either reduced or absent. NPY deficiency attenuates the obesity syndrome of mice deficient for leptin (ob/ob), but these effects are not mediated by NPY signaling through the Y5R because Y5R-null ob/ob mice are equally obese. These results demonstrate that the Y5R contributes to feeding induced by centrally administered NPY and its analogs, but is not a critical physiological feeding receptor in mice.

Topics: Animals; Body Weight; Dose-Response Relationship, Drug; Feeding Behavior; Female; Genotype; Humans; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Mice, Mutant Strains; Molecular Sequence Data; Mutagenesis, Site-Directed; Mutation; Neuropeptide Y; Obesity; Pancreatic Polypeptide; Peptide YY; Peptides, Cyclic; Phenotype; Proteins; Receptors, Neuropeptide Y; RNA, Messenger; Time Factors

Neuropeptide Y (NPY) potently induces feeding, reduces thermogenesis and induces obesity in rats when injected into the cerebral ventricles. Groups of male Wistar rats were either restricted to 60% of their normal daily food intake over 10 days or made obese by presenting them with a high-calorie diet rich in sugars and fat over 6 weeks. Food restricted rats lost up to 20% of their body weight, compared with control rats and had large reductions in their body fat mass. By contrast, rats with dietary-induced obesity weighed 26% more than controls due mainly to increased body fat mass. Quantitative receptor autoradiography demonstrated reduced [(125)I]PYY binding in the hypothalamic lateral (perifornical) and dorsal areas, hypothalamic ventromedial, arcuate and dorsomedial nuclei, hippocampal CA3 region, centromedial amygdaloid nucleus and thalamic paraventricular and reuniens nuclei in dietary restricted rats compared with controls. By contrast, regional [(125)I]PYY binding was significantly increased in hypothalamic lateral and dorsal areas, hypothalamic arcuate and dorsomedial nuclei, amygdaloid medial and centromedial nuclei, thalamic centromedial and paraventricular nuclei of dietary obese rats versus controls. Masking NPY Y1 receptors with 1 microM BIBP3226, a selective Y1 receptor antagonist, revealed that the changes in [(125)I]PYY binding in brains of food-restricted and dietary-obese rats were due to changes in BIBP3226-insensitive binding sites, presumably Y2 or Y5 NPY receptors. These data suggest that dietary-restriction stimulates NPY release resulting in down-regulation of NPY Y5 'feeding' and/or Y2 receptors and reduced BAT thermogenesis thereby providing an increased drive to eat to restore normal caloric intake whilst reducing thermogenesis in order to conserve fat reserves. By contrast, the up-regulation of NPY Y5 and/or Y2 receptors in dietary-induced obesity is consistent with inhibition of NPY release in the hypothalamus, amygdala and thalamus. Overall, we suggest that there is a regional increase in NPY release during negative energy balance, such as during food-restriction and a reduced regional release of NPY in positive energy balance, such as during hyperphagia associated with the development of obesity.

Topics: Amygdala; Animals; Arginine; Autoradiography; Binding Sites; Diet; Hypothalamus; Male; Obesity; Peptide YY; Rats; Rats, Wistar; Receptors, Neuropeptide Y; Thalamic Nuclei; Tissue Distribution

1. Plasma pancreatic polypeptide, plasma catecholamine, blood glucose, plasma insulin and plasma peptide YY concentrations were studied to assess differences between eight formerly obese and eight never-obese control women during 25 min of sham-feeding (with the sight and smell of an English breakfast) and for 5 h after they had ingested the meal (3514 kJ, 50% fat, 35% carbohydrate). The post-obese women had maintained their normal body weight for at least 3 months before the study. 2. The plasma noradrenaline concentration was not different between the groups either during fasting (post-obese women 0.08 +/- 0.01 ng/ml versus control women 0.10 +/- 0.01 ng/ml) or in the significant postprandial increase (P < 0.001). The plasma adrenaline concentration increased significantly during sham-feeding in the control group from 0.024 +/- 0.004 ng/ml to 0.033 +/- 0.004 ng/ml (P = 0.02) in contrast with the post-obese women, who had significantly lower plasma concentrations of adrenaline in the fasting state (post-obese 0.016 +/- 0.003 ng/ml versus control women 0.024 +/- 0.004 ng/ml, P = 0.003), during sham-feeding (post-obese women 0.018 +/- 0.002 ng/ml versus control women 0.033 +/- 0.004 ng/ml, P = 0.003) and in the postprandial increase (P = 0.003). The maximal postprandial response concentrations recorded 5 h after the meal were 0.025 +/- 0.003 ng/ml in post-obese women and 0.035 +/- 0.004 ng/ml in control subjects (P = 0.04). There were no significant differences in plasma pancreatic polypeptide, plasma peptide YY, plasma insulin, or blood glucose concentrations between the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Blood Glucose; Energy Intake; Epinephrine; Fasting; Female; Gastrointestinal Hormones; Humans; Insulin; Norepinephrine; Obesity; Pancreatic Polypeptide; Peptide YY; Peptides; Time Factors; Weight Loss