cholecystokinin 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

Food addiction may play a role in rising obesity rates in connection with obesogenic environments and processed food availability, however the concept of food addiction remains controversial. While animal studies show evidence for addictive processes in relation to processed foods, most human studies are psychologically focussed and there is a need to better understand evidence for biological mechanisms of food addiction in humans. Several key hormones are implicated in models of food addiction, due to their key roles in feeding, energy metabolism, stress and addictive behaviours. This systematic literature review examines evidence for relationships between food addiction, hormones and other blood biomarkers.. A series of literature searches was performed in Scopus, PsychInfo, MedLine, ProQuest, CINAHL and Web of Science. A total of 3111 articles were found, of which 1045 were duplicates. Articles were included if they contained a psychometric measurement of food addiction, such as the Yale Food Addiction Scale, as well as addressed the association between FA and hormones or blood biomarkers in humans. Articles were assessed for eligibility by two independent reviewers.. Sixteen studies were identified that examined relationships between food addiction and blood biomarkers, published between 2015 and 2021. Significant findings were reported for leptin, ghrelin, cortisol, insulin and glucose, oxytocin, cholesterol, plasma dopamine, thyroid stimulating hormone (TSH), haemoglobin A1c (HbA1c), triglyceride (TG), amylin, tumour necrosis factor alpha (TNF- α) and cholecystokinin (CCK). Methodological issues included small sample sizes and variation in obesity status, sex and mental health-related comorbidities. Due to methodological limitations, definite connections between FA, hormones and other blood biomarkers cannot yet be determined.. This systematic review identified preliminary evidence linking FA symptoms to hormones and other blood biomarkers related to feeding, addiction, and stress. However, due to the small number of studies and methodological limitations, further research is needed to evaluate biopsychosocial models of FA and to resolve controversies.

Topics: Animals; Behavior, Addictive; Biomarkers; Cholecystokinin; Feeding Behavior; Food Addiction; Humans; Obesity

Topics: Animals; Cancer-Associated Fibroblasts; Carcinoma, Pancreatic Ductal; Cholecystokinin; Drug Resistance, Neoplasm; Humans; Immune Checkpoint Inhibitors; Insulin-Secreting Cells; Mice; Mutation; Neoplasm Recurrence, Local; Obesity; Pancreatic Neoplasms; Risk Factors

In 1973, Gibbs, Young, and Smith showed that exogenous cholecystokinin (CCK) administration reduces food intake in rats. This initial report has led to thousands of studies investigating the physiological role of CCK in regulating feeding behavior. CCK is released from enteroendocrine I cells present along the gastrointestinal (GI) tract. CCK binding to its receptor CCK1R leads to vagal afferent activation providing post-ingestive feedback to the hindbrain. Vagal afferent neurons' (VAN) sensitivity to CCK is modulated by energy status while CCK signaling regulates gene expression of other feeding related signals and receptors expressed by VAN. In addition to its satiation effects, CCK acts all along the GI tract to optimize digestion and nutrient absorption. Diet-induced obesity (DIO) is characterized by reduced sensitivity to CCK and every part of the CCK system is negatively affected by chronic intake of energy-dense foods. EEC have recently been shown to adapt to diet, CCK1R is affected by dietary fats consumption, and the VAN phenotypic flexibility is lost in DIO. Altered endocannabinoid tone, changes in gut microbiota composition, and chronic inflammation are currently being explored as potential mechanisms for diet driven loss in CCK signaling. This review discusses our current understanding of how CCK controls food intake in conditions of leanness and how control is lost in chronic energy excess and obesity, potentially perpetuating excessive intake.

Topics: Animals; Cholecystokinin; Diet, High-Fat; Dietary Fats; Eating; Feeding Behavior; Gastrointestinal Tract; Humans; Neurons, Afferent; Obesity; Rats; Receptor, Cholecystokinin A

We are currently facing an obesity pandemic, with worldwide obesity rates having tripled since 1975. Obesity is one of the main risk factors for the development of non-communicable diseases, which are now the leading cause of death worldwide. This calls for urgent action towards understanding the underlying mechanisms behind the development of obesity as well as developing more effective treatments and interventions. Appetite is carefully regulated in humans via the interaction between the central nervous system and peripheral hormones. This involves a delicate balance in external stimuli, circulating satiating and appetite stimulating hormones, and correct functioning of neuronal signals. Any changes in this equilibrium can lead to an imbalance in energy intake versus expenditure, which often leads to overeating, and potentially weight gain resulting in overweight or obesity. Several lines of research have shown imbalances in gut hormones are found in those who are overweight or obese, which may be contributing to their condition. Therefore, this review examines the evidence for targeting gut hormones in the treatment of obesity by discussing how their dysregulation influences food intake, the potential possibility of altering the circulating levels of these hormones for treating obesity, as well as the role of short chain fatty acids and protein as novel treatments.

Topics: Acetic Acid; Animals; Appetite; Appetite Regulation; Butyrates; Central Nervous System; Cholecystokinin; Dipeptides; Energy Intake; Energy Metabolism; Fatty Acids, Volatile; Gastrointestinal Hormones; Gastrointestinal Tract; Ghrelin; Glucagon-Like Peptide 1; Humans; Hyperphagia; Mice; Neuropeptide Y; Obesity; Overweight; Oxyntomodulin; Pancreatic Polypeptide; Propionates; Satiation

Cholecystokinin is a gastrointestinal peptide hormone with important roles in metabolic physiology and the maintenance of normal nutritional status, as well as potential roles in the prevention and management of obesity, currently one of the dominant causes of direct or indirect morbidity and mortality. In this review, we discuss the roles of this hormone and its receptors in maintaining nutritional homeostasis, with a particular focus on appetite control. Targeting this action led to the development of full agonists of the type 1 cholecystokinin receptor that have so far failed in clinical trials for obesity. The possible reasons for clinical failure are discussed, along with alternative pharmacologic strategies to target this receptor for prevention and management of obesity, including development of biased agonists and allosteric modulators. Cellular cholesterol is a natural modulator of the type 1 cholecystokinin receptor, with elevated levels disrupting normal stimulus-activity coupling. The molecular basis for this is discussed, along with strategies to overcome this challenge with a corrective positive allosteric modulator. There remains substantial scope for development of drugs to target the type 1 cholecystokinin receptor with these new pharmacologic strategies and such drugs may provide new approaches for treatment of obesity.

Topics: Allosteric Regulation; Animals; Cholecystokinin; Cholesterol; Humans; Obesity; Receptors, Cholecystokinin

This review describes the premises for accurate measurement of the gut hormone and satiety factor cholecystokinin (CCK) in circulation. Such a description is useful for nutrition and obesity research in which CCK in its satiety role has evoked considerable interest during the last decades. The background for the review is two sorts of considerations or concerns. First, CCK is a complex peptide system that in several ways challenges plasma measurements because the concentrations in plasma are very low (in the femtomolar to low picomolar range), and the bioactive CCK circulates in different molecular forms (CCK-58, -33, -22, and -8). Furthermore, there are major specificity problems because the structurally similar gastrin hormone circulates in 10- to 20-fold higher concentrations, and in addition, plasma proteins may, due to their high concentration, interfere in an unspecific way with immunoassay measurements. The second concern is that several obesity studies in recent decades have been based on commercial CCK kits with often inadequate documentation of the reliability in plasma measurement. Consequently, many plasma CCK results in today's obesity studies are difficult to compare. Moreover, the use of even fairly reliable commercial CCK kits has recently suffered from sudden discontinuation of the kit production, which has endangered several projects in nutrition and obesity research.

Topics: Animals; Appetite Regulation; Bias; Biomedical Research; Blood Chemical Analysis; Blood Proteins; Cholecystokinin; Gastrins; Humans; Nutritional Sciences; Nutritional Status; Obesity; Peptide Fragments; Plasma; Satiety Response

This paper describes the early history of Gastric Inhibitory Polypeptide, better referred to simply as GIP, from its isolation by purification from a crude preparation of CCK-PZ (cholecystokinin/pancreozymin) to its recognition as a key player in the pathogenesis of obesity and other metabolic disorders far removed from the enterogastrone properties by which it was originally identified. Augmentation of glucose mediated insulin release, the incretin effect, was discovered soon after GIP was first isolated and only much later was its important role in the pathogenesis of obesity, through mechanism other than insulin secretion, appreciated. Immunoassay - the only method by which the concentration of GIP was measured in plasma until quite recently - was found to be flawed and to depend upon which specific epitope of the hormone an assay detected. This was especially true if it was an amino-acid sequence specific to porcine rather than human GIP. A further confounder was the discovery that much of the GIP measured by immunoassay was its biological antagonist produced by cleavage of its two N-terminal amino-acids in the circulation by the same dipeptidyl-peptidase as de-activates GLP-1. Potential use of synthetic agonistic and antagonistic GIP analogues in therapeutics was barely alluded to before year 2000.

Topics: Cholecystokinin; Epitopes; Gastric Inhibitory Polypeptide; Gastrointestinal Hormones; Glucagon-Like Peptide 1; Glucagon-Like Peptide Receptors; Glucose; Humans; Incretins; Insulin; Obesity; Peptides

Several cases of cholelithiasis and cholecystitis have been reported in patients treated with glucagon-like peptide 1 (GLP-1) receptor agonists (GLP-1RAs) and GLP-2 receptor agonists (GLP-2RAs), respectively. Thus, the effects of GLP-1 and GLP-2 on gallbladder motility have been investigated. We have provided an overview of the mechanisms regulating gallbladder motility and highlight novel findings on the effects of bile acids and glucagon-like peptides on gallbladder motility.. The articles included in the present review were identified using electronic literature searches. The search results were narrowed to data reporting the effects of bile acids and GLPs on gallbladder motility.. Bile acids negate the effect of postprandial cholecystokinin-mediated gallbladder contraction. Two bile acid receptors seem to be involved in this feedback mechanism, the transmembrane Takeda G protein-coupled receptor 5 (TGR5) and the nuclear farnesoid X receptor. Furthermore, activation of TGR5 in enteroendocrine L cells leads to release of GLP-1 and, possibly, GLP-2. Recent findings have pointed to the existence of a bile acid-TGR5-L cell-GLP-2 axis that serves to terminate meal-induced gallbladder contraction and thereby initiate gallbladder refilling. GLP-2 might play a dominant role in this axis by directly relaxing the gallbladder. Moreover, recent findings have suggested GLP-1RA treatment prolongs the refilling phase of the gallbladder.. GLP-2 receptor activation in rodents acutely increases the volume of the gallbladder, which might explain the risk of gallbladder diseases associated with GLP-2RA treatment observed in humans. GLP-1RA-induced prolongation of human gallbladder refilling may explain the gallbladder events observed in GLP-1RA clinical trials.

Topics: Bile Acids and Salts; Cholecystitis; Cholecystokinin; Cholelithiasis; Diabetes Mellitus, Type 2; Gallbladder; Gallbladder Emptying; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptide-2 Receptor; Glucagon-Like Peptides; Humans; Muscle Contraction; Muscle, Smooth; Obesity; Postprandial Period

Cholecystokinin (CCK) is a hormone secreted from I-cells of the gut, as well as neurons in the enteric and central nervous system, that binds and activates CCK-1 and CCK-2 receptors to mediate its biological actions. To date knowledge relating to the physiological significance of CCK has predominantly focused around induction of short-term satiety. However, CCK has also been highlighted to possess important actions in relation to the regulation of insulin secretion, as well as overall beta-cell function and survival. Consequently, this has led to the development of enzymatically stable, biologically active, CCK peptide analogues with proposed therapeutic promise for both obesity and type 2 diabetes. In addition, several studies have demonstrated metabolic, and therapeutically relevant, complementary biological actions of CCK with those of the incretin hormones GIP and GLP-1, as well as with amylin and leptin. Thus, stable CCK derivatives not only offer promise as potential independent weight-reducing and glucose-lowering drugs, but also as effective adjunctive therapies. This review focuses on the recent and ongoing developments of CCK in the context of new therapies for obesity and type 2 diabetes.

Topics: Cholecystokinin; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose; Humans; Insulin; Obesity; Peptides; Receptor, Cholecystokinin B

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

The vagal link between the gastrointestinal tract and the central nervous system (CNS) has numerous vital functions for maintaining homeostasis. The regulation of energy balance is one which is attracting more and more attention due to the potential for exploiting peripheral hormonal targets as treatments for conditions such as obesity. While physiologically, this system is well tuned and demonstrated to be effective in the regulation of both local function and promoting/terminating food intake the neural connection represents a susceptible pathway for disruption in various disease states. Numerous studies have revealed that obesity in particularly is associated with an array of modifications in vagal afferent function from changes in expression of signaling molecules to altered activation mechanics. In general, these changes in vagal afferent function in obesity further promote food intake instead of the more desirable reduction in food intake. It is essential to gain a comprehensive understanding of the mechanisms responsible for these detrimental effects before we can establish more effective pharmacotherapies or lifestyle strategies for the treatment of obesity and the maintenance of weight loss.

Topics: Animals; Cholecystokinin; Dipeptides; Eating; Gastrointestinal Tract; Ghrelin; Glucagon-Like Peptide 1; Humans; Leptin; Microbiota; Neuronal Plasticity; Obesity; Satiation; Signal Transduction; 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

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

Obesity is one of the major challenges for public health in 21st century, with 1.9 billion people being considered as overweight and 600 million as obese. There are certain diseases such as type 2 diabetes, hypertension, cardiovascular disease, and several forms of cancer which were found to be associated with obesity. Therefore, understanding the key molecular mechanisms involved in the pathogenesis of obesity could be beneficial for the development of a therapeutic approach. Hormones such as ghrelin, glucagon like peptide 1 (GLP-1) peptide YY (PYY), pancreatic polypeptide (PP), cholecystokinin (CCK) secreted by an endocrine organ gut, have an intense impact on energy balance and maintenance of homeostasis by inducing satiety and meal termination. Glucose and energy homeostasis are also affected by lipid sensing in which different organs respond in different ways. However, there is one common mechanism i.e. formation of esterified lipids (long chain fatty acyl CoAs) and the activation of protein kinase C δ (PKC δ) involved in all these organs. The possible role of gut microbiota and obesity has been addressed by several researchers in recent years, indicating the possible therapeutic approach toward the management of obesity by the introduction of an external living system such as a probiotic. The proposed mechanism behind this activity is attributed by metabolites produced by gut microbial organisms. Thus, this review summarizes the role of various physiological factors such as gut hormone and lipid sensing involved in various tissues and organ and most important by the role of gut microbiota in weight management.

Topics: Adipose Tissue; Brain; Cholecystokinin; Cholesterol, VLDL; Gastrointestinal Hormones; Gastrointestinal Microbiome; Glucagon-Like Peptide 1; Humans; Insulin Resistance; Lipid Metabolism; Obesity; PPAR gamma

Cholecystokinin (CCK) regulates appetite and reduces food intake by activating the type 1 CCK receptor (CCK1R). Attempts to develop CCK1R agonists for obesity have yielded active agents that have not reached clinical practice. Here we discuss why, along with new strategies to target CCK1R more effectively. We examine signaling events and the possibility of developing agents that exhibit ligand-directed bias, to dissociate satiety activity from undesirable side effects. Potential allosteric sites of modulation are also discussed, along with desired properties of a positive allosteric modulator (PAM) without intrinsic agonist action as another strategy to treat obesity. These new types of CCK1R-active drugs could be useful as standalone agents or as part of a rational drug combination for management of obesity.

Topics: Allosteric Regulation; Animals; Cholecystokinin; Humans; Obesity; Receptor, Cholecystokinin A; Receptors, Cholecystokinin

Precise control of blood glucose is dependent on adequate β-cell mass and function. Thus, reductions in β-cell mass and function lead to insufficient insulin production to meet demand, and result in diabetes. Recent evidence suggests that paracrine signaling in the islet might be important in obesity, and disruption of this signaling could play a role in the pathogenesis of diabetes. For example, we recently discovered a novel islet incretin axis where glucagon-like peptide-1 regulates β-cell production of another classic gut hormone, cholecystokinin. This axis is stimulated by obesity, and plays a role in enhancing β-cell survival. In the present review, we place our observations in the wider context of the literature on incretin regulation in the islet, and discuss the potential for therapeutic targeting of these pathways.

Topics: Animals; Cholecystokinin; Glucagon-Like Peptide 1; Humans; Incretins; Islets of Langerhans; Obesity; Paracrine Communication

Bariatric surgery (e.g. Roux-en-Y gastric bypass (RYGB)) has proven the most effective way of achieving sustainable weight losses and remission of type 2 diabetes (T2D). Studies indicate that the effectiveness of RYGB is mediated by an altered gastrointestinal tract anatomy, which in particular favours release of the gut incretin hormone glucagon-like peptide-1 (GLP-1). The EndoBarrier gastrointestinal liner or duodenal-jejunal bypass sleeve (DJBS) is an endoscopic deployable minimally invasive and fully reversible technique designed to mimic the bypass component of the RYGB. Not only GLP-1 is released when nutrients enter the gastrointestinal tract. Cholecystokinin (CCK), secreted from duodenal I cells, elicits gallbladder emptying. Traditionally, bile acids are thought of as essential elements for fat absorption. However, growing evidence suggests that bile acids have additional effects in metabolism. Thus, bile acids appear to increase GLP-1 secretion via activation of the TGR5 receptor on the intestinal L cell. Recently FXR receptors were postulated to contribute to GLP-1 secretion too. Furthermore, metformin has been shown to increase circulating GLP-1 levels but although the exact mechanism is not fully elucidated it may involve metformin-induced inhibition of bile acid reuptake from the small intestines. Small-sized studies reported varying degrees of weight loss and, in some, improvement of glucose metabolism. Therefore, the objectives of this thesis were to collect existing information on the DJBS in order to evaluate clinical efficacy and safety (study I and II). Furthermore, since the endocrine impact of the DJBS is not fully elucidated, and DJBS is expected to mimic RYGB, we investigated postprandial metabolic changes following 26 weeks of DJBS treatment in ten obese subjects with normal glucose tolerance (NGT) and nine matched patients with T2D (study III). Finally, we studied the single and combined effects of CCK induced gallbladder emptying and single-dose metformin on human GLP-1 secretion in ten healthy subjects (study IV). We hypothesized that metformin-induced GLP-1 secretion - at least partly - would be dependent on gallbladder emptying and the presence of bile acids in the gut. DJBS appears to lead to moderate weight losses in obese subjects compared to diet or lifestyle modifications (study II). DJBS had insignificant and small effects (compared to diet) on glycaemic regulation. Adverse events consisted mainly of mild-to-moderate tr

Topics: Animals; Bariatric Surgery; Bile Acids and Salts; Cholecystokinin; Diabetes Mellitus, Type 2; Gastric Bypass; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Glycated Hemoglobin; Humans; Incretins; Metformin; Obesity; Weight Loss

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

Synergism between the Columbia University Appetitive Behavior Seminar and the research program of Smith and Gibbs on the satiating effect of cholecystokinin during the past 40 years is described. The Seminar was synergistic with the research program in five ways. First, the steady parade of speakers gave us a window on the varied and interesting work going on in the field. Second, the Seminar was the kind of audience for presentations of the work-in-progress on CCK that scientists hope for and rarely find. Criticism by members of the Seminar was relentless and constructive, and ideas for further experiments or new ways to tackle problematic data poured forth. Third, members of the Seminar did experiments that facilitated the experimental success of the research program. Fourth, members of the Seminar tutored us on topics that we wanted to import into the research program on CCK. Fifth, and probably most important, members of the Seminar gave us the encouragement, good humor, and friendship so necessary for coping with the struggles of the scientific life.

Topics: Animals; Appetitive Behavior; Cholecystokinin; Congresses as Topic; Feeding Behavior; Humans; Obesity; Satiation

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

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

Hormones from the gastrointestinal (GI) tract are released following food ingestion and trigger a range of physiological responses including the coordination of appetite and glucose homoeostasis. The aim of this review is to discuss the pathways by which food ingestion triggers secretion of cholecystokinin (CCK), glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) and the altered patterns of gut hormone release observed following gastric bypass surgery. Our understanding of how ingested nutrients trigger secretion of these gut hormones has increased dramatically, as a result of physiological studies in human subjects and animal models and in vitro studies on cell lines and primary intestinal cultures. Specialised enteroendocrine cells located within the gut epithelium are capable of directly detecting a range of nutrient stimuli through a range of receptors and transporters. It is concluded that the arrival of nutrients at the apical surface of enteroendocrine cells is a major stimulus for gut hormone release, thereby coupling these endocrine signals to the arrival of absorbed nutrients in the bloodstream.

Topics: Animals; Cholecystokinin; Diabetes Mellitus, Type 2; Eating; Enteroendocrine Cells; Gastrointestinal Tract; Glucagon-Like Peptide 1; Homeostasis; Humans; Obesity; Postprandial Period; Receptors, Gastrointestinal Hormone; Signal Transduction

The vagal afferent pathway is the major neural pathway by which information about ingested nutrients reaches the CNS and influences both GI function and feeding behavior. Vagal afferent neurons (VAN) express receptors for many of the regulatory peptides and molecules released from the intestinal wall, pancreas, and adipocytes that influence GI function, glucose homeostasis, and regulate food intake and body weight. As such, they play a critical role in both physiology and pathophysiology, such as obesity, where there is evidence that vagal afferent function is altered. This review will summarize recent findings on changes in vagal afferent function in response to ingestion of high fat diets and explore the hypothesis that changes in gut microbiota and integrity of the epithelium may not only be important in inducing these changes but may be the initial events that lead to dysregulation of food intake and body weight in response to high fat, high energy diets.

Topics: Animals; Cholecystokinin; Diet, High-Fat; Eating; Inflammation; Intestinal Mucosa; Intestines; Neurons, Afferent; Obesity; Vagus Nerve

Childhood obesity is a global epidemic and associated with an increased risk of hypertension, diabetes mellitus, and coronary heart disease, in addition to psychological disorders. Interventions such as bariatric surgery are highly invasive and lifestyle modifications are often unsuccessful because of disturbed perceptions of satiety. New signaling peptides discovered in recent years that are produced in peripheral tissues such as the gut, adipose tissue, and pancreas communicate with brain centers of energy homeostasis, such as the hypothalamus and hindbrain. This review discusses the major known gut- and adipose tissue-derived hormones involved in the regulation of food intake and energy homeostasis and their serum levels in childhood obesity before and after weight loss as well as their relationship to consequences of obesity. Since most of the changes of gastrointestinal hormones and adipokines normalize in weight loss, pharmacological interventions based on these hormones will likely not solve the obesity epidemic in childhood. However, a better understanding of the pathways of body weight- and food intake-regulating gut- and adipose tissue-derived hormones will help to find new strategies to treat obesity and its consequences.

Topics: Adipokines; Adipose Tissue; Child; Cholecystokinin; Diabetes Mellitus, Type 2; Dipeptides; Enteropeptidase; Exercise; Glucagon-Like Peptide 1; Health Behavior; Health Promotion; Humans; Hypothalamus; Life Style; Obesity; Oxyntomodulin; Pancreatic Polypeptide; Rhombencephalon; Weight Loss

Although energy balance is tightly regulated in order to maintain a specific level of adiposity, the incidence of obesity continues to increase. Consequently, it is essential that effective therapeutics for the treatment and prevention of obesity be developed. This review provides a brief update on some recent advances in the characterization of neuroendocrine targets for obesity therapy.. During the review period, considerable progress occurred in the understanding of previously described neuroendocrine regulators of energy balance, and several novel targets have been identified. Moreover, the understanding of the neural circuitry and molecular mechanisms of the neuroendocrine regulation of energy homeostasis has been expanded.. Energy balance is maintained by neuroendocrine signals arising from many tissues including the gastrointestinal tract and adipose tissue. These signals are integral to the cessation of meals and to the ability of the brain to monitor energy status and respond accordingly. Many current targets for obesity therapy are based on manipulating the activity of these signals and their receptors; however, to date, clinical-weight loss based on this strategy has been minimal and alternative approaches such as combinatorial therapies are emerging.

Topics: Adipose Tissue; Animals; Appetite Regulation; Cholecystokinin; Energy Intake; Gastrointestinal Tract; Ghrelin; Glucagon-Like Peptide 1; Humans; Insulin; Leptin; Mice; Neurosecretory Systems; Obesity; 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

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

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

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

Cholecystokinin (CCK) is a brain gut peptide that plays an important role in satiety. CCK inhibits food intake by reducing meal size. CCK's satiety actions are mediating through its interaction with CCK1 receptors. Otsuka Long Evans Tokushima Fatty (OLETF) rats are a CCK1 receptor knockout model that allows the study of multiple CCK functions. OLETF rats are hyperphagic with the hyperphagia expressed as a significant increase in the size of meals. OLETF rat obesity is secondary to the hyperphagia and has been proposed to derive from two regulatory deficits. One is secondary to the loss of a feedback satiety signal. The other results from increased dorsomedial hypothalamic NPY expression. Recent studies have examined developmental aspects of altered feeding, body weight and orexigenic signaling in OLETF rats. OLETF rats demonstrate increases in meal size in independent ingestion tests as early as two days of age. OLETF pups are also more efficient in suckling situations. Consistent with such developmental differences, examinations of patterns of hypothalamic gene expression in OLETF pups indicate significant increases in DMH NPY expression as early as postnatal day 15. Access to a running wheel and the resulting exercise have age dependent effects on OLETF food intake and obesity. With running wheel access shortly after weaning, food intake decreases to the levels of LETO controls. When running wheel access is discontinued, food intake temporarily increases resulting in an intermediate phenotype and the absence of diabetes. Together these data demonstrate roles for peripheral CCK and CCK in feeding and body weight control and support the use of the OLETF rat as a model for examining obesity development and for investigating how interventions at critical developmental time points can alter genetic influences on food intake and body weight.

Topics: Animals; Cholecystokinin; Eating; Hypothalamus; Obesity; Physical Conditioning, Animal; Rats; Rats, Inbred OLETF; Receptor, Cholecystokinin A

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

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

An understanding of the mechanisms that regulate energy homeostasis is essential for understanding novel obesity therapies. The status of energy reserves is communicated to the brain by adiposity and satiety signals. These signals modify either anabolic or catabolic pathways and, consequently, alter food intake in line with signaled energy requirements. New antiobesity therapies are in development that target anabolic or catabolic regulatory networks to reduce food intake and/or increase energy expenditure to promote weight loss.

Topics: Adiposity; Animals; Anti-Obesity Agents; Body Weight; Cannabinoid Receptor Modulators; Cholecystokinin; Energy Metabolism; Glucagon-Like Peptide 1; Humans; Leptin; Melanocyte-Stimulating Hormones; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; Receptor, Cannabinoid, CB1; Serotonin; Serotonin Receptor Agonists; Thyroid Hormones

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

Review of the ontogeny of the controls of independent ingestion reveals that some of the direct and indirect controls of meal size identified in adult rats function in the first three postnatal weeks. The controls appear sequentially and some of them change their potency after they emerge. Indirect controls exerted by metabolism and adiposity do not emerge until the fourth postnatal week or later in the postweaning period. Recent experiments in rats with monogenic obesities involving the leptin and cholecystokinin receptors have demonstrated the usefulness of independent ingestion in the detection of the earliest expression of hyperphagia. Although much remains to be learned about the normal controls of independent ingestion, it is clear that it provides relevant information about the development of normal and abnormal controls of meal size in rodents that is useful for translational research into the controls of meal size in normal and obese children.

Topics: Animals; Animals, Newborn; Cholecystokinin; Deoxyglucose; Dopamine; Energy Intake; Environment; Feedback; Feeding Behavior; Food Deprivation; Glucose; Leptin; Obesity; Physical Stimulation; Vagus Nerve

Otsuka Long Evans Tokushima Fatty (OLETF) rats have a deletion in the gene encoding the cholecystokinin-1 (CCK1) receptor. This deletion prevents protein expression, making the OLETF rat a CCK1 receptor knockout model. Consistent with the absence of CCK1 receptors, OLETF rats do not reduce their food intake in response to exogenously administered CCK and consume larger than normal meals. This deficit in within-meal feedback signaling is evident in liquid as well as solid meals. Neonatal OLETF rats show similar differences in independent ingestion tests. Intake is higher and is reflected in greater licking behavior. Neonatal OLETF rats also have diminished latencies to consume and higher initial ingestion rats. Adult OLETF rats are hyperphagic and obese. Although arcuate nucleus peptide gene expression is apparently normal in OLETF rats, when obesity is prevented through pair-feeding to amounts consumed by control Long Evans Tokushima Otsuka (LETO) rats, dorsomedial hypothalamic NPY mRNA expression is significantly elevated in OLETF rats. NPY overexpression is also evident in preobese, juvenile OLETF rats suggesting a causal role for this overexpression in the hyperphagia and obesity. Running wheel exercise normalizes food intake and body weight in OLETF rats. When access to exercise is provided at a time when OLETF rats are obese, the effects are limited to the period of exercise. When running wheel access is available to younger, preobese OLETF rats, exercise results in long lasting reductions in food intake and body weight and improved glucose regulation. These lasting metabolic effects of exercise may be secondary to an exercise induced reduction in DMH NPY mRNA expression.

Topics: Animals; Cholecystokinin; Energy Intake; Feeding Behavior; Gene Deletion; Hyperphagia; Mediodorsal Thalamic Nucleus; Obesity; Rats; Rats, Inbred OLETF; Receptors, Cholecystokinin; RNA, Messenger

Summary Cholecystokinin (CCK), a peptide that is distributed widely throughout the gastrointestinal tract and the central nervous system, has a number of physiological effects including the stimulation of gallbladder contraction and pancreatic and gastric acid secretion, slowing of gastric emptying and suppression of energy intake. This review focuses on current knowledge relating to (i) the effects of CCK on energy intake; (ii) the role for CCK in the pathophysiology of obesity; and (iii) the therapeutic potential for strategies which modulate the action or secretion of CCK in the management of obesity. While CCK plays a role in the acute regulation of appetite and energy intake, there is little evidence to suggest that specific CCK receptor agonists, or modulation of the actions of endogenous CCK by dietary manipulation, have sustainable inhibitory effects on energy intake. Hence, it appears unlikely that manipulating the pathways by which CCK modulates energy intake will prove to be an effective strategy in the long term management of obesity.

Topics: Animals; Appetite; Body Weight; Cholecystokinin; Digestive System Physiological Phenomena; Energy Intake; Gastrointestinal Hormones; Hormone Antagonists; Humans; Obesity; Proglumide; Receptors, Cholecystokinin

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

Understanding normal and dysfunctional energy regulation and body weight regulation requires neural evaluation of the signals involved in the control of food intake within a meal, as well as signals related to the availability of stored fuels. Work from our laboratory has focused on peripheral and central nervous system studies of behavior and physiology designed to improve our understanding of the role of gut-brain communication in the control of food intake and energy homeostasis. Gastrointestinal administration of nutrients reduces subsequent meal size, suggesting a potent role for peripheral nutrient sensing in the negative feedback control of ingestion. Vagal afferent nerves supply gastrointestinal sites stimulated during food intake, and these nerves are responsive to mechanical and nutrient chemical properties of ingested food. In addition, the presence of nutrients in these gastrointestinal sites stimulates the release of peptides that affect energy intake. These gut peptides also modulate the activity of peripheral gastrointestinal sensory nerves in ways that may contribute to their effects on food intake. In the central nervous system, adiposity hormones and their downstream mediators have been shown to work at both hindbrain and forebrain sites to affect food intake and metabolism. Importantly, recent data has shown that adiposity hormones acting in the brain increase the behavioral and neural potency of feeding inhibitory gastrointestinal stimuli. These data support the suggestion that insensitivity to adiposity hormones in obesity may be characterized by alterations in their ability to modulate the neural processing of food signals important in determining how much food is consumed during a meal.

Topics: Brain; Cholecystokinin; Eating; Gastrointestinal Tract; Humans; Leptin; Neuropeptides; Obesity; Satiation; Vagus Nerve

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

Humans in many countries are currently experiencing what has been called an epidemic of obesity. That is, the average body weight (and amount of fat stored in the body) is increasing over years, carrying with it a multitude of associated medical, psychological, and economic problems. While there is no shortage of possible causes of this epidemic, increased availability and consumption of high-fat (HF), calorically dense and generally quite palatable food is often touted as a likely culprit. In order to better assess the impact of consuming a diet with those qualities, we have developed a well-controlled animal model in which the effects of chronic consumption of a high-fat diet can be dissociated from those of becoming obese per se. Long-Evans rats are fed one of two semipurified pelleted diets, a HF diet that contains 20% fat by weight and a low-fat (LF) diet that contains 4% fat by weight. Pair-fed animals consume the HF diet but are limited to the daily caloric intake of LF rats. Another group receives pelleted chow. Relative to animals consuming diets low in fat, HF animals weigh more, have more carcass fat, are hyperinsulinemic and hyperleptinemic, and are insulin resistant. HF-fed animals, independent of whether they become obese or not, also have central insulin and MTII insensitivity. Finally, HF rats have a down-regulated hypothalamic apo A-IV system that could contribute to their hyperphagia.

Topics: Animals; Body Weight; Cholecystokinin; Dietary Fats; Disease Models, Animal; Energy Intake; Energy Metabolism; Homeostasis; Humans; Insulin; Obesity; Rats; Time Factors

Ethanol is a caloric compound, and ethanol drinking and food intake are both appetitive and consummatory behaviors. Furthermore, both ethanol and food have rewarding properties. It is therefore possible that overlapping central pathways are involved with uncontrolled eating and excessive ethanol consumption. A growing list of peptides has been shown to regulate food intake and/or energy homeostasis. Peptides such as the melanocortins, corticotropin releasing factor, and cholecystokinin promote reductions of food intake while others such as galanin and neuropeptide Y stimulate feeding. The present review highlights research aimed at determining if ingestive peptides also regulate voluntary ethanol intake, with an emphasis on the melanocortins and neuropeptide Y. It is suggested that research directed at ingestive peptides may expand our understanding of the neurobiological mechanisms that drive ethanol self-administration, and may reveal new therapeutic candidates for treating alcohol abuse and alcoholism.

Topics: Adrenocorticotropic Hormone; Alcoholism; alpha-MSH; Animals; beta-MSH; Brain; Cholecystokinin; Corticotropin-Releasing Hormone; Eating; Ethanol; Galanin; gamma-MSH; Humans; Narcotics; Neuropeptide Y; Obesity; Receptors, Melanocortin

A number of epidemiological studies has established obesity as a risk factor for gallstone disease. More recently, studies have suggested a relationship between gallstone disease and the metabolic syndrome linked to central adiposity, whose cardinal feature is represented by hyperinsulinaemia. Studies on fasting gall-bladder volume in obese subjects show that this parameter correlates with weight, body mass index (BMI) and body surface area; however, this is also true for large-sized non-obese subjects. Gall-bladder volume also correlates with abdominal fat and with impaired glucose tolerance. In contrast to the well-established role of bile supersaturation in the pathogenesis of gallstones in obesity, data are controversial on whether gall-bladder motor function is defective in obese subjects. However, studies were heterogeneous for subjects' BMI, emptying stimulus, technique used and parameters assessed to evaluate gall-bladder motor function. Also, differences in baseline gall-bladder volume may lead to wide differences in bile 'washout' effect despite apparently similar percentage changes in volume or content. Although post-prandial plasma levels of cholecystokinin (CCK) are normal in obese subjects, there is some evidence that a sub-group of obese subjects could have decreased sensitivity to CCK, possibly mediated by hyperinsulinaemia. Further studies using standard physiological stimuli and controlling for glucose tolerance, fasting insulin levels and baseline gall-bladder volume are needed to establish the role of gall-bladder motor function in the pathogenesis of gallstone disease in obesity.

Topics: Body Mass Index; Cholecystokinin; Cholelithiasis; Gallbladder; Gastrointestinal Motility; Humans; Hyperinsulinism; Muscle Contraction; Muscle, Smooth; Obesity; Postprandial Period

The pathophysiology of obesity is complex with many different pathways involved. A better understanding of these weight-regulating mechanisms has lead to the identification of new targets for anti-obesity agents. Most attention has been given to the centrally acting neuropeptides regulating food intake. Leptin, playing a key-role, exerts its action through several neuropeptides such as neuropeptide Y, alpha-melanocyte stimulating hormone and agouti related protein. Cocaine- and amphetamine-regulated transcript peptide and the orexins are the latest discovered peptides acting at the level of the hypothalamus. Targets for new drugs acting on peptides secreted from the periphery are cholecystokinin and glucagon-like peptide 1. Another potential target in the treatment of obesity is increasing energy expenditure via beta3 adrenoceptors or uncoupling proteins. These new pharmacological agents in development could be valuable adjuncts to more traditional treatment strategies such as dietary treatment, behavioural/psychological counselling and physical activity.

Topics: Behavior Therapy; Central Nervous System Stimulants; Cholecystokinin; Combined Modality Therapy; Counseling; Eating; Energy Metabolism; Forecasting; Humans; Hypothalamus; Leptin; Obesity; Peptide Fragments

In the almost 30 years since the ability of peripheral administration of the brain/gut peptide cholecystokinin (CCK) to inhibit food intake was first demonstrated, significant progress in our overall understanding of the role of CCK in ingestive behavior has been made. A physiologic role for endogenous CCK in the control of meal size has been demonstrated and sites and mechanisms of action for CCK in food intake have been investigated. Recent work has uncovered roles for the CCK satiety pathway in the mediation of the feeding modulatory actions of estradiol, insulin, and leptin. The availability of the Otsuka Long Evans Tokushima Fatty (OLETF) rat, a strain lacking CCK(A) receptors, provides a unique model for the study of how deficits in a within-meals satiety signaling pathway may result in long-term changes in food intake and body weight.

Topics: Animals; Appetite Regulation; Cholecystokinin; Eating; Energy Metabolism; Humans; Hyperphagia; Models, Animal; Obesity; Rats; Rats, Inbred OLETF; Receptors, Cholecystokinin; Satiation

Obesity: a bio-behavioural-environmental phenomenon: Obesity is on the increase all over the world in technologically advanced countries, developing countries and rural communities. What is causing this upward drift in body weight? Can drugs do anything to ameliorate the situation? It is generally agreed that obesity results from genetic vulnerability combined with a provocative environmental situation. This provides the basis for a psychobiological interaction in which behaviour plays a key role. This is the case since it is behaviour which translates biological propensities into action on the environment, and it is behaviour which mediates (in part) the effect of the environment upon biology. Two particularly important behavioural aspects of the genes-environment interaction are low levels of physical activity (high sedentariness) and dietary habits which favour overconsumption (high intake of energy, particularly as fat). One continuing theme of research is the development of drugs to allow people to gain control over appetite by modifying eating patterns (dietary habits) through a number of possible mechanisms. The use of drugs to make people more willing or more able to engage in physical activity is not widely discussed although the use of drugs to increase total energy expenditure (via a variety of mechanisms) is actively researched. More than a decade ago Sullivan defined the framework for the development of anti-obesity drugs by specifying that drugs could act on energy intake, energy output or on those mechanisms involved in the assimilation and storage of lipids in the body.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Body Weight; Cholecystokinin; Feeding Behavior; Forecasting; Humans; Obesity; Serotonin Receptor Agonists; Sympathomimetics

Steatosis and steatohepatitis are associated with obesity. Despite florid histological changes, patients with non-alcoholic steatohepatitis generally remain asymptomatic, and it usually runs a relatively benign course. An elevated insulin level may be important in the pathogenesis. There is a marked regression of fatty changes after weight reduction. In obese subjects the risk of developing gallstones is increased due to an increased saturation of gallbladder bile with cholesterol and possible gallbladder stasis. During weight reduction with very low calorie diets the incidence in gallstones increases probably because of an increased saturation of bile during the loss of weight. Ursodeoxycholic acid appears to be a promising prophylactic agent. Chenodeoxycholic acid is not useful for these subjects. There is controversy over whether obesity contributes to gastroesophageal reflux and gastric emptying disturbances. There are changes in gastrointestinal peptide plasma levels in obesity but it is not clear if this contributes to its development. The risk for high-risk colorectal adenomas and carcinomas is reported to be increased in obese males. Vertical banded gastroplasty and gastric bypass procedures are nowadays the surgical options for the treatment of obesity. Nutritional deficiencies, particularly of vitamin B12, folate and iron are common after gastric bypass and must be sought and treated. Dumping is another potential complication of this operation. If stenosis and gastric outlet obstruction develop endoscopic dilatation is a good therapeutic option.

Topics: Animals; Bombesin; Cholecystokinin; Cholelithiasis; Diet Therapy; Fatty Liver; Fatty Liver, Alcoholic; Gastrointestinal Diseases; Gastrointestinal Motility; Gastrointestinal Neoplasms; Humans; Male; Obesity; Peptides; Peripheral Nervous System Diseases; Risk Factors

In the past 20 years, the mechanisms of the satiating effect of food that terminate a meal have been investigated intensively in rodents and in humans. This research has revealed that three peptides, cholecystokinin, pancreatic glucagon, and bombesin, released by ingested food from the gastrointestinal tract decrease meal size in a specific, dose-related manner without signs of acute toxicity or tolerance. In humans, the three peptides decrease meal size without decreasing the reported pleasure or satisfaction of the meal. Although their chemical structure and specific effect justify calling these peptides a new class of anorectic agents, not enough work has been done to evaluate their efficacy for weight loss in obese humans or their safety when administered for months.

Topics: Animals; Appetite Depressants; Bombesin; Cholecystokinin; Glucagon; Humans; Obesity; Satiation

Topics: Animals; Appetite; Appetite Depressants; Cholecystokinin; Citrates; Dogs; Female; Humans; Male; Narcotic Antagonists; Obesity; Rats; Rats, Inbred Strains; Serotonin Antagonists

Of the many factors that influence food intake, there is strong evidence that opioid and CCK peptides, which stimulate feeding and elicit satiety, respectively, are important components that may act in concert to regulate energy balance. Cholecystokinin peptides have been isolated in both the brain and gastrointestinal tract, and changes in concentration in the brain and in plasma have been shown to vary with feeding. Peripherally injected CCK has been shown to elicit satiety in many species, including humans, an effect that may be mediated in the CNS via the vagus. In several species, most notably the sheep, direct injection into the CSF potently decreases food intake. Questions remaining regarding the role of CCK peptides in eliciting satiety include the sites and mechanisms of action. It is unknown whether CCK acts directly on receptors, indirectly on some other parameter, or as a neurotransmitter. Although opioid peptides have also been localized in portions of both the periphery and brain, a specific physiological role for their presence has not yet been determined. Opioid peptides from three families--endorphins, enkephalins, and dynorphins--have been shown to stimulate feeding in various species. They have been active at several opioid receptor types in the CNS, but there is limited evidence to suggest they affect food intake when administered peripherally. In contrast, peripheral injection of opiate antagonists has effectively decreased food intake, an observation that led to the original hypothesis that opioids were involved in the hunger component in the control of food intake and that excess concentrations might be involved in the development of obesity. An increasing body of evidence supports the concept that opioid and CCK peptides may interact to control food intake, but the evidence is more suggestive than conclusive.

Topics: Amino Acid Sequence; Animals; Behavior, Animal; beta-Endorphin; beta-Lipotropin; Brain; Ceruletide; Cholecystokinin; Digestive System Physiological Phenomena; Dynorphins; Eating; Endorphins; Enkephalins; Fasting; Food; Humans; Immunologic Techniques; Kinetics; Morphine; Nervous System; Neurons; Obesity; Peptide Fragments; Protein Precursors; Receptors, Cell Surface; Receptors, Cholecystokinin; Satiation; Sincalide; Species Specificity; Structure-Activity Relationship; Tissue Distribution

Since the mid-1970s, evidence has accumulated that cholecystokinin (CCK) has a role as a neuromodulator or neurotransmitter in the central nervous system as well as in the periphery. CCK has been shown to have a variety of effects on gastrointestinal functions and is one of the main candidates for a role as a peripheral negative feedback signal to stop feeding behavior. CCK produces satiety not only in animals but also in man: it reduces appetite and activation arising from the preparation of a meal and inhibits intake of liquid and solid food in both lean and obese subjects. The closely related peptide caerulein has similar effects. The site of action of peripherally administered CCK seems to be on an abdominal organ innervated by gastric vagal branches and relayed to the brain by afferent vagal fibres, since selective gastric vagotomy blocks the satiety effect, but pharmacological antagonism of vagal motor effects or lesions of the ventromedial hypothalamus do not. CCK also may have a role in the regulation of pain perception. In mice, CCK and caerulein were shown to produce a decrement in response to noxious stimulation after peripheral and central administration. In man, caerulein was demonstrated to relieve pain originating from biliary and renal colic as well as from cancer and ischemia. A series of studies in healthy man revealed that caerulein also alleviates experimentally induced cutaneous pain. Data from animal studies suggest that CCK-like peptides not only are able to produce analgesic effects on their own, but also are involved in the modulation of opioid systems mediating analgesia. Further study of these effects of CCK should elucidate the regulatory connections between the life-sustaining functions of feeding and pain sensation.

Topics: Analgesics; Animals; Appetite Depressants; Central Nervous System; Ceruletide; Cholecystokinin; Digestive System; Dogs; Endorphins; Feeding Behavior; Female; Gastrointestinal Motility; Haplorhini; Humans; Hunger; Male; Mice; Neural Pathways; Obesity; Pain; Rats; Satiety Response; Sincalide; Vagus Nerve

Topics: Afferent Pathways; Animals; Bombesin; Brain Mapping; Calcitonin; Calcitonin Gene-Related Peptide; Cholecystokinin; Corticotropin-Releasing Hormone; Disease Models, Animal; Endorphins; Feeding Behavior; Glucagon; Humans; Insulin; Motilin; Nerve Tissue Proteins; Neuropeptide Y; Neurotensin; Obesity; Pancreatic Polypeptide; Satiety Response; Somatostatin; Species Specificity; Stress, Psychological; Taste; Thyrotropin-Releasing Hormone

A review of the satiating effect of cholecystokinin in humans reveals that the synthetic C-terminal octapeptide of cholecystokinin (CCK-8) inhibits liquid and solid food intake in non-obese men and women, and in obese men. Side effects, such as nausea, slight stomach sickness or abdominal cramps are infrequent and transient, and they are neither necessary nor sufficient for the inhibition of intake. These results demonstrate the efficacy of the satiating effect of CCK-8 in humans. The therapeutic potential of CCK-8 cannot be estimated until further studies are performed that demonstrate the efficacy of CCK-8 for decreasing body weight and that the safety of CCK-8 when it is administered repetitively for prolonged periods is established.

Topics: Cholecystokinin; Eating; Humans; Obesity; Satiety Response; Sincalide

Topics: Animals; Appetite Regulation; beta-Endorphin; Bombesin; Cholecystokinin; Endorphins; Gastrointestinal Hormones; Mice; Nerve Tissue Proteins; Neurotensin; Obesity; Pancreatic Polypeptide; Peptides; Rats; Somatostatin

In the past 10 years, numerous gut peptides have been tested for their satiating effect on food intake. Cholecystokinin (CCK), bombesin, pancreatic glucagon, and somatostatin have the best supporting evidence for such a specific behavioral effect. The satiety effect of CCK, somatostatin, and glucagon is abolished or markedly reduced by abdominal vagotomy, but the satiety effect of bombesin is not. The effect of vagotomy has been interpreted as the result of the loss of vagal afferent fibers that are necessary for carrying information about visceral effects of these peptides to the brain. This hypothesis is under active investigation. There are three reports that CCK decreases the size of a test meal in lean and obese humans. This suggests that CCK or the other peptides may be useful in treating human obesity and bulimia.

Topics: Animals; Appetite Regulation; Bombesin; Cholecystokinin; Eating; Glucagon; Humans; Neurons, Afferent; Obesity; Peptides; Somatostatin; Vagus Nerve

Topics: Animals; Anorexia Nervosa; Autonomic Nervous System; Body Weight; Brain; Cholecystokinin; Eating; Feeding Behavior; Gastric Emptying; Homeostasis; Humans; Hunger; Hypothalamus; Insulin; Intestinal Absorption; Liver; Obesity; Receptor, Insulin; Satiation; Thirst

Topics: Cholecystokinin; Diabetes Mellitus, Type 2; Digestive System Physiological Phenomena; Gastric Inhibitory Polypeptide; Gastrins; Gastrointestinal Hormones; Glucagon; Glucagon-Like Peptides; Humans; Insulin; Motilin; Neurotensin; Obesity; Pancreatic Polypeptide; Pentagastrin; Secretin; Somatostatin; Vasoactive Intestinal Peptide

The satiety effect of cholecystokinin (CCK) that was first observed in rats has now been extended to chickens, rabbits, pigs, sheep, rhesus monkeys, lean mice, genetically obese mice and rats, neurologically obese rats, lean men and women, and obese men. The effect is specific and can be obtained in animals and humans without reports or signs of sickness. The mechanism of the effect is unknown, but the gastric vagal fibers are necessary for the effect. This has led to the hypothesis that the satiety effect is due to activation of vagal afferent fibers that inhibit the central control system of feeding by CCK acting directly on recently described vagal CCK receptors and/or indirectly through a gastric smooth muscle effect that vagal receptors are sensitive to.

Topics: Animals; Brain; Cholecystokinin; Eating; Feeding Behavior; Humans; Muscle, Smooth; Obesity; Peptide Fragments; Satiation; Sincalide; Stomach; Vagotomy; Vagus Nerve

Topics: Animals; Anura; Brain; Chemical Phenomena; Chemistry; Cholecystokinin; Humans; Huntington Disease; Intestine, Small; Neurotransmitter Agents; Obesity; Pancreatitis; Species Specificity; Swine

l-Tryptophan reduces energy intake in healthy men. The underlying mechanisms, including appetite, plasma cholecystokinin (CCK), tryptophan (Trp), and the ratio of Trp to large neutral amino acids (Trp:LNAAs ratio), and whether responses differ in lean and obese individuals, are uncertain.. We evaluated the effects of intragastric Trp on energy intake (primary outcome) and their potential mechanisms, pre- and postmeal, in lean men and those with obesity.. Twelve lean men [mean ± SD age: 30 ± 3 y; BMI (in kg/m2): 23 ± 1] and 13 men with obesity (mean ± SD age: 31 ± 3 y; BMI: 33 ± 1) received, on 3 separate occasions, in double-blind, randomized order, 3 g ("Trp-3") or 1.5 g ("Trp-1.5") Trp, or control ("C"), intragastrically, 30 min before a buffet-meal. Energy intake from the buffet-meal, hunger, fullness, and plasma CCK and amino acid concentrations were measured in response to Trp alone and for 2 h postmeal. Data were analyzed using maximum likelihood mixed-effects models, with treatment, group, and treatment-by-group interaction as fixed effects.. Trp alone increased plasma CCK, Trp, and the Trp:LNAAs ratio (all P < 0.001), with no difference between groups. Trp suppressed energy intake (P < 0.001), with no difference between groups (lean, C: 1085 ± 102 kcal, Trp-1.5: 1009 ± 92 kcal, Trp-3: 868 ± 104 kcal; obese, C: 1249 ± 98 kcal, Trp-1.5: 1217 ± 90 kcal, Trp-3: 1012 ± 100 kcal). Postmeal, fullness was greater after Trp-3 than after C and Trp-1.5 (all P < 0.05), and in men with obesity than in lean men (P < 0.05). Plasma Trp and the Trp:LNAAs ratio were greater after Trp-3 and Trp-1.5 than after C (all P < 0.001), and tended to be less in men with obesity than in the lean (P = 0.07) (Trp:LNAAs ratio: lean, C: 1.5 ± 0.2, Trp-1.5: 6.9 ± 0.7, Trp-3: 10.7 ± 1.4; obese, C: 1.4 ± 0.1, Trp-1.5: 4.6 ± 0.7, Trp-3: 7.8 ± 1.3). There were inverse correlations of energy intake with plasma Trp and the Trp:LNAAs ratio in both groups (lean, both r = -0.50, P < 0.01; obese, both r = -0.40, P < 0.05).. Intragastric Trp has potent energy intake-suppressant effects, in both lean men and those with obesity, apparently related to the Trp:LNAAs ratio.

Topics: Adult; Appetite; Cholecystokinin; Double-Blind Method; Energy Intake; Humans; Male; Obesity; Tryptophan

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

Circulating tryptophan/large neutral amino acids (tryptophan/LNAA) ratio, an indicator of brain serotonin levels, may be important in appetite regulation, together with gastrointestinal (gastric emptying, plasma cholecystokinin) mechanisms. We have compared effects of intragastric tryptophan ('Trp') on the plasma tryptophan/LNAA ratio in lean and obese men, and the associations of the tryptophan/LNAA ratio, gastric emptying and CCK concentrations with energy intake. Lean and obese male participants (n = 16 each) received 3 g Trp or volume-matched control intragastrically, 15 min before a mixed-nutrient drink (300 mL, 400 kcal) (t = 0 min) in randomised, double-blind fashion. Plasma amino acid (for calculation of the plasma tryptophan/LNAA ratio) and CCK concentrations were measured from t = -20-60 min. Gastric emptying was assessed from t = 0-60 min, and ad-libitum energy intake from a standardised buffet-style meal from t = 60-90 min. The increase in the plasma tryptophan/LNAA ratio was less in obese, than lean, participants (P < 0.05), and greater in lean participants who reduced their energy intake (by >0 kcal) after Trp compared with those who did not (by ≤0 kcal) (P < 0.05). Moreover, in participants who reduced their energy intake, the ratio was lower in obese, than in lean (P < 0.05). There was a trend for an inverse correlation between energy intake with the plasma tryptophan/LNAA ratio in lean (r = -0.4, P = 0.08), but not in obese, participants. There was no significant difference in gastric emptying or CCK between participants who reduced their energy intake and those who did not. In conclusion, the plasma tryptophan/LNAA ratio appears to be a determinant of the suppression of energy intake in response to tryptophan in normal-weight people, but not in those with obesity. The role of the plasma tryptophan/LNAA ratio to regulate energy intake, and potential changes in obesity, warrant evaluation in prospective studies.

Topics: Adult; Amino Acids; Amino Acids, Neutral; Appetite Regulation; Body Mass Index; Cholecystokinin; Double-Blind Method; Energy Intake; Gastric Emptying; Humans; Ideal Body Weight; Infusions, Parenteral; Male; Meals; Obesity; Tryptophan

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

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

Tryptophan stimulates plasma cholecystokinin and pyloric pressures, both of which slow gastric emptying. Gastric emptying regulates postprandial blood glucose. Tryptophan has been reported to decrease energy intake. We investigated the effects of intragastric tryptophan on the glycaemic response to, and gastric emptying of, a mixed-nutrient drink, and subsequent energy intake. Lean and obese participants (

Topics: Administration, Oral; Adult; Appetite Depressants; Beverages; Biomarkers; Blood Glucose; C-Peptide; Cholecystokinin; Double-Blind Method; Energy Intake; Food, Formulated; Gastric Emptying; Glucagon; Humans; Male; Obesity; Postprandial Period; South Australia; Time Factors; Treatment Outcome; Tryptophan

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

Gut hormones such as cholecystokinin (CCK) and glucagon-like peptide-1 (GLP-1) play a role as satiation factors. Strategies to enhance satiation peptide secretion could provide a therapeutic approach for obesity. Carbohydrates and lipids have been extensively investigated in relation to peptide release. In contrast, the role of proteins or amino acids is less clear. Our aim was to compare the effects of the amino acids L-tryptophan (L-trp) and L-leucine (L-leu) separately on gastric emptying and gut peptide secretion.. The study was conducted as a randomized (balanced), double-blind, parallel-group trial. A total of 10 lean and 10 non-diabetic obese participants were included. Participants received intragastric loads of L-trp (0.52 g and 1.56 g) and L-leu (1.56 g), dissolved in 300 mL tap water; 75 g glucose and 300 mL tap water served as control treatments.. Results of the study are: i) L-trp at the higher dose stimulates CCK release (p = 0.0018), and induces a significant retardation in gastric emptying (p = 0.0033); ii) L-trp at the higher dose induced a small increase in GLP-1 secretion (p = 0.0257); iii) neither of the amino acids modulated subjective appetite feelings; and iv) the two amino acids did not alter insulin or glucose concentrations.. L-trp is a luminal regulator of CCK release with effects on gastric emptying, an effect that could be mediated by CCK. L-trp's effect on GLP-1 secretion is only minor. At the doses given, the two amino acids did not affect subjective appetite feelings.. ClinicalTrials.gov NCT02563847.

Topics: Adult; Appetite; Cholecystokinin; Double-Blind Method; Female; Gastric Emptying; Glucagon-Like Peptide 1; Humans; Leucine; Male; Middle Aged; Obesity; Tryptophan

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

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

Obesity, type 2 diabetes and associated metabolic diseases are characterized by low-grade systemic inflammation which involves interplay of nutrition and monocyte/macrophage functions. We suggested that some factors such as nutrient components, neuropeptides involved in the control of gastrointestinal functions, and gastrointestinal hormones might influence immune cell functions and in this way contribute to the disease pathogenesis. The aim of this study was to investigate the mRNA expression of twelve nutrition-associated receptors in peripheral blood mononuclear cells (PBMC), isolated monocytes and monocyte-derived macrophages and their regulation under the switching from the high-carbohydrate low-fat diet to the low-carbohydrate high-fat (LC/HFD) isocaloric diet in healthy humans. The mRNA expression of receptors for short chain fatty acids (GPR41, GPR43), bile acids (TGR5), incretins (GIPR, GLP1R), cholecystokinin (CCKAR), neuropeptides VIP and PACAP (VIPR1, VIPR2), and neurotensin (NTSR1) was detected in PBMC and monocytes, while GPR41, GPR43, GIPR, TGR5, and VIPR1 were found in macrophages. Correlations of the receptor expression in monocytes with a range of metabolic and inflammatory markers were found. In non-obese subjects, the dietary switch to LC/HFD induced the increase of GPR43 and VIPR1 expression in monocytes. No significant differences of receptor expression between normal weight and moderately obese subjects were found. Our study characterized for the first time the expression pattern of nutrition-associated receptors in human blood monocytes and its dietary-induced changes linking metabolic responses to nutrition with immune functions in health and metabolic diseases.

Topics: Adult; Case-Control Studies; Cholecystokinin; Diet, Fat-Restricted; Diet, High-Fat; Dietary Carbohydrates; Dietary Fats; Female; Gene Expression Regulation; Humans; Incretins; Macrophages; Male; Monocytes; Neuropeptides; Obesity; Organ Specificity; Primary Cell Culture; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Receptors, Neurotensin

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 is centrally and peripherally mediated by gastrointestinal peptides and the vagal nerve. We aimed to investigate whether intragastric balloon treatment affects satiety through effects on fasting and meal-stimulated cholecystokinin (CCK) and pancreatic polypeptide (PP) secretion.. Patients referred for obesity treatment were randomised to 13 weeks of sham treatment followed by 13 weeks of balloon treatment (group 1; sham/balloon) or to twice a 13-week period of balloon treatment (group 2; balloon/balloon). Blood samples were taken for fasting and meal-stimulated CCK and PP levels at the start (T0) and after 13 (T1) and 26 (T2) weeks. Patients filled out visual analogue scales (VAS) to assess satiety.. Forty-two patients (35 females, body weight 125.1 kg, BMI 43.3 kg/m(2)) participated. In group 1, basal CCK levels decreased but meal-stimulated response remained unchanged after 13 weeks of sham treatment. In group 2, basal and meal-stimulated CCK levels decreased after 13 weeks of balloon treatment. At the end of the second 13-week period, when group 1 had their first balloon treatment, they duplicated the initial 13-week results of group 2, whereas group 2 continued their balloon treatment and reduced meal-stimulated CCK release. Both groups showed reduced meal-stimulated PP secretions at T1 and T2 compared to T0. Changes in diet composition and VAS scores were similar. Improvements in glucose homeostasis partly explained the PP results.. The reduced CCK and PP secretion after balloon positioning was unexpected and may reflect delayed gastric emptying induced by the balloon. Improved glucose metabolism partly explained the reduced PP secretion. Satiety and weight loss were not adversely influenced by these hormonal changes.

Topics: Adult; Cholecystokinin; Eating; Fasting; Female; Gastric Balloon; Humans; Male; Middle Aged; Obesity; Pain Measurement; Pancreatic Polypeptide; Postprandial Period; Satiation; Treatment Outcome; Weight Loss

The effect of exercise on body mass is likely to be partially mediated through changes in appetite control. However, no studies have examined the effect of chronic exercise on obestatin and cholecystokinin (CCK) plasma concentrations or the sensitivity to detect differences in preload energy in obese individuals. The objective of this study was to investigate the effects of chronic exercise on 1) fasting and postprandial plasma concentrations of obestatin, CCK, leptin, and glucose insulinotropic peptide (GIP) and 2) the accuracy of energy compensation in response to covert preload manipulation.. This study used a 12-wk supervised exercise program in 22 sedentary overweight/obese individuals. Fasting/postprandial plasma concentrations of obestatin, CCK, leptin, and GIP were assessed before and after the intervention. Energy compensation at a 30-min test meal after a high-energy (607 kcal) or a low-energy (246 kcal) preload and for the rest of the day (cumulative energy intake [EI]) was also measured.. There was a significant reduction in the plasma concentration of fasting plasma GIP and both fasting and postprandial leptin concentrations after the exercise intervention (P < 0.05 for all). No significant changes were observed for CCK or obestatin. A significant preload-exercise interaction (P = 0.011) was observed on cumulative EI and energy compensation for the same period (-87% ± 196% vs 68% ± 165%, P = 0.011). Weight loss (3.5 ± 1.4 kg, P < 0.0001) was not correlated with changes in energy compensation.. This study suggests that exercise improves the accuracy of compensation for previous EI, independent of weight loss. Unexpectedly, and in contrast to GIP and leptin, exercise-induced weight loss had no effect on obestatin or CCK concentrations.

Topics: Adult; Appetite; Cholecystokinin; Cross-Over Studies; Exercise; Exercise Therapy; Female; Gastric Inhibitory Polypeptide; Ghrelin; Humans; Leptin; Male; Obesity; Overweight; Physical Fitness; Postprandial Period

Obesity is an energy balance problem caused by overeating. Obesity treatment includes diet, exercise, behaviour treatment, pharmacotherapy and surgery; in addition, acupuncture is also an option.. To investigate the effect of acupuncture on weight loss and whether a brief acupuncture treatment of 5 weeks can change circulating levels of leptin, ghrelin, insulin and cholecystokinin (CCK) in obese women.. 40 women with a body mass index (BMI)>30 kg/m(2) were equally randomised to either an acupuncture group or a sham (non-penetrating) acupuncture group and received treatment at LI4, HT7, ST36, ST44 and SP6 bilaterally. Both groups had two sessions of 20 min/week for a total of 10 sessions. Serum insulin, leptin, plasma ghrelin and CCK levels were measured by ELISA.. Acupuncture treatment decreased insulin and leptin levels and induced weight loss, together with a decrease in BMI compared with sham acupuncture. Furthermore, between-group analyses demonstrated increases in plasma ghrelin and CCK levels in subjects who received acupuncture treatment.. These findings suggest that acupuncture may help to regulate weight owing to its beneficial effects on hormones such as insulin, leptin, ghrelin and CCK in obese subjects even after a few weeks of treatment.

Topics: Acupuncture Points; Acupuncture Therapy; Adult; Body Mass Index; Cholecystokinin; Female; Ghrelin; Humans; Insulin; Leptin; Middle Aged; Obesity; Weight Loss

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

Mastication is the first step in ingesting food, but the effects of mastication on energy intake and gut hormones in both obese and lean subjects have not been extensively evaluated.. The current study aimed to compare the differences in chewing activities between obese and lean subjects and to examine the effects of chewing on energy intake and gut hormone concentrations in both obese and lean subjects.. Sixteen lean and 14 obese young men participated in the current research. In study 1, we investigated whether the chewing factors of obese subjects were different from those of lean subjects. In study 2, we explored the effects of chewing on energy intake. A test meal consisting of 2200 kJ (68% of energy as carbohydrate, 21% of energy as fat, and 11% of energy as protein) was then consumed on 2 different sessions (15 chews and 40 chews per bite of 10 g of food) by each subject to assess the effects of chewing on plasma gut hormone concentrations.. Compared with lean participants, obese participants had a higher ingestion rate and a lower number of chews per 1 g of food. However, obese participants had a bite size similar to that of lean subjects. Regardless of status, the subjects ingested 11.9% less after 40 chews than after 15 chews. Compared with 15 chews, 40 chews resulted in lower energy intake and postprandial ghrelin concentration and higher postprandial glucagon-like peptide 1 and cholecystokinin concentrations in both lean and obese subjects.. Interventions aimed at improving chewing activity could become a useful tool for combating obesity. This trial was registered at chictr.org as ChiCTR-OCC-10001181.

Topics: Adult; Asian People; Cholecystokinin; Energy Intake; Ghrelin; Glucagon-Like Peptide 1; Humans; Male; Mastication; Obesity; Postprandial Period; Thinness; Young Adult

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

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

Glycomacropeptide (GMP) is the hydrophilic 64-amino acid C-terminal glycopeptide released into cheese whey when kappa-casein is cleaved by chymosin. GMP exists as a mixture of different glycoforms due to the carbohydrates sialic acid (N-acetylneuraminic acid, NeuNAc), galactose (Gal), galactosamine and glucosamine attached by O-glycosidic linkages. GMP reportedly stimulates the release of cholecystokinin (CCK), which may promote satiety. The objectives of the present study were to manufacture three glycoforms of GMP, minimally glycosylated GMP (3.5 (sd 0.1) % NeuNAc and 1.5 (sd 0.1) % Gal), glycosylated GMP (12.0 (sd 0.3) % NeuNAc and 4.2 (sd 0.2) % Gal) and a GMP-depleted whey protein concentrate, and to assess the effects of these fractions relative to glucose on CCK, subjective measures of satiety and food intake. In a randomised double-blind acute study, twenty overweight/obese males (56.9 (sd 7.2) years, 97.4 (sd 8.1) kg, 31.5 (sd 3.0) kg/m2) were recruited to consume four 50 g preloads (two GMP preparations, GMP-depleted whey and glucose) containing 895 kJ. Blood samples and subjective measures of satiety were collected before and at 15, 30, 60, 90, 120 and 180 min after the consumption of preload, and CCK levels were measured. A lunchtime meal of hot food was provided from which subjects ate ad libitum until satisfied. Energy and nutrient intakes from the food consumed were calculated. There was no significant difference in CCK levels, subjective measures of satiety or food intake between treatments at the given preload level. These results suggest that the protein fractions at the dose employed do not influence satiety, CCK levels or energy intake at a subsequent meal.

Topics: Adult; Aged; Appetite Regulation; Caseins; Cholecystokinin; Double-Blind Method; Eating; Humans; Male; Middle Aged; Obesity; Overweight; Peptide Fragments; Satiation; Time Factors; Young Adult

L-Phenylalanine (Phe), is a potent releaser of the satiety hormone, cholecystokinin (CCK) and previous studies, conducted primarily in men, show that ingestion of Phe reduces energy intake. The objective of the current study was to test the effects of Phe on energy intake in overweight and obese women. Subjects (n=32) received three treatments (high-dose (10 g Phe), low-dose (5 g Phe and 5 g glucose) or control (10 g glucose)) 20 min before an ad libitum lunch and dinner meal in a within-subjects', counterbalanced, double-blind study. No effect of Phe was found, however, interactions with dietary restraint status were detected in post-hoc analyses. Energy intake over the day was 11% lower following high-dose Phe versus control for women classified in the lower tertile of rigid restraint, a subscale of the dietary restraint scale, whereas no effects were noted for women in the middle and upper tertiles. High-dose Phe increased ratings of nausea, however, reduced energy intake in the high-dose condition was noted only for subjects with low nausea ratings. These results suggest that the satiety response to Phe is modulated by rigid restraint status and that reductions in food intake occur independently of Phe's effects on nausea.

Topics: Adult; Caloric Restriction; Cholecystokinin; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Eating; Energy Intake; Female; Humans; Middle Aged; Nausea; Obesity; Overweight; Phenylalanine; Satiation

To assess weight maintenance after weight loss by consumption of yoghurt with a novel fat emulsion (Olibra) including effects on body composition, resting energy expenditure (REE), fat oxidation, hunger feelings and satiety hormones.. A randomized, placebo-controlled, double-blind, parallel design. A 6-week weight loss period (2.1 MJ/day) was followed by 18 weeks weight maintenance with test (Olibra) or placebo yoghurt.. Fifty overweight women (age: 18-58 years, body mass index (BMI) 25-32 kg/m2).. In weeks 1, 7 and 25, a satiety test with questionnaires and blood samples for analysis of satiety hormones. In weeks 2, 8 and 26, REE, body weight and body composition.. During weight maintenance after significant body weight reduction, there was no significant increase in body weight in the test group (1.1+/-3.4 kg); the placebo group did gain weight (3.0+/-3.1 kg, P<0.001). Compared to the placebo group, the test group was less hungry 4 h after yoghurt consumption in week 25 (P<0.05) and showed increased glucagon like peptide-1 values 180 min after yoghurt consumption (week 25 vs week 1, P<0.05). Measured REE as a function of fat-free mass (FFM) was significantly higher than predicted REE (P<0.05) in week 26 for the test group, but not for the placebo group. Fat mass (FM) was significantly more decreased in the test group (6.5+/-4.1 kg) compared to the placebo group (4.1+/-3.6 kg) (week 26 vs week 2, P<0.05).. Consumption of Olibra yoghurt improved weight maintenance compared to placebo, which can be explained by the relatively higher REE as a function of FFM, relatively higher decrease in FM and the relatively lower increase in hunger.

Topics: Adolescent; Adult; Appetite Depressants; Body Mass Index; Body Weight; Caloric Restriction; Cholecystokinin; Dietary Supplements; Double-Blind Method; Emulsions; Energy Metabolism; Fats; Female; Ghrelin; Glucagon-Like Peptide 1; Humans; Hunger; Middle Aged; Obesity; Overweight; Peptide Hormones; Satiety Response; Weight Gain; Weight Loss; Yogurt

To investigate appetite responses over 4 h to fructose beverages in obese men, relative to glucose and whey protein. Second, to investigate the effect of combining whey and fructose on postprandial appetite hormones.. Randomized, double-blind crossover study of four beverages (1.1 MJ) containing 50 g of whey, fructose, glucose or 25 g whey+25 g fructose. Blood samples and appetite ratings were collected for 4 h then a buffet meal was offered.. Twenty-eight obese men (age: 57.0+/-1.6 years, body mass index: 32.5+/-0.6 kg/m(2)).. Plasma ghrelin (total), glucagon-like peptide-1 (GLP-1 7-36), cholecystokinin-8, glucose, insulin and appetite ratings were assessed at baseline and 30, 45, 60, 90, 120, 180, 240 min after beverages, followed by measurement of ad libitum energy intake.. Fructose produced lower glycaemia and insulinaemia compared to the glucose treatment (P<0.0001); whereas postprandial ghrelin, GLP-1 and cholecystokinin responses were similar after both treatments. Whey protein produced a prolonged (2-4 h) suppression of ghrelin (P=0.001) and elevation of GLP-1 (P=0.002) and cholecystokinin (P=0.003) that were reduced when combined with fructose, while glucose and insulin responses were similar. Energy intake after 4 h was independent of beverage type (glucose 4.7+/-0.2 MJ; fructose 4.9+/-0.3 MJ; whey 4.6+/-0.3 MJ; whey/fructose 4.8+/-0.3 MJ; P>0.05).. In obese men, fructose- and glucose-based beverages had similar effects on appetite and associated regulatory hormones, independent of the differing glycaemic and insulinaemic responses. The contrasting profile of plasma ghrelin, GLP-1 and cholecystokinin after whey protein consumption did not impact on ad libitum intake 4 h later and was attenuated when 50% of whey was replaced with fructose.

Topics: Appetite; Beverages; Blood Glucose; Cholecystokinin; Cross-Over Studies; Dietary Carbohydrates; Double-Blind Method; Energy Intake; Fructose; Ghrelin; Glucagon-Like Peptide 1; Glucose; Humans; Insulin; Male; Middle Aged; Milk Proteins; Obesity; Peptide Fragments; Peptide Hormones; Whey Proteins

Dietary proteins appear to be more satiating than carbohydrate. The mechanism and effect of protein and carbohydrate type are unclear.. The objective of the study is to compare the acute effect of different proteins and carbohydrates on indicators of appetite and appetite regulatory hormones.. This is a randomized cross-over study of four orally consumed preloads followed by blood sampling (+15, 30, 45, 60, 90, 120, 180 min), then a buffet meal.. The study was carried out in an outpatient clinic.. Nineteen overweight (body mass index 32.1 +/- 0.9 kg/m(2)) men participated.. Liquid preloads (1 MJ) contained whey (55 g), casein (55 g), lactose (56 g), or glucose (56 g).. Plasma ghrelin, cholecystokinin (CCK), insulin, glucose and amino acids, gastric emptying rate (plasma paracetamol), appetite rating (visual analog scale), and ad libitum energy intake were the main outcome measures.. Energy intake was 10 +/- 3% higher after the glucose preload compared with lactose and protein preloads (P < 0.05), which were predicted by ghrelin at 120 min (P < 0.05). CCK was 71 +/- 6% higher 90 min after the protein preloads compared with glucose and lactose (P < 0.05), which predicted appetite at 180 min (P < 0.05). There was a small increase in branched chain amino acids after the whey preload compared with casein (P < 0.01), but this was independent of appetite and energy intake.. Acute appetite and energy intake are equally reduced after consumption of lactose, casein, or whey compared with glucose, which was consistent with differences in plasma ghrelin. Higher CCK responses after proteins correlated with satiety but did not affect energy intake.

Topics: Acetaminophen; Adult; Amino Acids; Analgesics, Non-Narcotic; Blood Glucose; Caseins; Cholecystokinin; Cross-Over Studies; Diet; Dietary Carbohydrates; Dietary Proteins; Energy Intake; Ghrelin; Glucose; Humans; Insulin; Lactose; Male; Milk Proteins; Obesity; Peptide Hormones; Regression Analysis; Satiety Response; Whey Proteins

Accelerated gastric emptying of solids may play a role in the pathogenesis of obesity. Orlistat, a potent lipase inhibitor, induces fat malabsorption and body weight loss but might accelerate gastric emptying as a result of suppressed CCK release. The aim was to investigate the role of fat restriction and lipase inhibition in CCK release and gastric emptying.. A total of 28 patients (three male (M)/25 female (F); mean (s.d.) BMI 37.4(3.9) kg/m2) entering a randomized, double-blind, placebo-controlled study.. CCK release and gastric emptying by scintigraphy at the start (T0), after 1 month of an energy- and fat-restricted diet and placebo (T1), and after 1 month (T2) and 1 year (T3) of randomization to placebo or 120 mg orlistat three times a day.. One month of dieting and a weight loss of 2.3 kg (2.1% of initial weight) did not affect gastric emptying of liquids and solids. Basal and meal-stimulated CCK levels remained unaltered. Placebo-treated subjects who continued the diet for 1 month demonstrated a borderline significant suppressed CCK secretion and a weight loss of 1.2 kg (1.0%) without an effect on gastric emptying. After 1 year, the CCK secretion recovered to or beyond values at the start. A significantly slower emptying of solids (17.6 (T3) versus 25.9 (T1)%/h) and a weight loss of 10.4 kg (9.9%) was observed. Subjects on 120 mg orlistat lost 2.5 kg (2.5%) after 1 month, and 9.8 kg (9.9%) after 1 year. Basal and postprandial CCK release decreased significantly after the first month of orlistat treatment but normalized after 1 year. Diet and lipase inhibition did not have any influence on gastric emptying.. Energy and fat restriction of 1 month did not alter gastric emptying in the whole group. Continuation of the diet for 1 year resulted in a delayed gastric emptying of solids. Lipase inhibition did not result in a sustained depressed CCK release and the anticipated acceleration of gastric emptying did not occur.

Topics: Anti-Obesity Agents; Cholecystokinin; Diet, Fat-Restricted; Diet, Reducing; Enzyme Inhibitors; Female; Gastric Emptying; Humans; Lactones; Lipase; Male; Middle Aged; Obesity; Orlistat; Satiety Response; Weight Loss

Although dietary protein produces higher acute satiety relative to carbohydrate, the influence of protein source and body mass index (BMI) has not been clearly described.. The objective of the study was to assess postprandial responses to different protein sources, compared with glucose, in males with normal and high BMI.. This was a randomized, crossover study of four preloads followed by blood sampling (+15, 30, 45, 60, 90, 120, 180 min) and buffet meal.. The study was conducted at an outpatient clinic.. The study population included 72 men, with a BMI range 20.6-39.9 kg/m(2).. Interventions consisted of liquid preloads (1.1 MJ, 450 ml) containing 50 g whey, soy, gluten, or glucose.. Fasting and postprandial plasma glucose, insulin, ghrelin, glucagon-like peptide-1 (GLP-1) and cholecystokinin (n = 38), ad libitum energy intake, and appetite ratings were measured.. Energy intake was 10% lower after all protein preloads, compared with the glucose treatment (P < 0.05), independent of BMI status and protein type. All protein loads prolonged the postprandial suppression of ghrelin (P < 0.01) and elevation of GLP-1 (P < 0.01) and cholecystokinin (P < 0.05). Fasting GLP-1 concentrations [overweight, 17.5 +/- 1.3; lean, 14.7 +/- 0.1 pg/ml (5.2 +/- 0.4 and 4.4 +/- 0.1 pmol/liter, respectively); P < 0.001] and postprandial responses (P = 0.038) were higher in overweight subjects.. Whey, soy, and gluten similarly tend to reduce ad libitum food intake 3 h later in lean and overweight males relative to glucose. Postprandial ghrelin, GLP-1, insulin, and cholecystokinin may contribute to this higher satiety after protein consumption. GLP-1 concentrations are increased in overweight subjects, which may affect satiety responses in this group.

Topics: Adult; Aged; Appetite Regulation; Blood Glucose; Body Mass Index; Body Weight; Cholecystokinin; Cross-Over Studies; Dietary Proteins; Eating; Energy Intake; Ghrelin; Glucagon-Like Peptide 1; Glutens; Hormones; Humans; Insulin; Kinetics; Male; Middle Aged; Milk Proteins; Obesity; Peptide Hormones; Regression Analysis; Satiation; Soybean Proteins; Whey Proteins

Binge-eating disorder (BED), characterized by binge meals without purging afterward, is found in about 30% of obese individuals seeking treatment. The study objective was to ascertain abnormalities in hormones influencing appetite in BED, especially ghrelin, an appetite-stimulating peptide, which was expected to be elevated. Measurements were made of plasma insulin, leptin, glucagon, cholecystokinin, and ghrelin, as well as glucose following an overnight 12-h fast, prior to and after ingestion (from 0 to 5 min) of a nutritionally complete liquid meal (1254 kJ) at 0830 h, at -15, 0, 5, 15, 30, 60, 90, and 120 min. Appetite ratings including hunger and fullness were also obtained. An acetaminophen tracer was used to assess gastric emptying rate. Three groups of comparably obese women (BMI = 35.9 +/- 5.5; % body fat = 44.9 +/- 4.7) participated: 12 nonbinge eating normals (NB), 14 subthreshold BED, and 11 BED. The BED subjects, compared to NB subjects, had lower baseline ghrelin concentrations prior to the meal, a lower area under the curve (AUC), with lower levels at 5, 15, 30, 90, and 120 min, and a smaller decline in ghrelin postmeal (all P < 0.03). The other blood values did not differ among groups, and neither did gastric emptying rate nor ratings of fullness. The BED subjects were then randomly assigned to treatment with cognitive-behavior therapy and diet (n = 5) or to a wait-list control (n = 4). Baseline ghrelin (P = 0.01) and AUC increased (P = 0.02), across both conditions, in which most subjects (7 of 9) stopped binge eating. The lower fasting and postmeal plasma ghrelin levels in BED are consistent with lower ghrelin levels in obese compared to lean individuals and suggests downregulation by binge eating.

Topics: Adult; Appetite; Area Under Curve; Blood Glucose; Body Mass Index; Bulimia; Cholecystokinin; Cognitive Behavioral Therapy; Diet; Female; Ghrelin; Humans; Leptin; Obesity; Peptide Hormones; Postprandial Period; Premenopause; Reference Values

Obese subjects are at risk of developing gallstones as a result of the obese state and during weight reduction.. To study whether orlistat, by lipase inhibition, impairs gall-bladder emptying, thus further predisposing weight-losing obese subjects to gallstone formation.. Patients entering a randomized clinical trial of 1 month of diet, followed by treatment with placebo, 3 x 60 mg orlistat or 3 x 120 mg orlistat, underwent gall-bladder emptying studies measured by ultrasound. Meal-induced cholecystokinin release and gall-bladder emptying were investigated at the start, at randomization and after 1 and 12 months.. One month of dieting did not change gall-bladder emptying and cholecystokinin release. After 1 month, placebo treatment resulted in a decreased fasting volume of 11%, compared with increases of 26% and 47% with 60 and 120 mg orlistat, respectively. Gall-bladder emptying increased by 9% with placebo and decreased by 15% and 53% with 60 and 120 mg orlistat, respectively. Fasting cholecystokinin values and cholecystokinin release decreased significantly in the orlistat group. After 1 year, a persistent but attenuated effect of orlistat on gall-bladder emptying and cholecystokinin release remained. Three of 40 patients developed gallstones, two on placebo with major weight loss and one on 60 mg orlistat.. One month of lipase inhibition by orlistat significantly impaired gall-bladder motility, which persisted to some extent after 1 year. Obese subjects with diabetes or hyperlipidaemia, who are more at risk of gallstones, should be followed carefully.

Topics: Adult; Anti-Obesity Agents; Body Weight; Cholecystokinin; Female; Gallbladder; Humans; Lactones; Lipase; Male; Middle Aged; Obesity; Orlistat; Weight Loss

The aim of this study was to investigate whether infusion of bombesin, when combined with a gastric preload, influence satiety and foot intake in obese and lean healthy women.. Double blind, placebo controlled study.. Department of Gastroenterology, Leiden University Medical Center, The Netherlands.. Obese (n = 7) and lean (n = 7) healthy women.. Intravenous infusion of bombesin (0.09 nmol/kg ideal weight/h) or placebo for 165 min. Gastric preload of banana slices was administered at time 60 min. Meal ingestion started at time 75 min (banana slices). Food intake was calculated and satiety was measured by visual analog scales.. During infusion of bombesin the amount of food eaten by the lean individuals (193+/-37 g) was significantly reduced compared to saline infusion (365+/-42 g, P < 0.05). However, bombesin induced no significant feeding suppression in obese women when compared to saline (241+/-46 vs 301+/-45 g, respectively). The decrease in food intake during bombesin infusion compared to saline was significantly greater in lean subjects (173+/-30 g) than in obese subjects (59+/-35 g; P < 0.05). Only in lean subjects subjective preprandial hunger feelings were significantly affected by bombesin infusion.. Infusion of bombesin, when combined with a gastric preload, inhibits food intake and increases satiety in lean women. Obese women are less sensitive for these bombesin induced satiety effects.

Topics: Adult; Bombesin; Cholecystokinin; Double-Blind Method; Drug Tolerance; Eating; Female; Humans; Middle Aged; Obesity; Placebos; Satiation

To investigate the weight-reducing effect of cimetidine in overweight patients with Type 2 diabetes.. A 12-week clinical intervention study of 400 mg cimetidine prescribed three times daily in a randomised, double-blind, placebo-controlled design.. Forty-three overweight patients with Type 2 diabetes (age 18-65 y, body mass index (BMI) 27.2-48.2 kg/m2).. Body weight, BMI, body fat, waist and hip circumference, waist/hip ratio, blood pressure, fasting blood glucose, HbA1c, plasma concentrations of insulin, insulin/glucose ratio and lipids at the start and after 12 weeks, and daily recordings of appetite.. Subjects given cimetidine (n = 19) and placebo (n = 24) lost 5.0 +/- 2.2 kg (mean +/- s.d.) and 1.3 +/- 1.1 kg, respectively. Significant reductions were observed in appetite, body fat (29.9 +/- 6.6% to 25.3 +/- 7.4%), waist circumference (111.5 +/- 10.3 cm to 107.4 +/- 10.6 cm), waist/hip ratio (0.96 +/- 0.08 to 0.94 +/- 0.08), and systolic and diastolic blood pressure (reductions of 6.9 +/- 11.4 mm Hg and 6.0 +/- 6.6 mm Hg, respectively) in cimetidine group only. Significant decreases in fasting concentrations of blood glucose, HbA1c, plasma insulin, insulin/glucose ratio, plasma triglycerides and a significant increase in plasma high-density lipoprotein cholesterol were observed in the cimetidine group only.. Cimetidine reduces appetite and body weight, and improves metabolic control in overweight subjects with Type 2 diabetes.

Topics: Adolescent; Adult; Appetite; Blood Glucose; Body Constitution; Cholecystokinin; Cholesterol, HDL; Cimetidine; Diabetes Mellitus; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glycated Hemoglobin; Histamine H2 Antagonists; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Obesity; Triglycerides; Weight Loss

The aim of this work was to determine whether infusion of bombesin inhibits intake of a carbohydrate-rich meal in lean and obese women. A double blind study was carried out using bombesin or saline infusion. The subjects were nine lean and nine obese women of the same age. Food intake and hunger feelings were measured. During infusion of bombesin, the amount of food eaten by the lean individuals (294 +/- 55 g) was significantly less than during infusion of saline (467 +/- 69 g, P < 0.01). However, bombesin induced no significant feeding suppression in the obese women when compared to saline (431 +/- 60 vs 499 +/- 99 g). Subjective hunger feelings were significantly affected by bombesin infusion in the lean subjects only. It was concluded that bombesin infusion inhibits food intake and increases satiety in lean women, whereas obese women are less sensitive to these bombesin-induced satiety effects.

Topics: Adult; Bombesin; Cholecystokinin; Dietary Carbohydrates; Double-Blind Method; Eating; Female; Humans; Hunger; Obesity; Satiation

Studies were carried out on eight obese (BMI 30-34.6 kg/m2) and seven age and sex-matched normal weight volunteers (BMI 20-25 kg/m2) to investigate the gastric emptying, mouth to caecum transit time (MCTT), plasma cholecystokinin (CCK) and sensory responses to high (30 g margarine; 1327 kJ (317 kcal)) and low (301 kJ (72 kcal)) fat soups. Gastric emptying was measured by gamma scintigraphy, MCTT was measured by the breath hydrogen technique, plasma CCK was measured using a bioassay technique and subjective sensations were recorded on visual analogue scales. The high fat meal emptied more slowly than the low fat meal in both the normal subjects (t1/2 = 86.3 +/- 9.2 vs. 36.7 +/- 2.8 min) but there were no differences in the emptying of either meal between the two groups of subjects. Increasing the fat content of the meal did not affect the mouth to caecum transit time (MCTT) in either group, nor were there differences between the groups in MCTT (180 +/- 23 vs. 188 +/- 35 min, normal vs. obese MCTT after low fat soup; 228 +/- 17 vs. 227 +/- 29 min, normal vs. obese MCTT after high fat soup). Despite similar rates of gastric emptying, the obese group showed a higher CCK production following the high fat meal than the normal weight group (540.4 +/- 65.9 vs. 336.9 +/- 51.4 pmol.min, 2 h integrated CCK production, obese vs. normal; P < 0.05). The obese group also reported feeling less hungry throughout the study than the controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Body Mass Index; Cholecystokinin; Dietary Fats; Digestive System; Female; Gastric Emptying; Gastrointestinal Transit; Humans; Male; Middle Aged; Obesity; Satiation

Cholecystokinin (CCK) is a gut peptide whose proposed effect on satiety is thought to be related to gastric volume and to be signaled through vagal afferent fibers to the medial hypothalamus. To test these hypotheses we infused CCK C-terminal octapeptide (CCK-8) or saline in a random double-blind fashion in three groups of subjects: 17 obese subjects, 6 of whom subsequently received a gastric bubble, and 5 obese subjects whose obesity was due to hypothalamic injury. The number of sandwich canapes eaten after saline or CCK-8 infusion was recorded during three consecutive 10-min eating periods. Each subject served as his/her own control. The prior infusion of CCK-8 significantly decreased the consumption of sandwich canapes in the first eating period in both the control obese subjects and the subjects with obesity due to hypothalamic injury. Insertion of a gastric bubble did not enhance the satiety effect of CCK-8. These studies support the hypothesis that CCK produces satiety in a time-dependent manner that is not enhanced after the insertion of a gastric bubble but is operative in obese subjects with hypothalamic injury.

Topics: Cholecystokinin; Eating; Female; Gastric Balloon; Humans; Hypothalamic Diseases; Male; Obesity; Satiety Response; Time Factors

As pectin delays gastric emptying in normal subjects and satiety may be linked to the rate of gastric emptying, we designed this study to evaluate, in a group of obese subjects, the effect of adding pectin to a meal on gastric emptying, sensation of satiety, and postprandial plasma cholecystokinin and pancreatic polypeptide levels. We studied gastric emptying of solids in 9 adult obese subjects on 2 separate days in a randomized fashion. On day 1, 15 g of pectin was added to the meal, and on day 2 15 g of methylcellulose was added and served as control. Satiety was evaluated by an analogue rating scale. Pectin significantly delayed gastric emptying time [t1/2 = 116 +/- 23 min vs. 71 +/- 17 min observed with methylcellulose (p less than 0.001)]. Pectin also significantly increased subjects' sensation of satiety [98 +/- 7 vs. 74 +/- 17 (p less than 0.001)]. Postprandial release of cholecystokinin and pancreatic polypeptide was not modified by pectin. As pectin induces satiety and delays gastric emptying in obese patients, it may be a useful adjuvant in the treatment of disorders of overeating.

Topics: Adult; Cholecystokinin; Female; Gastric Emptying; Humans; Male; Methylcellulose; Middle Aged; Obesity; Pancreatic Polypeptide; Pectins; Random Allocation; Satiation

Six of eight obese men ate significantly less food during an intravenous infusion of the C-terminal octapeptide of cholecystokinin (CCK-8, 4 ng . kg-1 . min-1) than during a saline infusion in a double blind experimental paradigm. Subjects stopped eating sooner during CCK-8. CCK-8 did not change the rate of eating. No overt side effects were reported or observed. This is the first report of the satiety effect of CCK-8 in obese humans and it suggests that the therapeutic potential of CCK-8 for the treatment of obesity deserves investigation.

Topics: Body Weight; Cholecystokinin; Eating; Energy Intake; Humans; Male; Obesity; Peptide Fragments; Sincalide

Obesity increases asthma prevalence and severity. However, the underlying mechanisms are poorly understood, and consequently, therapeutic options for asthma patients with obesity remain limited. Here we report that cholecystokinin-a metabolic hormone best known for its role in signaling satiation and fat metabolism-is increased in the lungs of obese mice and that pharmacological blockade of cholecystokinin A receptor signaling reduces obesity-associated airway hyperresponsiveness. Activation of cholecystokinin A receptor by the hormone induces contraction of airway smooth muscle cells. In vivo, cholecystokinin level is elevated in the lungs of both genetically and diet-induced obese mice. Importantly, intranasal administration of cholecystokinin A receptor antagonists (proglumide and devazepide) suppresses the airway hyperresponsiveness in the obese mice. Together, our results reveal an unexpected role for cholecystokinin in the lung and support the repurposing of cholecystokinin A receptor antagonists as a potential therapy for asthma patients with obesity.

Topics: Animals; Asthma; Cholecystokinin; Lung; Mice; Mice, Obese; Obesity; Receptor, Cholecystokinin A; Respiratory Hypersensitivity

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

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

Immunoglobulin-like Domain-Containing Receptor 1 (ILDR1) is expressed on nutrient sensing cholecystokinin-positive enteroendocrine cells of the gastrointestinal tract and it has the unique ability to induce fat-mediated CCK secretion. However, the role of ILDR1 in CCK-mediated regulation of satiety is unknown. In this study, we examined the effects of ILDR1 on food intake and metabolic activity using mice with genetically-deleted Ildr1.. The expression of ILDR1 in murine tissues and the measurement of adipocyte cell size were evaluated by light and fluorescence confocal microscopy. The effects of Ildr1 deletion on mouse metabolism were quantitated using CLAMS chambers and by targeted metabolomics assays of multiple tissues. Hormone levels were measured by ELISA. The effects of Ildr1 gene deletion on glucose and insulin levels were determined using in vivo oral glucose tolerance, meal tolerance, and insulin tolerance tests, as well as ex vivo islet perifusion.. ILDR1 is expressed in a wide range of tissues. Analysis of metabolic data revealed that although Ildr1-/- mice consumed more food than wild-type littermates, they gained less weight on a high fat diet and exhibited increased metabolic activity. Adipocytes in Ildr1-/- mice were significantly smaller than in wild-type mice fed either low or high fat diets. ILDR1 was expressed in both alpha and beta cells of pancreatic islets. Based on oral glucose and mixed meal tolerance tests, Ildr1-/- mice were more effective at lowering post-prandial glucose levels, had improved insulin sensitivity, and glucose-regulated insulin secretion was enhanced in mice lacking ILDR1.. Ildr1 loss significantly modified metabolic activity in these mutant mice. While Ildr1 gene deletion increased high fat food intake, it reduced weight gain and improved glucose tolerance. These findings indicate that ILDR1 modulates metabolic responses to feeding in mice.

Topics: Animals; Cholecystokinin; Diet, High-Fat; Gene Deletion; Glucose; Hyperglycemia; Insulin; Insulin Resistance; Mice; Mice, Inbred C57BL; Obesity; Receptors, Cell Surface

Obesity has become a prevailing health burden globally and particularly in the US. It is associated with many health problems, including cardiovascular disease, diabetes and poorer mental health. Hence, there is a high demand to find safe and effective therapeutics for sustainable weight loss. Cholecystokinin (CCK) has been implicated as one of the first gastrointestinal hormones to reduce overeating and suppress appetite by activating the type 1 cholecystokinin receptor (CCK1R). Several drug development campaigns have focused on finding CCK1R-specific agonists, which showed promising efficacy for reducing meal size and weight, but fell short on FDA approval, likely due to side effects associated with potent, long-lasting activation of CCK1Rs. Positive allosteric modulators (PAMs) without inherent agonist activity have been proposed to overcome the shortcomings of traditional, orthosteric agonists and restore CCK1R signaling in failing physiologic systems. However, drug discovery campaigns searching for such novel acting CCK1R agents remain limited. Here we report a high-throughput screening effort and the establishment of a testing funnel, which led to the identification of novel CCK1R modulators. We utilized IP-One accumulation to develop robust functional equilibrium assays tailored to either detect PAMs, agonists or non-specific activators. In addition, we established the CCK1R multiplex PAM assay as a novel method to evaluate functional selectivity capable of recording CCK1R-induced cAMP accumulation and β-arrestin recruitment in the same well. This selection and arrangement of methods enabled the discovery of three scaffolds, which we characterized and validated in an array of functional and binding assays. We found two hits incorporating a tetracyclic scaffold that significantly enhanced CCK signaling at CCK1Rs without intrinsically activating CCK1Rs in an overexpressing system. Our results demonstrate that a well-thought-out testing funnel can identify small molecules with a distinct pharmacological profile and provides an important milestone for the development of novel potential treatments of obesity.

Topics: beta-Arrestins; Cholecystokinin; Humans; Obesity; Receptors, Cholecystokinin

To better understand the physiological basis of obesity in women, we investigated whether obesity or menstrual cycle phase affects laboratory test-meal size or meal-stimulated plasma cholecystokinin (CCK) concentration. Women with healthy weight (body mass index [BMI] of 18.5-24.9 kg/m2, N = 16) or obesity (BMI 30-39.9 kg/m2, N = 20) were tested once in the late-follicular or peri-ovulatory phase (LF/PO) and once in the mid-luteal phase (ML). Meals of ham sandwiches were offered and blood was sampled. Menstrual cycle phases were verified with participants' reports of menses and measurements of progesterone and luteinizing hormone (LH) concentrations. Women with obesity ate significantly larger meals than women with healthy weight, (mean, 711 [95% CI, 402-1013] kJ, P = 0.001, during the LF/PO and 426 [105-734] kJ, P = 0.027, larger during the ML). Women with healthy weight ate smaller meals during LF/PO than ML (decrease, 510 [192-821 kJ], P = 0.008), but women with obesity did not (decrease, 226 [-87-542] kJ, P = 0.15). CCK concentrations 18 to 30 minutes after meal onset were lower in women with obesity than in women with healthy weight during LF/PO (3.6 [3.1-4.1] vs 6.1 [4.5-7.7] pmol/L; P = 0.004), but not during ML, with a significant interaction effect (1.8 [1.2-2.4] pmol/L, P = 0.048). Women with obesity consumed larger meals than women with healthy weight but displayed reduced meal-stimulated plasma CCK concentrations. These data are consistent with the hypothesis that a defect in CCK secretion compromises satiation in obese women and contributes to the development or maintenance of obesity.

Topics: Body Mass Index; Cholecystokinin; Female; Humans; Meals; Menstrual Cycle; Obesity

Aging in mammals is characterized by failure of the homeostatic mechanisms that regulate energy balance. Several mechanisms have been proposed such as the presence of a low-grade chronic inflammation in different tissues, as well as leptin and insulin resistance, but the primary alteration is not fully elucidated. The gut microbiota has recently emerged as a key player in a variety of metabolic and neurological disorders. A main concept in this context is the gut-brain axis that refers to alterations in the gut that mediate effects in the central nervous system, including those related with the control of energy balance. Using 16S rRNA analysis, we demonstrate that aged male Wistar rats have increased presence of mucin-degrading and lipopolysaccharide (LPS)-producing bacteria. In addition, old animals exhibit a lower number of neutral mucin secreting goblet cells, and a decrease of tight junctions and adherens junctions marker proteins, zonula occludens protein-1 (ZO-1) and β-catenin, respectively. These data are compatible with a thinner mucus layer and a weaker gut barrier in older animals that likely facilitate LPS leakage. Our data also show that cholecystokinin (CCK) satiating effect is impaired in aged rats, one of the expected effects of increased LPS leakage. In contrast, no overt signs of gut or systemic inflammation are observed. Changes in microbiota in old male Wistar rats present features of situations of increased adiposity, but different from those of obese animals. These could partly explain the increased adiposity and fat deposition in liver and heart as observed here.

Topics: Aging; Animals; Brain-Gut Axis; Cholecystokinin; Diet, High-Fat; Gastrointestinal Microbiome; Inflammation; Lipopolysaccharides; Male; Mucins; Obesity; Rats; Rats, Wistar; RNA, Ribosomal, 16S

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

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

Overfeeding and rapid weight gain during early life are risk factors for the development of obesity in adulthood. This metabolic malprogramming may be mediated by endocrine disturbances during critical periods of development. Cholecystokinin (CCK) acts on the central nervous system by elevating thermogenesis and the activity of anorectic neurons, modulating overall energy balance. Therefore, we tested the hypothesis that postnatal overfeeding impaired CCK effects. Pups were raised in either a litter of three (neonatal overnutrition/small litter group) or 12 (controls/normal litter group) pups per dam to study the effects of postnatal overfeeding on the central and peripheral CCK systems in adulthood. Rats raised in small litters became overweight during lactation and remained overweight as adults, with increased adiposity and plasma levels of lipids, glucose, insulin, and leptin. Neonatally over-nourished rats showed attenuation of gastric emptying and anorexigenic response to CCK, suggesting that offspring from the SL group may present CCK resistance as adult male rats. Consistent with this idea, overweight rats displayed impaired central response in c-Fos immunoreactivity on the nucleus tractus solitarius, area postrema, paraventricular nucleus, central amygdala, arcuate nucleus, and dorsomedial hypothalamus in response to peripheral CCK at adulthood. The small litter group of adult male rats also exhibited reduced norepinephrine- and CCK-stimulated thermogenesis. Unresponsiveness to the effects of CCK may contribute to overweight and metabolic dysfunctions observed in postnatally over-nourished adult rats. Thus, the involvement of an impaired CCK system, among other neurohormonal failures, may contribute to the development of obesity.

Topics: Adipose Tissue; Adiposity; Animals; Animals, Newborn; Brain Mapping; Central Nervous System; Cholecystokinin; Endocrine System; Energy Metabolism; Female; Gastric Emptying; Glucose; Homeostasis; Hypothalamus; Leptin; Lipids; Male; Obesity; Overnutrition; Proto-Oncogene Proteins c-fos; Rats; Rats, Wistar; Thermogenesis; Weight Gain

To observe the effect of electroacupuncture (EA) of ". Among the fifty 8-week-old healthy SPF male Wistar rats, 10 rats were randomly selected and fed with normal diet; after 8 weeks, 8 rats were randomly selected as a normal group. The remaining 40 rats were fed with high-fat diet to establish the model of obsesity IR; after 8 weeks, 24 rats with successful model of obsesity IR were randomly divided into a model group, an EA group and a sham EA group, 8 rats in each group. Eight weeks after model establishment, the rats in the EA group were intervened with EA at "Fenglong" (ST 40), "Zhongwan" (CV 12), "Guanyuan" (CV 4) and "Zusanli" (ST 36), with continuous wave, in frequency of 2 Hz, and current intensity of 1 mA, for 10 min each time. The rats in the sham EA group were intervened with EA at the points 5 mm next to the acupoints used in the EA group and no electricity was given; the sham EA was given for 10 min each time. Both the treatments were given once every other day for 8 weeks. The Lee's index and food intake were observed before the intervention as well as 2 weeks, 4 weeks, 6 weeks and 8 weeks into intervention; after the intervention, serum insulin (INS) and glucose infusion rate (GIR) were detected; serum cholecystokinin (CCK) level was detected by ELISA; c-fos expression in the area postrema (AP) and nucleus tractus solitarius (NTS) of medulla oblongata was detected by immunohistochemistry.. Before the intervention as well as 2 weeks, 4 weeks, 6 weeks and 8 weeks into intervention, the Lee's index and food intake in the model group were higher than those in normal group (. EA of "

Topics: Acupuncture Points; Animals; Cholecystokinin; Electroacupuncture; Insulin Resistance; Male; Obesity; Random Allocation; Rats; Rats, Wistar

To investigate the effect of electroacupuncture (EA) on gastrointestinal motility and expression of leptin(LEP) and cholecystokinin(CCK) in the small intestine in obese rats，so as to explore the mechanism of EA underlying improvement of obesity.. Male Wistar rats were randomized into 5 groups: normal control, obesity model, abdominal acupoints ［"Guanyuan" (CV4), "Zhongwan" (CV12) and bilateral "Tianshu" (ST25)］, lower-leg acupoints ［bilateral "Zusanli" (ST36) and bilateral "Fenglong" (ST40)］, and abdominal+ lower-leg acupoints (. Following modeling, the food intake, body mass, weight of white adipose around the testicles and abdomen, the gastric empty rate, and serum TC, TG, NEFA and LEP contents as well as intestinal LEP expression were significantly increased (. EA stimulation of the abdominal and lower-leg acupoints or both can reduce body weight on obesity rats, which is associated with its functions in regulating intestinal motility, food intake, and secretion of LEP and CCK.

Topics: Acupuncture Points; Animals; Cholecystokinin; Electroacupuncture; Gastrointestinal Motility; Intestines; Leptin; Lipids; Male; Obesity; Rats; Rats, Wistar

Cholecystokinin (CCK) is a regulator of appetite and energy intake in man. The aim of this study was to determine the effect of NN9056, a long-acting CCK-1 receptor-selective CCK analogue, on food intake and body weight (BW) in obese Göttingen Minipigs.. Tolerability of NN9056 and acute effects on food intake, pancreas histology, amylase and lipase levels were assessed in lean domestic pigs in doses up to 100 nmol/kg (n = 3-4). Subsequently, obese Göttingen Minipigs were treated subcutaneously (s.c.) once daily for 13 weeks with vehicle, NN9056 low dose (regulated from 5 to 2 nmol/kg) or NN9056 high dose (10 nmol/kg) (n = 7-8). Food intake was measured daily and BW twice weekly. At the end of the treatment period, an intravenous glucose tolerance test (IVGTT) and a 24-h exposure profile was obtained. Data are mean ± SD.. The acute studies in domestic pigs showed significant and dose-dependent effect of NN9056 on food intake, acceptable tolerability and no histopathological signs of pancreatitis. Sub-chronic treatment in obese Göttingen Minipigs was also well tolerated and accumulated food intake was significantly lower in both treated groups compared to vehicle, with no significant difference between the dose levels of NN9056 (41.8 ± 12.6, 51.5 ± 13.8 and 86.5 ± 19.5 kg in high-dose, low-dose and vehicle groups, respectively, p = 0.012 and p < 0.0001 for low and high dose vs. vehicle, respectively). Accordingly, there was a weight loss in both treated groups vs. a weight gain in the vehicle group (-7.2 ± 4.6%, -2.3 ± 3.2% and 12.3 ± 3.9% in the high-dose, low-dose and vehicle groups, respectively, p < 0.0001 for both vs. vehicle). IVGTT data were not significantly different between groups.. NN9056, a long-acting CCK-1 receptor-selective CCK analogue, significantly reduced food intake and BW in obese Göttingen Minipigs after once daily s.c. dosing for 13 weeks.

Topics: Animals; Body Weight; Cholecystokinin; Disease Models, Animal; Eating; Energy Intake; Female; Humans; Obesity; Protein Binding; Swine; Swine, Miniature

The satiety effects and metabolic actions of cholecystokinin (CCK) have been recognized as potential therapeutic targets in obesity for decades. We identified a potentially novel Ca2+-activated chloride (Cl-) current (CaCC) that is induced by CCK in intestinal vagal afferents of nodose neurons. The CaCC subunit Anoctamin 2 (Ano2/TMEM16B) is the dominant contributor to this current. Its expression is reduced, as is CCK current activity in obese mice on a high-fat diet (HFD). Reduced expression of TMEM16B in the heterozygote KO of the channel in sensory neurons results in an obese phenotype with a loss of CCK sensitivity in intestinal nodose neurons, a loss of CCK-induced satiety, and metabolic changes, including decreased energy expenditure. The effect on energy expenditure is further supported by evidence in rats showing that CCK enhances sympathetic nerve activity and thermogenesis in brown adipose tissue, and these effects are abrogated by a HFD and vagotomy. Our findings reveal that Ano2/TMEM16B is a Ca2+-activated chloride channel in vagal afferents of nodose neurons and a major determinant of CCK-induced satiety, body weight control, and energy expenditure, making it a potential therapeutic target in obesity.

Topics: Adipose Tissue, Brown; Animals; Anoctamins; Cholecystokinin; Diet, High-Fat; Disease Models, Animal; Intestines; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Obesity; Rats; Sensory Receptor Cells; Transcriptome; Vagus Nerve

This study investigated whether individual differences in behavioral responses to palatable food and to the satiation signal cholecystokinin (CCK) in outbred chow-maintained Sprague-Dawley rats enabled prediction of individual differences in weight gained after subsequent high-fat/high-sugar diet (HFHSD) maintenance.. Meal size, meal number, and early dark cycle intake during initial HFHSD exposure were measured, as were early dark cycle sucrose solution and chow intake, chow meal size and meal number, the intake-suppressive effects of 0.5-µg/kg CCK injection, and CCK-induced c-Fos activation in the nucleus tractus solitarius. Subsequently, rats were maintained on an HFHSD for 5 weeks, and weight gain was determined.. Rats that took larger and less frequent meals on the first day of HFHSD exposure, whose early dark cycle intake (HFHSD and sucrose) was larger during initial HFHSD exposure, gained more weight after HFHSD maintenance. Rats with lesser sucrose intake suppression in response to CCK gained more weight after HFHSD maintenance and displayed reduced CCK-induced c-Fos activation in the nucleus tractus solitarius.. Together, these data identify individual differences in behavioral responses to palatable food and to CCK as novel predictors of diet-induced obesity.

Topics: Animals; Cholecystokinin; Eating; Food; Male; Obesity; Rats; Rats, Sprague-Dawley

Roux-en-Y gastric bypass (RYGB) leads to rapid remission of type 2 diabetes (T2D) and sustained body weight loss, but the underlying molecular mechanisms are still not fully understood. To further elucidate these mechanisms and identify potentially novel preprohormone encoding genes with anti-diabetic and/or anti-obesity properties, we performed a comprehensive analysis of gene expression changes in enteroendocrine cells after RYGB in diet-induced obese (DIO) rats.. The mRNA expression profiles of enteroendocrine cell enriched samples were characterized at 9, 22 and 60 days after RYGB surgery in a DIO rat model. Enteroendocrine cells were identified by chromogranin A immunohistochemistry and isolated by laser capture microdissection (LCM) from five regions covering the full rostro-caudal extension of the gastrointestinal (GI) tract. RNA sequencing and bioinformatic analyses were subsequently applied to identify differentially expressed preprohormone encoding genes.. From the analysis of enteroendocrine cell mRNA expression profiles, a total of 54 preprohormones encoding genes were found to be differentially regulated at one or more time-points following RYGB. These included well-known RYGB associated preprohormone genes (e.g. Gcg, Cck, Gip, Pyy and Sct) and less characterized genes with putative metabolic effects (e.g. Nmu, Guca2a, Guca2b, Npw and Adm), but also 16 predicted novel preprohormone genes. Among the list of gene transcripts, Npw, Apln and Fam3d were further validated using in situ mRNA hybridization and corresponding peptides were characterized for acute effects on food intake and glucose tolerance in mice.. We present a comprehensive mRNA expression profile of chromogranin A positive enteroendocrine cells following RYGB in rats. The data provides a region-specific characterization of all regulated preprohormone encoding genes in the rat GI tract including 16 not hitherto known. The comprehensive catalogue of preprohormone expression changes may support our understanding of hormone mediated effects of RYGB on diabetes remission and body weight reduction.

Topics: Animals; Cholecystokinin; Computational Biology; Enteroendocrine Cells; Gastric Bypass; Gastric Inhibitory Polypeptide; Immunohistochemistry; In Situ Hybridization; Laser Capture Microdissection; Male; Mice; Obesity; Peptide Hormones; Protein Precursors; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sequence Analysis, RNA; Somatostatin; Transcriptome

Investigations into the relationship between dietary carbohydrate restriction and health are mixed. Current guidelines for nutrition promote low-fat foods and higher carbohydrate consumption for optimal health and weight loss. However, high-fat, low-carbohydrate diets are revealing both intra- and extracellular adaptations that have been shown to elicit favorable cardiometabolic changes associated with obesity. Moreover, dietary fat is associated with higher satiety levels from the hormones adiponectin, leptin, and cholecystokinin. Additionally, insulin responses from high-glycemic carbohydrates are known to alter these pathways, potentially leading to an increase in energy consumption and a possible mechanism for obesity.. There is convincing evidence of beneficial effects of controlled trials implementing high-fat, low-carbohydrate diets in both sedentary and obese individuals, but longer duration clinical trials are required to confirm this hypothesis.

Topics: Adiponectin; Cholecystokinin; Diet, Carbohydrate-Restricted; Diet, High-Fat; Energy Intake; Humans; Insulin; Leptin; Nutrition Policy; Obesity; Satiation; Weight Loss

Combination approaches for the treatment of metabolic diseases such as obesity and diabetes are becoming increasingly relevant. Co-administration of a glucagon-like peptide-1 receptor (GLP-1R) agonist with a cholecystokinin receptor-1 (CCKR1) agonist exert synergistic effects on weight loss in obese rodents. Here, we report on the effects of a novel fusion peptide (C2816) comprised of a stabilized GLP-1R agonist, AC3174, and a CCKR1-selective agonist, AC170222. C2816 was constructed such that AC3174 was linked to the N-terminus of AC170222, thus preserving the C-terminal amide of the CCK moiety. In functional in vitro assays C2816 retained full agonism at GLP-1R and CCKR1 at lower potency compared to parent molecules, whereas a previously reported fusion peptide in the opposite orientation, (pGlu-Gln)-CCK-8/exendin-4, exhibited no activity at either receptor. Acutely, in vivo, C2816 increased cFos in key central nuclei relevant to feeding behavior, and reduced food intake in wildtype (WT), but less so in GLP-1R-deficient (GLP-1RKO), mice. In sub-chronic studies in diet-induced obese (DIO) mice, C2816 exerted superior reduction in body weight compared to co-administration of AC3174 and AC170222 albeit at a higher molar dose. These data suggest that the synergistic pharmacological effects of GLP-1 and CCK pathways can be harnessed in a single therapeutic peptide.

Topics: Animals; Anti-Obesity Agents; Brain; Cholecystokinin; Drug Synergism; Eating; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Peptides; Rats, Sprague-Dawley; Receptor, Cholecystokinin A; Weight Loss

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

Topics: Adult; Aged; Anti-Obesity Agents; Appetite Regulation; Blood Glucose; Cholecystokinin; Cholesterol, HDL; Diabetes Mellitus; Female; Hemoglobins; Humans; Hypoglycemic Agents; Lipids; Male; Middle Aged; Obesity; Phenotype; Receptors, Cholecystokinin; Reference Values; Satiation; Signal Transduction; Triglycerides

The sites of action regulating meal size (MS) and intermeal interval (IMI) length by glucagon like peptide-1 (7-36) (GLP-1 (7-36)) and cholecystokinin-8 (CCK-8) reside in the areas supplied by the two major branches of the abdominal aorta, celiac and cranial mesenteric arteries. We hypothesized that infusing GLP-1 near those sites reduces body weight (BW) and adding CCK-8 to this infusion enhances the reduction. Here, we measured BW in diet-induced obese (DIO) male rats maintained and tested on normal rat chow and infused with saline, GLP-1 (0.5nmol/kg) and GLP-1+CCK-8 (0.5nmol/kg each) in the aorta once daily for 21days. We found that GLP-1 and GLP-1+CCK-8 decrease BW relative to saline vehicle and GLP-1+CCK-8 reduced it more than GLP-1 alone. Reduction of BW by GLP-1 alone was accompanied by decreased 24-h food intake, first MS, duration of first meal and number of meals, and an increase in latency to first meal. Reduction of BW by the combination of the peptides was accompanied by decrease 24-h food intake, first MS, duration of first meal and number of meals, and increase in the IMI length, satiety ratio and latency to first meal. In conclusion, GLP-1 reduces BW and CCK-8 enhances this reduction if the peptides are given near their sites of action.

Topics: Animals; Anti-Obesity Agents; Aorta; Cholecystokinin; Diet, High-Fat; Disease Models, Animal; Drug Therapy, Combination; Eating; Feeding Behavior; Glucagon-Like Peptide 1; Male; Obesity; Peptide Fragments; Rats, Sprague-Dawley; Satiation; Time Factors; Weight Loss

High-protein diet (HPD) curtails obesity and/or fat mass, but it is unknown whether it reverses neuroinflammation or alters glucose levels, CCK sensitivity, and gut microbiome in rats fed a Western diet (WD)-induced obesity (DIO). Male rats fed a WD (high fat and sugar) for 12 wk were switched to a HPD for 6 wk. Body composition, food intake, meal pattern, sensitivity to intraperitoneal CCK-8S, blood glucose, brain signaling, and cecal microbiota were assessed. When compared with a normal diet, WD increased body weight (9.3%) and fat mass (73.4%). CCK-8S (1.8 or 5.2 nmol/kg) did not alter food intake and meal pattern in DIO rats. Switching to a HPD for 6 wk reduced fat mass (15.7%) with a nonsignificantly reduced body weight gain, normalized blood glucose, and decreased feeding after CCK-8S. DIO rats on the WD or switched to a HPD showed comparable microbial diversity. However, in HPD versus WD rats, there was enrichment of 114 operational taxonomic units (OTUs) and depletion of 188 OTUs. Of those,

Topics: Animals; Blood Glucose; Body Composition; Body Weight; Brain; Cecum; Cholecystokinin; Cytokines; Diet, Western; Dietary Proteins; Eating; Encephalitis; Male; Microbiota; Obesity; Rats; Rats, Sprague-Dawley

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

We hypothesized that exogenous gastrin releasing peptide-29 (GRP-29), cholecystokinin-8 (CCK-8) and their combination reduce body weight (BW). To test this hypothesis, BW was measured in four groups of diet-induced obese (DIO) male rats infused in the aorta (close to the junctions of the celiac and cranial mesenteric arteries) with saline, CCK-8 (0.5 nmol/kg), GRP-29 (0.5 nmol/kg) and CCK-8+GRP-29 (0.5 nmol/kg each) once daily for a total of 23 days. We found that CCK-8, GRP-29 and CCK-8+GRP-29 reduce BW relative to saline control. In conclusion, CCK-8, GRP-29 and their combination reduce BW in the DIO rat model. If infused near their gastrointestinal sites of action CCK-8, GRP-29 and their combination may have a role in regulating BW.

Topics: Animals; Body Weight; Cholecystokinin; Diet; Drug Therapy, Combination; Gastrin-Releasing Peptide; Gastrointestinal Agents; Infusions, Parenteral; Male; Obesity; Peptide Fragments; Rats; Weight Loss

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

Consumption of sugar-sweetened beverages is associated with overweight and obesity. In this study, we hypothesized that obesity-prone (OP) mice fed a high-fat high-sucrose diet (HFHS) are more sensitive to consumption of sucrose-sweetened water (SSW) than obesity-resistant (OR) mice. After 3weeks of ad libitum access to the HFHS diet (7.5h/day), 180 male mice were classified as either OP (upper quartile of body weight gain, 5.2±0.1g, n=45) or OR (lower quartile, 3.2±0.1g, n=45). OP and OR mice were subsequently divided into 3 subgroups that had access to HFHS (7.5h/day) for 16weeks, supplemented with: i) water (OP/water and OR/water); ii) water and SSW (12.6% w/v), available for 2h/day randomly when access to HFHS was available and for 5 randomly-chosen days/week (OP/SSW and OR/SSW); or iii) water and SSW for 8weeks, then only water for 8weeks (OP/SSW-water and OR/SSW-water). OR/SSW mice decreased their food intake compared to OR/water mice, while OP/SSW mice exhibited an increase in food and total energy intake compared to OP/water mice. OP/SSW mice also gained more body weight and fat mass than OP/water mice, showed an increase in liver triglycerides and developed insulin resistance. These effects were fully reversed in OP/SSW-water mice. In the gut, OR/SSW mice, but not OP/SSW mice, had an increase GLP-1 and CCK response to a liquid meal compared to mice drinking only water. OP/SSW mice had a decreased expression of melanocortin receptor 4 in the hypothalamus and increased expression of delta opioid receptor in the nucleus accumbens compared to OP/water mice when fasted that could explain the hyperphagia in these mice. When access to the sucrose solution was removed for 8weeks, OP mice had increased dopaminergic and opioidergic response to a sucrose solution. Thus, intermittent access to a sucrose solution in mice fed a HFHS diet induces changes in the gut and brain signaling, leading to increased energy intake and adverse metabolic consequences only in mice prone to HFHS-induced obesity.

Topics: Animals; Body Composition; Body Weight; Cholecystokinin; Diet, High-Fat; Disease Models, Animal; Drinking; Eating; Energy Metabolism; Gene Expression Regulation; Glucagon-Like Peptide 1; Glucose Tolerance Test; Hyperphagia; Lipid Peroxidation; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Sucrose; Sweetening Agents

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

Neurons in the brainstem are the input for a neural circuit that integrates nutrient signals to control feeding behavior.

Topics: Appetite; Brain Stem; Cholecystokinin; Feeding Behavior; Humans; Hypothalamus; Obesity; Solitary Nucleus

Exact cause of the metabolic syndrome [MS], a global epidemic, is still unclear. Man has same fundamental needs to live as animals but modern man's life-style compels him to acquire certainty of resources for all his needs in a complex social network. Today money has become the sole life essential need. Contrarily none of the animals needs to earn money. Brain is also an organ of the human body with a unique thought process to define logical actions to achieve a person's goals. This way life is a flow of desires followed by logical actions. The person struggles to attain desired goals via the allostatic load but a perceived insurmountable threat can make his flow of life stalled to freeze him. Published data from varied branches of medical science indicates role of hormones in overall homeostasis. Particularly multifaceted role of serotonin is well documented. Adrenalin being the primary mediator of Cori cycle is also well known. From the integration of observations from published data with reference to common human's modern lifestyle, it is hypothesized that a perceived trapped situation in life creates acute chaos of thoughts in brain, which results in acute excess of stress hormones and concurrent depletion of resting hormones, which in turn triggers MS. In global terms, MS indicates an acute imbalance of a few hormones and implies psychosomatic roots of the disorder. This may pave a better way in deciding a personalized holistic protocol with combination of counter regulatory psychoactive medications.

Topics: Acidosis, Lactic; Allostasis; Animals; Brain; Cardiovascular Diseases; Cholecystokinin; Cholesterol; Diabetes Mellitus, Type 2; Diet; Dopamine; Epinephrine; Exercise; Homeostasis; Hormones; Humans; Hypertension; Life Style; Metabolic Syndrome; Microbiota; Models, Theoretical; Motivation; Obesity; Oxytocin; Psychophysiologic Disorders; Risk Factors; Serotonin

To test the impact of cholecystokinin (CCK) plus either amylin or a glucagon-like peptide-1 receptor (GLP-1R) agonist on metabolic variables in diet-induced obese (DIO) rodents.. A stabilized acetylated version of CCK-8 (Ac-Y*-CCK-8), selective CCK1 receptor (CCK1R) or CCK2 receptor (CCK2R) agonists, amylin or the GLP-1R agonist and exenatide analogue AC3174 were administered in select combinations via continuous subcutaneous infusion to DIO rats for 14 days, or Lep(ob) /Lep(ob) mice for 28 days, and metabolic variables were assessed.. Combined administration of Ac-Y*-CCK-8 with either amylin or AC3174 induced greater than additive weight loss in DIO rats, with the overall magnitude of effect being greater with AC3174 + Ac-Y*-CCK-8 treatment. Co-infusion of AC3174 with a specific CCK1R agonist, but not a CCK2R agonist, recapitulated the weight loss mediated by AC3174 + Ac-Y*-CCK-8 in DIO rats, suggesting that synergy is mediated by CCK1R activation. In a 4 × 4 full-factorial response surface methodology study in DIO rats, a synergistic interaction between AC3174 and the CCK1R-selective agonist on body weight and food intake was noted. Co-administration of AC3174 and the CCK1R-selective agonist to obese diabetic Lep(ob) /Lep(ob) mice elicited a significantly greater reduction in percentage of glycated haemoglobin and food intake relative to the sum effects of monotherapy groups.. The anti-obesity and antidiabetic potential of combined GLP-1R and CCK1R agonism is an approach that warrants further investigation.

Topics: Acetylation; Animals; Anti-Obesity Agents; Cholecystokinin; Diabetes Mellitus; Diet, High-Fat; Drug Synergism; Drug Therapy, Combination; Energy Intake; Glucagon-Like Peptide-1 Receptor; Hypoglycemic Agents; Infusions, Subcutaneous; Islet Amyloid Polypeptide; Male; Mice, Mutant Strains; Obesity; Peptides; Random Allocation; Rats, Sprague-Dawley; Receptor, Cholecystokinin A; Receptor, Cholecystokinin B; Receptors, Glucagon; Weight Loss

Formerly obese patients having undergone Roux-en-Y gastric bypass (RYGB) display both an accelerated digestion and absorption of carbohydrate and an increased plasma glucose clearance rate after meal ingestion. How RYGB effects postprandial kinetics of dietary lipids has yet not been investigated.. Plasma triglyceride (TG), apoB48, total apoB, bile acids (BA), fibroblast growth factor 19 (FGF19), and cholecystokinin (CCK) were measured in post-absorptive conditions and over 4-h following the ingestion of a mixed test meal in a cross-sectional, pilot study involving 11 formerly obese female patients 33.8 ± 16.4 months after RYGB surgery and in 11 weight- and age-matched female control participants.. Compared to controls, RYGB patients had faster (254 ± 14 vs. 327 ± 7 min, p < 0.05) and lower (0.14 ± 0.04 vs. 0.35 ± 0.07 mM, p < 0.05) peak TG responses, but their peak apoB48 responses tended to be higher (2692 ± 336 vs. 1841 ± 228 ng/ml, p = 0.09). Their postprandial total BA concentrations were significantly increased and peaked earlier after meal ingestion than in controls. Their FGF19 and CCK concentrations also peaked earlier and to a higher value.. The early postprandial apoB48 and BA responses indicate that RYGB accelerated the rate of dietary lipid absorption. The lower postprandial peak TG strongly suggests that the RYGB simultaneously increased the clearance of TG-rich lipoproteins.. NCT01891591.

Topics: Adult; Apolipoprotein B-48; Apolipoproteins B; Bile Acids and Salts; Blood Glucose; Body Mass Index; Cholecystokinin; Cross-Sectional Studies; Female; Fibroblast Growth Factors; Gastric Bypass; Glucagon-Like Peptide 1; Humans; Insulin; Meals; Obesity; Pilot Projects; Postprandial Period; Time Factors; Triglycerides

We have previously demonstrated that a number of rats fed a moderately high-fat diet (MHFD) become obese and hypertensive and had compromised sympathoinhibitory and vasodilator responses to the gut hormones cholecystokinin (CCK) and gastric leptin. This has implications for increased resistance in vascular beds that attract a large proportion of cardiac output after a meal and may be an important mechanism underlying the development of hypertension in obesity in which food consumption is greatly increased. The aim of this study was to determine whether swapping a MHFD for a low-fat diet (LFD) would induce weight loss in obese animals, reverse the signs of hypertension and restore sympathoinhibitory reflexes. Male Sprague-Dawley rats were placed on a LFD (controls; n = 8) or a MHFD (n = 24) for 11 weeks after which the latter displayed either an obesity-prone (OP) or obesity-resistant (OR) phenotype. All animals were fed a LFD for a further 6 weeks after which they were anaesthetised with isoflurane and artificially ventilated for evaluation of resting arterial pressure (AP) and renal sympathetic nerve responses to CCK (0.1-4 μg/kg) and leptin (15 μg/kg). Weight gain in OP animals remained higher than OR or controls following diet switch (P < 0.05 for both). Resting AP was not significantly different between OP (103 ± 4 mmHg), OR (102 ± 3 mmHg) or control (104 ± 3 mmHg) animals and sympathoinhibitory responses to CCK or leptin were not different between the groups (P > 0.05). These results demonstrate that diet modification can have beneficial effects on sympathetic function and restore normotension without the need for weight reduction.

Topics: Animals; Arterial Pressure; Autonomic Agents; Body Weight; Cholecystokinin; Diet, Fat-Restricted; Diet, High-Fat; Disease Models, Animal; Gastrointestinal Agents; Genetic Predisposition to Disease; Hypertension; Leptin; Male; Obesity; Rats, Sprague-Dawley; Sympathetic Nervous System

Seeds are excellent sources of proteinase inhibitors, some of which may have satietogenic and slimming actions. We evaluated the effect of a trypsin inhibitor from Tamarindus indica L. seeds on weight gain, food consumption and cholecystokinin levels in Wistar rats.. A trypsin inhibitor from Tamarindus was isolated using ammonium sulfate (30-60%) following precipitation with acetone and was further isolated with Trypsin-Sepharose affinity chromatography. Analyses were conducted to assess the in vivo digestibility, food intake, body weight evolution and cholecystokinin levels in Wistar rats. Histological analyses of organs and biochemical analyses of sera were performed.. The trypsin inhibitor from Tamarindus reduced food consumption, thereby reducing weight gain. The in vivo true digestibility was not significantly different between the control and Tamarindus trypsin inhibitor-treated groups. The trypsin inhibitor from Tamarindus did not cause alterations in biochemical parameters or liver, stomach, intestine or pancreas histology. Rats treated with the trypsin inhibitor showed significantly elevated cholecystokinin levels compared with animals receiving casein or water.. The results indicate that the isolated trypsin inhibitor from Tamarindus reduces weight gain by reducing food consumption, an effect that may be mediated by increased cholecystokinin. Thus, the potential use of this trypsin inhibitor in obesity prevention and/or treatment should be evaluated.

Topics: Animals; Body Weight; Cholecystokinin; Digestion; Eating; Gastrointestinal Tract; Male; Models, Animal; Obesity; Phytotherapy; Plant Extracts; Rats, Wistar; Satiation; Seeds; Tamarindus; Trypsin Inhibitors; Weight Gain

Glucagon-like peptide-1 (GLP-1) is secreted by distal enteroendocrine cells in response to luminal nutrients, and exerts insulinotropic and anorexigenic effects. Although GLP-1 secretory responses under established obese or diabetic conditions have been studied, it has not been investigated whether or how postprandial GLP-1 responses were affected during the progression of diet-induced obesity. In the present study, a meal tolerance test was performed every week in rats fed a high-fat and high-sucrose (HF/HS) diet to evaluate postprandial glycaemic, insulin and GLP-1 responses. In addition, gastric emptying was assessed by the acetaminophen method. After 8 weeks of HF/HS treatment, portal vein and intestinal mucosa were collected to examine GLP-1 production. Postprandial glucose in response to normal meal ingestion was increased in the HF/HS group within 2 weeks, and its elevation gradually returned close to that of the control group until day 50. Slower postprandial gastric emptying was observed in the HF/HS group on days 6, 13 and 34. Postprandial GLP-1 and insulin responses were increased in the HF/HS group at 7 weeks. Higher portal GLP-1 and insulin levels were observed in the HF/HS group, but mucosal gut hormone mRNA levels were unchanged. These results revealed that the postprandial GLP-1 response to meal ingestion is enhanced during the progression of diet-induced glucose intolerance and obesity in rats. The boosted postprandial GLP-1 secretion by chronic HF/HS diet treatment suggests increased sensitivity to luminal nutrients in the gut, and this may slow the establishment of glucose intolerance and obesity.

Topics: Animals; Blood Glucose; Body Composition; Body Fat Distribution; Cholecystokinin; Diet; Diet, High-Fat; Gastric Emptying; Gastrointestinal Tract; Glucagon-Like Peptide 1; Glucose Intolerance; Insulin; Insulin Resistance; Male; Obesity; Postprandial Period; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sucrose

Cholecystokinin (CCK) is a classic gut hormone that is also expressed in the pancreatic islet, where it is highly up-regulated with obesity. Loss of CCK results in increased β-cell apoptosis in obese mice. Similarly, islet α-cells produce increased amounts of another gut peptide, glucagon-like peptide 1 (GLP-1), in response to cytokine and nutrient stimulation. GLP-1 also protects β-cells from apoptosis via cAMP-mediated mechanisms. Therefore, we hypothesized that the activation of islet-derived CCK and GLP-1 may be linked. We show here that both human and mouse islets secrete active GLP-1 as a function of body mass index/obesity. Furthermore, GLP-1 can rapidly stimulate β-cell CCK production and secretion through direct targeting by the cAMP-modulated transcription factor, cAMP response element binding protein (CREB). We find that cAMP-mediated signaling is required for Cck expression, but CCK regulation by cAMP does not require stimulatory levels of glucose or insulin secretion. We also show that CREB directly targets the Cck promoter in islets from obese (Leptin(ob/ob)) mice. Finally, we demonstrate that the ability of GLP-1 to protect β-cells from cytokine-induced apoptosis is partially dependent on CCK receptor signaling. Taken together, our work suggests that in obesity, active GLP-1 produced in the islet stimulates CCK production and secretion in a paracrine manner via cAMP and CREB. This intraislet incretin loop may be one mechanism whereby GLP-1 protects β-cells from apoptosis.

Topics: Animals; Apoptosis; Base Sequence; Body Mass Index; Cell Line, Tumor; Cholecystokinin; Cyclic AMP; Cyclic AMP Response Element-Binding Protein; Cytoprotection; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Secretion; Insulin-Secreting Cells; Mice; Molecular Sequence Data; Obesity; Phosphorylation; Promoter Regions, Genetic; Protein Binding; Rats; Receptors, Cholecystokinin

Previously, we have identified a novel role for the cytoplasmic protein, synphilin-1(SP1), in the controls of food intake and body weight in both mice and Drosophila. Ubiquitous overexpression of human SP1 in brain neurons in transgenic mice results in hyperphagia expressed as an increase in meal size. However, the mechanisms underlying this action of SP1 remain to be determined. Here we investigate a potential role for altered gut feedback signaling in the effects of SP1 on food intake. We examined responses to peripheral administration of cholecytokinin (CCK), amylin, and the glucagon like peptide-1 (GLP-1) receptor agonist, exendin-4. Intraperitoneal administration of CCK at doses ranging from 1-10 nmol/kg significantly reduced glucose intake in wild type (WT) mice, but failed to affect intake in SP1 transgenic mice. Moreover, there was a significant attenuation of CCK-induced c-Fos expression in the dorsal vagal complex in SP1 transgenic mice. In contrast, WT and SP1 transgenic mice were similarly responsive to both amylin and exendin-4 treatment. These studies demonstrate that SP1 results in a CCK response deficiency that may contribute to the increased meal size and overall hyperphagia in synphillin-1 transgenic mice.

Topics: Animals; Body Weight; Brain; Carrier Proteins; Cholecystokinin; Cytoplasm; Eating; Exenatide; Feeding Behavior; Female; Gene Expression Regulation; Genotype; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hyperphagia; Infusions, Parenteral; Intestinal Mucosa; Intracellular Signaling Peptides and Proteins; Islet Amyloid Polypeptide; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nerve Tissue Proteins; Neurons; Obesity; Peptides; Proto-Oncogene Proteins c-fos; Signal Transduction; Venoms

In Drosophila, the monoamine octopamine, through mechanisms that are not completely understood, regulates both aggression and mating behavior. Interestingly, our study demonstrates that the Drosophila obesity-linked homologs Transcription factor AP-2 (TfAP-2; TFAP2B in humans) and Tiwaz (Twz; KCTD15 in humans) interact to modify male behavior by controlling the expression of Tyramine β-hydroxylase and Vesicular monanime transporter, genes necessary for octopamine production and secretion. Furthermore, we reveal that octopamine in turn regulates aggression through the Drosophila cholecystokinin satiation hormone homolog Drosulfakinin (Dsk). Finally, we establish that TfAP-2 is expressed in octopaminergic neurons known to control aggressive behavior and that TfAP-2 requires functional Twz for its activity. We conclude that genetically manipulating the obesity-linked homologs TfAP-2 and Twz is sufficient to affect octopamine signaling, which in turn modulates Drosophila male behavior through the regulation of the satiation hormone Dsk.

Topics: Adrenergic alpha-Antagonists; Aggression; Animals; Cholecystokinin; Dibenzazepines; Drosophila melanogaster; Drosophila Proteins; Histamine H1 Antagonists; Imidazoles; Male; Mixed Function Oxygenases; Obesity; Octopamine; Oligopeptides; Phentolamine; Satiety Response; Sexual Behavior, Animal; Signal Transduction; Transcription Factor AP-2; Tyrosine Decarboxylase; Vesicular Monoamine Transport Proteins

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 gut hormone cholecystokinin (CCK) acts at subdiaphragmatic vagal afferents to induce renal and splanchnic sympathoinhibition and vasodilatation, via reflex inhibition of a subclass of cardiovascular-controlling neurons in the rostroventrolateral medulla (RVLM). These sympathoinhibitory and vasodilator responses are blunted in obese, hypertensive rats and our aim in the present study was to determine whether this is attributable to (i) altered sensitivity of presympathetic vasomotor RVLM neurons, and (ii) aberrant peripheral or central signalling mechanisms. Using a diet-induced obesity model, male Sprague-Dawley rats exhibited either an obesity-prone (OP) or obesity-resistant (OR) phenotype when placed on a medium high fat diet for 13-15 weeks; control animals were placed on a low fat diet. OP animals had elevated resting arterial pressure compared to OR/control animals (P < 0.05). Barosensitivity of RVLM neurons was significantly attenuated in OP animals (P < 0.05), suggesting altered baroreflex gain. CCK induced inhibitory responses in RVLM neurons of OR/control animals but not OP animals. Subdiaphragmatic vagal nerve responsiveness to CCK and CCK1 receptor mRNA expression in nodose ganglia did not differ between the groups, but CCK induced significantly less Fos-like immunoreactivity in both the nucleus of the solitary tract and the caudal ventrolateral medulla of OP animals compared to controls (P < 0.05). These results suggest that blunted sympathoinhibitory and vasodilator responses in obesity-related hypertension are due to alterations in RVLM neuronal responses, resulting from aberrant central but not peripheral signalling mechanisms. In obesity, blunted sympathoinhibitory mechanisms may lead to increased regional vascular resistance and contribute to the development of hypertension.

Topics: Animals; Arterial Pressure; Baroreflex; Cholecystokinin; Disease Models, Animal; Hypertension; Male; Medulla Oblongata; Neural Inhibition; Nodose Ganglion; Obesity; Proto-Oncogene Proteins c-fos; Rats, Sprague-Dawley; Receptor, Cholecystokinin A; Signal Transduction; Sympathetic Nervous System

Apolipoprotein AIV (Apo AIV) and cholecystokinin (CCK) are secreted in response to fat consumption, and both cause satiation via CCK 1 receptor (CCK-1R)-containing vagal afferent nerves to the nucleus of the solitary tract (NTS), where Apo AIV is also synthesized. Fasted male Long-Evans rats received ip CCK-8 or fourth-ventricular (i4vt) Apo AIV alone or in combination. Food intake and c-Fos proteins (a product of the c-Fos immediate-early gene) were assessed. i4vt Apo AIV and/or ip CCK at effective doses reduced food intake and activated c-Fos proteins in the NTS and hypothalamic arcuate nucleus and paraventricular nucleus. Blockade of the CCK-1R by i4vt lorglumide adjacent to the NTS attenuated the satiating and c-Fos-stimulating effects of CCK and Apo AIV, alone or in combination. Maintenance on a high-fat diet (HFD) for 10 weeks resulted in weight gain and attenuation of both the behavioral and c-Fos responses to a greater extent than occurred in low-fat diet-fed and pair-fed HFD animals. These observations suggest that NTS Apo AIV or/and peripheral CCK requires vagal CCK-1R signaling to elicit satiation and that maintenance on a HFD reduces the satiating capacity of these 2 signals.

Topics: Animals; Apolipoproteins A; Appetite Depressants; Appetite Regulation; Appetite Stimulants; Appetitive Behavior; Behavior, Animal; Cholecystokinin; Diet, High-Fat; Hormone Antagonists; Infusions, Intraventricular; Injections, Intraperitoneal; Male; Nerve Tissue Proteins; Neurons, Afferent; Obesity; Rats; Rats, Long-Evans; Receptor, Cholecystokinin A; Recombinant Proteins; Sincalide; Solitary Nucleus

Dysregulation of hypothalamic-pituitary-adrenal (HPA) axis activity leads to debilitating neuroendocrine or metabolic disorders such as Cushing's syndrome (CS). Glucocorticoids control HPA axis activity through negative feedback to the pituitary gland and the central nervous system (CNS). However, the cellular mechanisms involved are poorly understood, particularly in the CNS. Here we show that, in mice, selective loss of TrkB signalling in cholecystokinin (CCK)-GABAergic neurons induces glucocorticoid resistance, resulting in increased corticotrophin-releasing hormone expression, chronic hypercortisolism, adrenocortical hyperplasia, glucose intolerance and mature-onset obesity, reminiscent of the human CS phenotype. Interestingly, obesity is not due to hyperphagia or decreased energy expenditure, but is associated with increased de novo lipogenesis in the liver. Our study therefore identifies CCK neurons as a novel and critical cellular component of the HPA axis, and demonstrates the requirement of TrkB for the transmission of glucocorticoid signalling.

Topics: Animals; Body Composition; Calorimetry, Indirect; Cholecystokinin; Cushing Syndrome; Eating; Female; GABAergic Neurons; Immunoblotting; In Situ Hybridization; Male; Membrane Glycoproteins; Mice; Mifepristone; Obesity; Protein-Tyrosine Kinases

Guggulsterone or guggulipid is a steroidal constituent present in the neutral fraction of gum resin of Commiphora mukul, commonly known as guggul. The traditional uses of guggul-resin extract are well documented in the Ayurveda-where it is prescribed to treat a variety of ailments including lipid-related disorders such as obesity and arteriosclerosis. The hypolipidemic activity of the extracts known since ancient times can be traced to the two closely related steroidal ketones, E-guggulsterone and Z-guggulsterone. In this study, we have investigated the dose dependent (100, 200, 400 mg/kg body weight) effect of guggulsterones on appetite regulating hormones [ghrelin, leptin, cholecystokinin (CCK)] and neurotransmitters (serotonin and dopamine), which play a major role in the energy homeostasis and thus influence obesity related factors. We have also studied its effect on food intake, body weight and plasma triglycerides and glucose in rats. Guggulsterones at the dose of 400 mg/kg body weight was able to significantly reduce food intake and limit body weight gain over a period of 15 days. It also significantly decreased the plasma ghrelin, glucose, triglyceride levels and increased plasma leptin, serotonin, dopamine levels, but did not show much effect on CCK levels.

Topics: Animals; Appetite; Blood Glucose; Cholecystokinin; Commiphora; Dopamine; Dose-Response Relationship, Drug; Eating; Energy Intake; Ghrelin; Leptin; Male; Obesity; Plant Extracts; Plant Gums; Pregnenediones; Rats, Wistar; Resins, Plant; Serotonin; Triglycerides; Weight Gain

Leptin is a critical regulator of metabolism, which acts on brain receptors (Lepr) to reduce energy intake and increase energy expenditure. Some of the cellular pathways mediating leptin's anorectic actions are identified, but those mediating the thermogenic effects have proven more difficult to decipher. We define a population of neurons in the dorsomedial hypothalamic nucleus (DMH) containing the RFamide PrRP, which is activated by leptin. Disruption of Lepr selectively in these cells blocks thermogenic responses to leptin and causes obesity. A separate population of leptin-insensitive PrRP neurons in the brainstem is required, instead, for the satiating actions of the gut-derived hormone cholecystokinin (CCK). Global deletion of PrRP (in a loxSTOPlox-PrRP mouse) results in obesity and attenuated responses to leptin and CCK. Cre-recombinase-mediated reactivation of PrRP in brainstem rescues the anorectic actions of CCK, but reactivation in the hypothalamus is required to re-establish the thermogenic effect of leptin.

Topics: Alleles; Animals; Cholecystokinin; Dorsomedial Hypothalamic Nucleus; Energy Metabolism; Leptin; Mice; Mice, Knockout; Mice, Transgenic; Neurons; Obesity; Prolactin-Releasing Hormone; Receptors, Leptin; Thermogenesis

Topics: Animals; Cholecystokinin; History, 20th Century; History, 21st Century; Humans; Leptin; Mice; Mice, Obese; Molecular Biology; Obesity

Cholecystokinin (CCK) is anorexic, irrespective whether it is applied intraperitoneally (IP) or intracerebroventricularly (ICV) in male Wistar rats. The metabolic effects depend on the route of administration: by the IP route it elicits hypothermia (presumably by type-1 receptors, CCK1R-s), while ICV administration is followed by fever-like hypermetabolism and hyperthermia via activation of CCK2R-s, which latter response seems to be most important in the postprandial (compensatory) hypermetabolism. The efficacy of the IP injected CCK varies with age: it causes strong anorexia in young adult 4 and 6-months old and again in old rats (aged 18-24 months), but the middle-aged (12-month old) ones seem to be resistant to this effect. Such pattern of effects may contribute to the explanation of age-related obesity observed in middle-aged animals as well as to the aging anorexia and loss of body weight in old ones. Diet-induced obesity accelerates the appearance of CCK-resistance as well as the return of high sensitivity to CCK in further aging, while chronic calorie-restriction prevents the development of resistance, as if the speed of the age-related regulatory changes was altered by the nutritional state. The effects of ICV applied CCK also change with age: the characteristic anorexic and hypermetabolic/hyperthermic effects can be observed in young adult rats, but the effects gradually and monotonically decline with age and disappear by the old age of 24 months. These disparate age-related patterns of CCK efficacy upon peripheral or central administration routes may indicate that although both peripheral and central CCKR-s exert anorexic effects, they may have dissimilar roles in the regulation of overall energy balance.

Topics: Aging; Animals; Anorexia; Body Temperature Regulation; Body Weight; Caloric Restriction; Cholecystokinin; Diet, High-Fat; Eating; Energy Metabolism; Injections, Intraperitoneal; Injections, Intraventricular; Male; Nutritional Status; Obesity; Rats; Rats, Wistar

Deficits in satiation signaling during obesogenic feeding have been proposed to play a role in hyperphagia and weight gain in animals prone to become obese. However, whether this impaired signaling is due to high fat (HF) feeding or to their obese phenotype is still unknown. Therefore, in the current study, we examined the effects of CCK-8 (0.5, 1.0, 2.0, and 4.0 μg/kg) on suppression of food intake of HF-fed obese prone (OP) and resistant (OR) rats. Additionally, we determined the role of endogenous CCK in lipid-induced satiation by measuring plasma CCK levels following a lipid gavage, and tested the effect of pretreatment with devazepide, a CCK-1R antagonist on intragastric lipid-induced satiation. Finally, we examined CCK-1R mRNA levels in the nodose ganglia. We show that OP rats have reduced feeding responses to the low doses of exogenous CCK-8 compared to OR rats. Furthermore, OP rats exhibit deficits in endogenous CCK signaling, as pretreatment with devazepide failed to abolish the reduction in food intake following lipid gavage. These effects were associated with reduced plasma CCK after intragastric lipid in OP but not OR rats. Furthermore, HF feeding resulted in downregulation of CCK-1Rs in the nodose ganglia of OP rats. Collectively, these results demonstrate that HF feeding leads to impairments in lipid-induced CCK satiation signaling in obese-prone rats, potentially contributing to hyperphagia and weight gain.

Topics: Animals; Cholecystokinin; Devazepide; Diet, High-Fat; Dietary Fats; Down-Regulation; Eating; Feeding Behavior; Hormone Antagonists; Male; Obesity; Rats; Signal Transduction; Sincalide

The gut and kidney command >50% of cardiac output postprandially, highlighting the importance of these vascular beds in cardiovascular homeostasis. The gastrointestinal peptide cholecystokinin (CCK) induces vagally mediated splanchnic sympathoinhibition that is attenuated in animals fed a medium high-fat diet (MHFD); therefore, our aim was to determine whether renal sympathetic nerve discharge (RSND) responses to CCK are also affected by this diet, and whether these changes are associated with obesity and hypertension. Another aim was to determine whether regional vasodilator responses to CCK are affected in obesity-related hypertension. In two separate studies, Sprague-Dawley rats were fed either a low-fat diet (LFD; control) or a MHFD for 13 weeks, after which MHFD animals were classified as obesity prone (OP) or obesity resistant (OR) based on their weight gain falling into the upper or lower tertile, respectively. Arterial pressure and heart rate were monitored in isoflurane-anaesthetized, artificially ventilated animals, and either RSND or regional vascular responses to CCK (0.1-8 μg kg(-1)) were evaluated. The OP rats had higher baseline arterial pressure compared with control/OR rats (P < 0.05). Administration of CCK inhibited RSND and increased renal vascular conductance in control/OR rats, and these responses were significantly blunted in OP rats (P < 0.05 for all). Baseline arterial pressure was positively correlated with weight gain and inversely correlated with CCK-induced vasodilatation (P < 0.05 for both). We hypothesize that in obesity-related hypertension, disruption of the sympathoinhibitory signals elicited by CCK reduces vasodilatation in the splanchnic/renal regions, leading to increased postprandial vascular resistance.

Topics: Animals; Blood Pressure; Cholecystokinin; Diet, Fat-Restricted; Diet, High-Fat; Heart Rate; Hypertension; Kidney; Male; Obesity; Rats; Rats, Sprague-Dawley; Sympathetic Nervous System; Vasodilation

The adipokine plasminogen activator inhibitor (PAI)-1 is increased in plasma of obese individuals and exhibits increased expression in the stomachs of individuals infected with Helicobacter. To investigate the relevance of gastric PAI-1, we used 1.1 kb of the H(+)/K(+)β subunit promoter to overexpress PAI-1 specifically in mouse gastric parietal cells (PAI-1-H/Kβ mice). We studied the physiological, biochemical, and behavioral characteristics of these and mice null for PAI-1 or a putative receptor, urokinase plasminogen activator receptor (uPAR). PAI-1-H/Kβ mice had increased plasma concentrations of PAI-1 and increased body mass, adiposity, and hyperphagia compared with wild-type mice. In the latter, food intake was inhibited by cholecystokinin (CCK)8s, but PAI-1-H/Kβ mice were insensitive to the satiating effects of CCK8s. PAI-1-H/Kβ mice also had significantly reduced expression of c-fos in the nucleus tractus solitarius in response to CCK8s and refeeding compared with wild-type mice. Exogenous PAI-1 reversed the effects of CCK8s on food intake and c-fos levels in the nucleus tractus solitarius of wild-type mice, but not uPAR-null mice. Infection of C57BL/6 mice with Helicobacter felis increased gastric abundance of PAI-1 and reduced the satiating effects of CCK8s, whereas the response to CCK8s was maintained in infected PAI-1-null mice. In cultured vagal afferent neurons, PAI-1 inhibited stimulation of neuropeptide Y type 2 receptor (Y2R) expression by CCK8s. Thus, gastric expression of PAI-1 is associated with hyperphagia, moderate obesity, and resistance to the satiating effects of CCK indicating a new role in suppressing signals from the upper gut that inhibit food intake.

Topics: Animals; Cholecystokinin; Gastric Mucosa; Helicobacter felis; Helicobacter Infections; Hyperphagia; Mice; Obesity; Plasminogen Activator Inhibitor 1; Receptors, Urokinase Plasminogen Activator; Satiation

Cholecystokinin (CCK) is a gastrointestinal hormone with potential therapeutic promise for obesity-diabetes. The present study examined the effects of twice daily administration of the N-terminally modified stable CCK-8 analogue, (pGlu-Gln)-CCK-8, on metabolic control and hypothalamic gene expression in high fat fed mice. Sub-chronic twice daily injection of (pGlu-Gln)-CCK-8 for 16 days significantly decreased body weight (p<0.05), energy intake (p<0.01), circulating blood glucose (p<0.001), and plasma insulin (p<0.001) compared to high fat controls. Furthermore, (pGlu-Gln)-CCK-8 markedly improved glucose tolerance (p<0.05) and insulin sensitivity (p<0.05). Assessment of hypothalamic gene expression on day 16 revealed significantly elevated NPY (p<0.05) and reduced POMC (p<0.05) and MC4R (p<0.05) mRNA expression in (pGlu-Gln)-CCK-8 treated mice. High fat feeding or (pGlu-Gln)-CCK-8 treatment had no significant effects on hypothalamic gene expression of receptors for leptin, CCK₁ and GLP-1. These studies underscore the potential of (pGlu-Gln)-CCK-8 for the treatment of obesity-diabetes and suggest modulation of NPY and melanocortin related pathways may be involved in the observed beneficial effects.

Topics: Animals; Blood Glucose; Cholecystokinin; Diet, High-Fat; Energy Intake; Gene Expression Regulation; Glucagon-Like Peptide 1; Humans; Hypothalamus; Insulin; Leptin; Male; Mice; Obesity; Peptide Fragments; Peptides; Pro-Opiomelanocortin; Receptor, Melanocortin, Type 4

Fatty infiltration of the internal organs--and the inflammation associated with it--is an increasingly common cause of gallbladder dysfunction. Here's what to keep in mind to identify it without delay.

Topics: Algorithms; Biliary Dyskinesia; Cholagogues and Choleretics; Cholecystectomy; Cholecystokinin; Endoscopy, Digestive System; Humans; Imino Acids; Obesity

By developing novel screening technologies to test effects of food ingredients on hormone release, which are comparable to the in vivo situation, fewer tests may have to be performed using volunteers, whereas it still provides information that can be extrapolated to the human situation. In an in vivo intervention study, 10 lean (BMI: 20-25 kg/m(2)) and 10 obese (BMI >30 kg/m(2)) were recruited. All subjects randomly received pea protein (PP) solutions or placebo, orally and intraduodenally. Cholecystokinin (CCK) and glucagon like peptide 1 (GLP-1) release was measured over 2 h. During the oral interventions, gastrointestinal (GI) fluids were retrieved. For the present ex vivo study, duodenal biopsies were taken and placed in Ussing chambers. The luminal side was exposed to PP, placebo, intraduodenal fluid after oral PP-intake and oral placebo-intake in vivo, and a commercial pea-hydrolysate for 2 h. CCK and GLP-1 levels were measured at the serosal side. After intraduodenal PP administration in vivo, the area under the curve (AUC) for both CCK and GLP-1 was significantly increased in both lean and obese subjects. In the ex vivo study, exposure to PP resulted in significantly elevated levels of CCK and GLP-1 compared to all other test solutions. These results indicate that the ex vivo Ussing chamber technology is a valid alternative for in vivo studies, and may therefore serve as a suitable screening tool for studying the effects of nutritional compounds on the release of satiety hormones.

Topics: Administration, Oral; Adult; Biopsy; Cholecystokinin; Diffusion Chambers, Culture; Duodenum; Female; Glucagon-Like Peptide 1; Humans; Intestinal Mucosa; Male; Obesity; Pisum sativum; Plant Proteins; Satiety Response

Five to ten percent of women of reproductive age suffer from polycystic ovary syndrome (PCOS). Leptin, NPY, galanin, cholecystokinin (CCK) are involved in the regulation of eating behavior. PPARγ are receptors that are probably involved in hyperandrogenism. This study was designed to assess associations between the Pro12Ala PPARγ2 gene polymorphism and satiety factors in PCOS. Fifty-four PCOS women and 51 healthy women were studied. Leptin, NPY, galanin, CCK levels, and genetic studies to detect Pro12Ala PPARγ2 gene polymorphism were assessed. The leptin levels in the PCOS women carrying Pro12Ala genotype were higher than in those with Pro12Pro and Ala12Ala. The PCOS women had higher leptin and NPY levels and lower galanin levels. Obese PCOS patients had lower CCK levels.. In the PCOS women, a single Ala allele may have a protective role as far as hyperleptinemia is concerned. The PCOS women may reveal a disrupted central leptin/NPY feedback loop with some shifts in food intake.

Topics: Adult; Body Mass Index; Cholecystokinin; Female; Galanin; Genotype; Humans; Hyperandrogenism; Insulin Resistance; Leptin; Neuropeptide Y; Obesity; Polycystic Ovary Syndrome; Polymorphism, Genetic; PPAR gamma; Satiation

The gastrointestinal hormone cholecystokinin (CCK) plays an important role in regulating meal size and duration by activating CCK1 receptors on vagal afferent neurons (VAN). Leptin enhances CCK signaling in VAN via an early growth response 1 (EGR1) dependent pathway thereby increasing their sensitivity to CCK. In response to a chronic ingestion of a high fat diet, VAN develop leptin resistance and the satiating effects of CCK are reduced. We tested the hypothesis that leptin resistance in VAN is responsible for reducing CCK signaling and satiation.. Lean Zucker rats sensitive to leptin signaling, significantly reduced their food intake following administration of CCK8S (0.22 nmol/kg, i.p.), while obese Zucker rats, insensitive to leptin, did not. CCK signaling in VAN of obese Zucker rats was reduced, preventing CCK-induced up-regulation of Y2 receptor and down-regulation of melanin concentrating hormone 1 receptor (MCH1R) and cannabinoid receptor (CB1). In VAN from diet-induced obese (DIO) Sprague Dawley rats, previously shown to become leptin resistant, we demonstrated that the reduction in EGR1 expression resulted in decreased sensitivity of VAN to CCK and reduced CCK-induced inhibition of food intake. The lowered sensitivity of VAN to CCK in DIO rats resulted in a decrease in Y2 expression and increased CB1 and MCH1R expression. These effects coincided with the onset of hyperphagia in DIO rats.. Leptin signaling in VAN is required for appropriate CCK signaling and satiation. In response to high fat feeding, the onset of leptin resistance reduces the sensitivity of VAN to CCK thus reducing the satiating effects of CCK.

Topics: Animals; Body Weight; Cells, Cultured; Cholecystokinin; Diet, High-Fat; Eating; Leptin; Male; Neurons, Afferent; Obesity; Phenotype; Rats; Rats, Sprague-Dawley; Rats, Zucker; Satiation; Signal Transduction; Vagus Nerve

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

Despite the fact that ∼85% of bariatric operations are performed in women, the effects of the reproductive axis function on outcome of bariatric surgery remain to be determined. Here we developed the first published model of Roux-en-Y gastric bypass (RYGB) in female rats. We show in ovariectomized rats receiving estradiol or control treatment that (1) RYGB-induced body weight loss and (2) the satiating efficacy of endogenous glucagon-like peptide-1 and cholecystokinin satiation were significantly increased in estradiol-treated rats. These data are relevant to the care of obese women, in particular perimenopausal women, undergoing bariatric surgery.

Topics: Animals; Biomarkers; Cholecystokinin; Estradiol; Estrogens; Feeding Behavior; Female; Gastric Bypass; Glucagon-Like Peptide 1; Menopause; Models, Animal; Obesity; Ovariectomy; Rats; Satiation; Treatment Outcome; Weight Loss

Cholecystokinin (CCK) is a rapidly degraded gastrointestinal peptide that stimulates satiety and insulin secretion. We aimed to investigate the beneficial weight-lowering and metabolic effects of the novel N-terminally modified CCK analogue, (pGlu-Gln)-CCK-8.. The biological actions of (pGlu-Gln)-CCK-8 were comprehensively evaluated in pancreatic clonal BRIN BD11 cells and in vivo in high-fat-fed and ob/ob mice.. (pGlu-Gln)-CCK-8 was completely resistant to enzymatic degradation and its satiating effects were significantly (p < 0.05 to p < 0.001) more potent than CCK-8. In BRIN-BD11 cells, (pGlu-Gln)-CCK-8 exhibited enhanced (p < 0.01 to p < 0.001) insulinotropic actions compared with CCK-8. When administered acutely to high-fat-fed or ob/ob mice, (pGlu-Gln)-CCK-8 improved glucose homeostasis. Sub-chronic twice daily injections of (pGlu-Gln)-CCK-8 in high-fat-fed mice for 28 days significantly decreased body weight (p < 0.05 to p < 0.001), accumulated food intake (p < 0.05 to p < 0.001), non-fasting glucose (p < 0.05) and triacylglycerol deposition in pancreatic (p < 0.01), adipose (p < 0.05) and liver (p < 0.001) tissue, and improved oral (p < 0.05) and i.p. (p < 0.05) glucose tolerance and insulin sensitivity (p < 0.001). Similar observations were noted in ob/ob mice given twice daily injections of (pGlu-Gln)-CCK-8. In addition, these beneficial effects were not reproduced by simple dietary restriction and were not associated with changes in energy expenditure. There was no evidence for development of tolerance to (pGlu-Gln)-CCK-8, and analysis of histology or blood-borne markers for pancreatic, liver and renal function in mice treated with (pGlu-Gln)-CCK-8 suggested little abnormal pathology.. These studies emphasise the potential of (pGlu-Gln)-CCK-8 for the alleviation of obesity and insulin resistance.

Topics: Animals; Cholecystokinin; Comorbidity; Diabetes Mellitus; Disease Models, Animal; Glucose; Homeostasis; Insulin Resistance; Male; Mice; Mice, Obese; Obesity; Sincalide

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

Gut hormones play key roles in the regulation of energy homeostasis. However, little is known about the long- and short-term effects of changing dietary fat content on gut hormones. We aim to examine the effects of changing dietary fat content on plasma gut hormone concentrations in diet-induced obese (DIO) and diet-resistant (DR) rats. After inducing obesity with a high-fat (HF) diet, male Sprague-Dawley rats were divided into three groups according to their body-weight gain: DIO; DR; control (CON). The DIO and DR rats were further divided in random into two groups. One continued on a HF diet and the other switched to a low-fat (LF) diet for an additional 4 weeks. Finally, each group was randomly divided into three subgroups (n 8): fasted; fasted-refed HF; fasted-refed LF diet groups. Replacing a HF diet with a LF diet for 4 weeks resulted in less fat mass, higher fasting and post-HF plasma ghrelin concentration and lower postprandial plasma cholecystokinin concentration in the DIO and DR rats. Acute switching dietary fat resulted in significantly higher post-HF plasma ghrelin concentrations than post-LF ghrelin concentrations in the DR rats on LF diet (DRLF) and DIO rats on LF diet (DIOLF) rats, and significantly higher post-HF obestatin concentrations than post-LF obestatin concentrations in the CON, DR rats on HF diet (DRHF) and DRLF rats. Dietary fat content appears to play a role in the gut hormone profile, which may consequently influence fat mass.

Topics: Adipose Tissue; Animals; Cholecystokinin; Diet, Fat-Restricted; Dietary Fats; Fasting; Ghrelin; Male; Obesity; Postprandial Period; Random Allocation; Rats; Rats, Sprague-Dawley; Weight Gain

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

Gastrointestinal vagal afferents transmit satiety signals to the brain via both chemical and mechanical mechanisms. There is indirect evidence that these signals may be attenuated in obesity. We hypothesized that responses to satiety mediators and distension of the gut would be attenuated after induction of diet induced obesity. Obesity was induced by feeding a high fat diet (60% kcal from fat). Low fat fed mice (10% kcal from fat) served as a control. High fat fed mice were obese, with increased visceral fat, but were not hyperglycaemic. Recordings from jejunal afferents demonstrated attenuated responses to the satiety mediators cholecystokinin (CCK, 100 nm) and 5-hydroxytryptamine (5-HT, 10 μm), as was the response to low intensity jejunal distension, while responses to higher distension pressures were preserved. We performed whole cell patch clamp recordings on nodose ganglion neurons, both unlabelled, and those labelled by fast blue injection into the wall of the jejunum. The cell membrane of both labelled and unlabelled nodose ganglion neurons was less excitable in HFF mice, with an elevated rheobase and decreased number of action potentials at twice rheobase. Input resistance of HFF neurons was also significantly decreased. Calcium imaging experiments revealed reduced proportion of nodose ganglion neurons responding to CCK and 5-HT in obese mice. These results demonstrate a marked reduction in afferent sensitivity to satiety related stimuli after a chronic high fat diet. A major mechanism underlying this change is reduced excitability of the neuronal cell membrane. This may explain the development of hyperphagia when a high fat diet is consumed. Improving sensitivity of gastrointestinal afferent nerves may prove useful to limit food intake in obesity.

Topics: Action Potentials; Afferent Pathways; Animals; Blood Glucose; Body Weight; Calcium Signaling; Cholecystokinin; Dietary Fats; Electric Impedance; Intestines; Intra-Abdominal Fat; Jejunum; Male; Mechanotransduction, Cellular; Membrane Potentials; Mice; Mice, Inbred C57BL; Neurons; Nodose Ganglion; Obesity; Patch-Clamp Techniques; Satiety Response; Serotonin; Vagus Nerve

Gastrointestinal (GI) motility and gut hormones have been considered to be involved in the development and maintenance of obesity. Our aim was to assess the relationships between gastric emptying (GE), GI transit and gut hormones and leptin concentrations in diet-induced obese rat model. Male 6-week-old Sprague-Dawley rats were fed with a high-fat (HF) diet for 8weeks to generate diet-induced obesity (DIO) and diet resistant (DR) rats. GE, GI transit and plasma ghrelin, cholecystokinin (CCK), PYY and leptin concentrations were determined in DIO, DR and control (CON) rats. The DIO rats had slower GE, higher plasma leptin and CCK concentrations, and lower plasma ghrelin concentration compared with CON and DR rats. GE was correlated with plasma ghrelin (r=0.402, P=0.028), CCK (r=-0.518, P=0.003) and leptin concentration (r=-0.514, P=0.004). The slower GE, which can be considered as an adaptive response aimed at HF diet induced obesity, may be mediated by changes of plasma ghrelin, CCK and leptin concentrations.

Topics: Animals; Cholecystokinin; Diet, High-Fat; Gastric Emptying; Ghrelin; Leptin; Male; Obesity; Rats; Rats, Sprague-Dawley

Deficits in satiation signals are strongly suspected of accompanying obesity and contributing to its pathogenesis in both humans and rats. One such satiation signal is cholecystokinin (CCK), whose effects on food intake are diminished in animals adapted to a high fat diet. In this study, we tested the hypothesis that diet-induced obese prone (OP) rats exhibit altered feeding and vagal responses to systemic (IP) administration of CCK-8 compared to diet-induced obese resistant (OR) rats. We found that CCK (4.0 microg/kg) suppressed food intake significantly more in OP than OR rats. To determine whether enhanced suppression of feeding is accompanied by altered vagal sensory responsiveness, we examined dorsal hindbrain expression of Fos-like immunoreactivity (Fos-Li) following IP CCK injection in OP and OR rats. After 4.0 microg/kg CCK, there were significantly more Fos-positive nuclei in the NTS of OP compared to OR rats. Treatment with 8.0 microg/kg CCK resulted in no significant difference in food intake or in Fos-Li between OP and OR rats. Also, we found that OP rats were hyperphagic on a regular chow diet and gained more weight compared to OR rats. Finally OP rats had decreased relative fat pad mass compared to OR rats. Collectively, these results show that OP rats exhibit a different behavioral and vagal neuronal responses to CCK than OR rats.

Topics: Adiposity; Analysis of Variance; Animals; Body Weight; Cell Count; Cholecystokinin; Diet; Eating; Feeding Behavior; Hyperphagia; Immunohistochemistry; Neurons; Obesity; Proto-Oncogene Proteins c-fos; Random Allocation; Rats; Rats, Sprague-Dawley; Rhombencephalon; Satiety Response; Time Factors; Vagus Nerve

Cholecystokinin (CCK) is a satiation peptide released during meals in response to lipid intake; it regulates pancreatic digestive enzymes that are required for absorption of nutrients. We proposed that mice with a disruption in the CCK gene (CCK knockout [CCK-KO] mice) that were fed a diet of 20% butter fat would have altered fat metabolism.. We used quantitative magnetic resonance imaging to determine body composition and monitored food intake of CCK-KO mice using an automated measurement system. Intestinal fat absorption and energy expenditure were determined using a noninvasive assessment of intestinal fat absorption and an open circuit calorimeter, respectively.. After consuming a high-fat diet for 10 weeks, CCK-KO mice had reduced body weight gain and body fat mass and enlarged adipocytes, despite the same level of food intake as wild-type mice. CCK-KO mice also had defects in fat absorption, especially of long-chain saturated fatty acids, but pancreatic triglyceride lipase did not appear to have a role in the fat malabsorption. Energy expenditure was higher in CCK-KO than wild-type mice, and CCK-KO mice had greater oxidation of carbohydrates while on the high-fat diet. Plasma leptin levels in the CCK-KO mice fed the high-fat diet were markedly lower than in wild-type mice, although levels of insulin, gastric-inhibitory polypeptide, and glucagon-like peptide-1 were normal.. CCK is involved in regulating the metabolic rate and is important for lipid absorption and control of body weight in mice placed on a high-fat diet.

Topics: Adiposity; Animals; Biomarkers; Butter; Calorimetry; Cholecystokinin; Dietary Fats; Disease Models, Animal; Eating; Energy Metabolism; Fatty Acids; Intestinal Absorption; Leptin; Lipase; Magnetic Resonance Imaging; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Motor Activity; Obesity; Time Factors; Weight Gain

Cholecystokinin (CCK) acutely synergizes with amylin to suppress food intake in lean mice. To extend on these findings, the present studies sought to identify neural correlates for the interaction of amylin and CCK, as well as further understand the therapeutic potential of CCK-based combinations in obesity. First, c-Fos activation was assessed in various brain nuclei after a single intraperitoneal injection of amylin (5microg/kg) and/or CCK (5microg/kg). Amylin and CCK additively increased c-Fos within the area postrema (AP), predominantly in noradrenergic (e.g., dopamine-beta-hydroxylase-containing) cells. Next, amylin (100 or 300microg/kg/d) and/or CCK (100 or 300microg/kg/d) were subcutaneously infused for 7days in diet-induced obese (DIO) rats. Amylin treatment of DIO rats for 7days induced significant body weight loss. CCK, while ineffective alone, significantly enhanced body weight loss when co-administered with the higher dose of amylin. Finally, the addition of CCK (300microg/kg/d) to leptin (125microg/kg/d), and to the combination of amylin (50microg/kg/d) and leptin (125microg/kg/d), was also explored in DIO rats via sustained subcutaneous infusion for 14days. Infusion of amylin/leptin/CCK for 14days exerted significantly greater body weight loss, inhibition of food intake, and reduction in adiposity compared to amylin/leptin treatment alone in DIO rats. However, co-infusion of CCK and leptin was an ineffective weight loss regimen in this model. Whereas CCK agonism alone is ineffective at eliciting or maintaining weight loss, it durably augmented the food intake and body weight-lowering effects of amylin and amylin/leptin in a relevant disease model, and when combined with amylin, cooperatively activated neurons within the caudal brainstem.

Topics: Amyloid; Analysis of Variance; Animals; Appetite Depressants; Area Postrema; Body Weight; Cholecystokinin; Disease Models, Animal; Dopamine beta-Hydroxylase; Dose-Response Relationship, Drug; Drug Therapy, Combination; Eating; Islet Amyloid Polypeptide; Leptin; Male; Neurons; Obesity; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Weight Loss

An absolute or functional deficit in beta-cell mass is a key factor in the pathogenesis of diabetes. We model obesity-driven beta-cell mass expansion by studying the diabetes-resistant C57BL/6-Leptin(ob/ob) mouse. We previously reported that cholecystokinin (Cck) was the most up-regulated gene in obese pancreatic islets. We now show that islet cholecystokinin (CCK) is up-regulated 500-fold by obesity and expressed in both alpha- and beta-cells. We bred a null Cck allele into the C57BL/6-Leptin(ob/ob) background and investigated beta-cell mass and metabolic parameters of Cck-deficient obese mice. Loss of CCK resulted in decreased islet size and reduced beta-cell mass through increased beta-cell death. CCK deficiency and decreased beta-cell mass exacerbated fasting hyperglycemia and reduced hyperinsulinemia. We further investigated whether CCK can directly affect beta-cell death in cell culture and isolated islets. CCK was able to directly reduce cytokine- and endoplasmic reticulum stress-induced cell death. In summary, CCK is up-regulated by islet cells during obesity and functions as a paracrine or autocrine factor to increase beta-cell survival and expand beta-cell mass to compensate for obesity-induced insulin resistance.

Topics: Animals; Cell Count; Cell Survival; Cells, Cultured; Cholecystokinin; Diabetes Mellitus; Insulin Resistance; Insulin-Secreting Cells; Islets of Langerhans; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Mice, Transgenic; Obesity; Organ Size; Up-Regulation

The objective of the study was to investigate the role of cholecystokinin (CCK) on the food-induced insulin sensitization phenomenon in healthy Long Evans Tokushima Otsuka (LETO) and Otsuka Long Evans Tokushima Fatty (OLETF) rats. Whole body insulin sensitivity determined by hyperinsulinaemic euglycaemic glucose clamping and the rapid insulin sensitivity test served as endpoints. Determinations were done in both fasted and re-fed animals. The involvement of CCK in post-prandial insulin sensitization was assessed by using proglumide, a CCK receptor blocker, by assessment of hypothalamic CCK-1/CCK-2 receptor expression by rt-PCR technique and by plasma insulin immunoreactivity determinations by means of radioimmunoassay as pharmacological, genetic and analytical approaches, respectively. The body weight of the OLETF rats and the amount of food consumed much exceeded those seen with LETO rats. The post-prandial increase in insulin sensitivity was marked in LETO, but not in OLETF rats. Intravenous proglumide attenuated post-prandial insulin sensitivity in LETO rats, with no effect in OLETF rats. Nevertheless, baseline insulin sensitivity was much lower in OLETF than in LETO rats. Treatment with rosiglitazone increased baseline insulin sensitivity of OLETF rats and evoked an increase in CCK-1 receptor gene expression in LETO rats. The results provide evidence for the involvement of CCK receptors in adjustment of both fasting and post-prandial insulin sensitivity. The data obtained with OLETF rats strongly suggest the predominant role of CCK-1 receptors.

Topics: Animals; Cholecystokinin; Gene Expression Regulation; Glucose Clamp Technique; Hypoglycemic Agents; Insulin; Insulin Resistance; Male; Obesity; Polymerase Chain Reaction; Postprandial Period; Rats; Rats, Inbred OLETF; Rats, Long-Evans; Receptor, Cholecystokinin A; Receptor, Cholecystokinin B; Rosiglitazone; Thiazolidinediones

A previous study demonstrated that ginseng crude saponins prevent obesity induced by a high-fat diet in rats. Ginseng crude saponins are known to contain a variety of bioactive saponins. The present study investigated and compared the antiobesity activity of protopanaxadiol (PD) and protopanaxatriol (PT) type saponins, major active compounds isolated from crude saponins. Male 4-week-old Sprague-Dawley rats were fed with normal diet (N) or high-fat diet (HF). After 5 weeks, the HF diet group was subdivided into the control HF diet, HF diet-PD and HF diet-PT group (50 mg/kg/day, 3 weeks, i.p.). Treatment with PD and PT in the HF diet group reduced the body weight, total food intake, fat contents, serum total cholesterol and leptin to levels equal to or below the N diet group. The hypothalamic expression of orexigenic neuropeptide Y was significantly decreased with PD or PT treatment, whereas that of anorexigenic cholecystokinin was increased, compared with the control HF diet group. In addition, PD type saponins had more potent antiobesity properties than PT saponins, indicating that PD-type saponins are the major components contributing to the antiobesity activities of ginseng crude saponins. The results suggest that the antiobesity activity of PD and PT type saponins may result from inhibiting energy gain, normalizing hypothalamic neuropeptides and serum biochemicals related to the control of obesity.

Topics: Animals; Anti-Obesity Agents; Body Weight; Cholecystokinin; Cholesterol; Eating; Hypothalamus; Leptin; Male; Neuropeptide Y; Obesity; Panax; Rats; Rats, Sprague-Dawley; Sapogenins; Triglycerides

Monosodium glutamate (MSG) treatment of neonatal mice results in a selective damage to the arcuate nucleus (ARC) and development of obesity with increased adiposity at sustained body weight in the adulthood. Feeding pattern of the MSG obese mice is unusual. Our previous results showed that after 24-h fasting, MSG mice consumed negligible amount of food in several hours and therefore, it was impossible to register the effect of peptides attenuating food intake such as cholecystokinin (CCK) or cocaine- and amphetamine-regulated transcript (CART) peptide. To overcome this problem, two findings were used: firstly, orexigenic effect of neuropeptide Y (NPY) was attenuated both by CCK or CART peptide in lean fed mice and secondly, orexigenic effect of NPY was preserved in fed rats with MSG obesity. In this study, short-term food intake in fed lean and MSG obese C57BL/6 male mice was measured after simultaneous central administration of orexigenic NPY with either CART peptide or peripherally administered CCK. Anorexigenic action of exogenous CART peptide was preserved in MSG obese mice. On the other hand, satiety effect of exogenous CCK was completely lost in MSG obese mice. In conclusion, effective leptin signaling in ARC is necessary for satiety effect of CCK.

Topics: Animals; Appetite Regulation; Arcuate Nucleus of Hypothalamus; Cholecystokinin; Disease Models, Animal; Male; Mice; Mice, Inbred C57BL; Nerve Tissue Proteins; Neuropeptide Y; Obesity; Sodium Glutamate

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

The entero-insular axis plays an important role in generation of satiety signal. Thus, disturbances in this axis can influence the path to a simple obesity. THE AIM OF THE STUDY was to assess the function of the hormonal part of the entero-insular axis in children with simple obesity.. Group of 13 girls with the simple obesity was analyzed and the results were compared with results taken in the control group of 10 healthy girls. Each girl was examined for the oral glucose tolerance and standard meal tests. Blood was collected before stimulation and after 15, 30, 60 and 120 min. Concentrations of insulin, glucagon, pancreatic polypeptide, cholecystokinin, gastric inhibitory peptide (GIP) and glucagon-like peptide 1 (GLP-1) were determined with radioimmunoassay. Fasted and postprandial levels of the peptides as well as their integrated outputs were measured.. The results indicated that the disturbances in th entero-insular axis were limited to hyperinsulinaemia and changes in secretion of cholecystokinin (CCK) and GLP-1 in obese subjects. The integrated output of CCK in obese girls was significantly higher (p<0.001) than in control group but exclusively after the meal test. Mean values of the integrated output of GLP-1 in both tests were significantly higher in the control group than in the obese girls (oral glucose tolerance test- OGTT: p<0.001; meal: p<0.05). After OGTT and test meal, neither plasma concentrations of glucagon, pancreatic polypeptide nor GIP differed in the obese girl and control groups.. Low postprandial level of GLP-1 in obese children seems to be responsible for excessive ingestion of food and a weaker inhibition of gastric emptying, both resulting in obesity.

Topics: Adolescent; Cholecystokinin; Female; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Obesity; Satiety Response

Food intake is regulated by a network of signals that emanate from the gut and the brainstem. The peripheral satiety signal cholecystokinin is released from the gut following food intake and acts on fibers of the vagus nerve, which project to the brainstem and activate neurons that modulate both gastrointestinal function and appetite. In this study, we found that neurons in the nucleus tractus solitarii of the brainstem that express prolactin-releasing peptide (PrRP) are activated rapidly by food ingestion. To further examine the role of this peptide in the control of food intake and energy metabolism, we generated PrRP-deficient mice and found that they displayed late-onset obesity and adiposity, phenotypes that reflected an increase in meal size, hyperphagia, and attenuated responses to the anorexigenic signals cholecystokinin and leptin. Hypothalamic expression of 6 other appetite-regulating peptides remained unchanged in the PrRP-deficient mice. Blockade of endogenous PrRP signaling in WT rats by central injection of PrRP-specific mAb resulted in an increase in food intake, as reflected by an increase in meal size. These data suggest that PrRP relays satiety signals within the brain and that selective disturbance of this system can result in obesity and associated metabolic disorders.

Topics: Adiposity; Animals; Antibodies, Monoclonal; Appetite Regulation; Cholecystokinin; Energy Metabolism; Hyperphagia; Intestinal Mucosa; Leptin; Mice; Mice, Knockout; Neurons; Obesity; Phenotype; Prolactin; Signal Transduction; Solitary Nucleus

Palatable food disrupts normal appetite regulation, which may contribute to the etiology of obesity. Neuropeptide Y (NPY) and cholecystokinin play critical roles in the regulation of food intake and energy homeostasis, while adiponectin and carnitine palmitoyltransferase (CPT) are important for insulin sensitivity and fatty acid oxidation. This study examined the impact of short- and long-term consumption of palatable high-fat diet (HFD) on these critical metabolic regulators.. Male C57BL/6 mice were exposed to laboratory chow (12% fat), or cafeteria-style palatable HFD (32% fat) for 2 or 10 weeks. Body weight and food intake were monitored throughout. Plasma leptin, hypothalamic NPY and cholecystokinin, and mRNA expression of leptin, adiponectin, their receptors and CPT-1, in fat and muscles were measured.. Caloric intake of the palatable HFD group was 2-3 times greater than control, resulting in a 37% higher body weight. Fat mass was already increased at 2 weeks; plasma leptin concentrations were 2.4 and 9 times higher than control at 2 and 10 weeks, respectively. Plasma adiponectin was increased at 10 weeks. Muscle adiponectin receptor 1 was increased at 2 weeks, while CPT-1 mRNA was markedly upregulated by HFD at both time points. Hypothalamic NPY and cholecystokinin content were significantly decreased at 10 weeks.. Palatable HFD induced hyperphagia, fat accumulation, increased adiponectin, leptin and muscle fatty acid oxidation, and reduced hypothalamic NPY and cholecystokinin. Our data suggest that the adaptive changes in hypothalamic NPY and muscle fatty acid oxidation are insufficient to reverse the progress of obesity and metabolic consequences induced by a palatable HFD.

Topics: Adiponectin; Animals; Body Weight; Cholecystokinin; Dietary Fats; Eating; Energy Metabolism; Hyperphagia; Leptin; Male; Mice; Mice, Inbred C57BL; Neuropeptide Y; Obesity; Receptors, Adiponectin; RNA, Messenger

Mice with a targeted disruption of bombesin receptor subtype-3 (BRS-3 KO) develop hyperphagia, obesity, hypertension, and impaired glucose metabolism. However, the factors contributing to their phenotype have not been clearly established. To determine whether their obesity is a result of increased food intake or a defect in energy regulation, we matched the caloric intake of BRS-3 KO mice to wild-type (WT) ad libitum (ad lib)-fed controls over 21 wk. Although BRS-3 KO ad lib-fed mice were 29% heavier, the body weights of BRS-3 KO pair-fed mice did not differ from WT ad lib-fed mice. Pair-feeding BRS-3 KO mice normalized plasma insulin but failed to completely reverse increased adiposity and leptin levels. Hyperphagia in ad lib-fed KO mice was due to an increase in meal size without a compensatory decrease in meal frequency resulting in an increase in total daily food intake. An examination of neuropeptide Y, proopiomelanocortin, and agouti-related peptide gene expression in the arcuate nucleus revealed that BRS-3 KO mice have some deficits in their response to energy regulatory signals. An evaluation of the satiety effects of cholecystokinin, bombesin, and gastrin-releasing peptide found no differences in feeding suppression by these peptides. We conclude that hyperphagia is a major factor leading to increased body weight and hyperinsulinemia in BRS-3 KO mice. However, our finding that pair-feeding did not completely normalize fat distribution and plasma leptin levels suggests there is also a metabolic dysregulation that may contribute to, or sustain, their obese phenotype.

Topics: Adiposity; Animals; Body Weight; Bombesin; Cholecystokinin; Eating; Energy Metabolism; Gastrin-Releasing Peptide; Glucose; Hyperinsulinism; Hyperphagia; Hypothalamus; Insulin; Leptin; Male; Mice; Mice, Knockout; Obesity; Receptors, Bombesin; Satiation; Weight Gain

Gastric electrical stimulation (GES) has been introduced for treating obesity. The hippocampus is known to be involved in the regulation of gastrointestinal motility. Changes in hypathalumus cholecystokinin (CCK) have been observed in genetically obese rodents. This experiment was to study the effect of GES on the activities of neurons and the expression of CCK in the hippocampus.. We investigated the effect of GES (GES-I: pulse train of standard parameters; GES-2: reduced train-on time; GES-3: increased pulse width; GES-4: reduced pulse frequency) on neurons responsive to gastric distention (GD) by recording extracellular potentials of single neurons and observing the expression of CCK in the rodent hippocampus by immunohistochemistry staining, radioimmunoassay, and real-time PCR.. 92.1% of neurons in the CA2-3 region responded to GD, 53.2% of which showed excitation (GD-E), and 46.8% showed inhibition (GD-I). 64.8% GD-responsive neurons were excited by GES. The response was associated with stimulation strength, pulse width, and frequency; 70.6, 57.1, 94.4, and 66.7% of GD-E and 72.7, 57.1, 86.4, and 50% of GD-I neurons showed excitatory responses to GES-I, -2, -3, and -4, respectively. CCK immunoreactive positive neurons (P<0.001), the content of CCK-like materials (P<0.05) and the amount of CCK mRNA were significantly increased after GES (P<0.05).. These findings suggest the central, neuronal, and hormonal mechanisms of GES. GES may excite the activity of GD-sensitive neurons and increase the expression of CCK in the hippocampus. These excitatory effects of GES seem to be related to the parameters of stimulation.

Topics: Animals; Cholecystokinin; Electric Stimulation; Electrophysiology; Gastric Dilatation; Hippocampus; Male; Neurons; Obesity; Rats; Rats, Wistar; RNA, Messenger; Stomach

Weight regain after weight loss may not be due primarily to voluntary return to social habits but may be explained by changes in peripheral hormonal signals activating hunger and encouraging feeding behavior.. The objective of this study was to investigate physiologic adaptations to weight loss that may encourage weight regain.. The study had a within-subject repeated-measure design [12 healthy, obese men, 33-64 y, body mass index (in kg/m(2)) 30-46] and was a clinical intervention investigation of circulating metabolites and hunger-satiety responses before and after weight loss. Measures included anthropometry (bioelectrical impedance, body weight, and waist circumference), concentrations of circulating hormones and metabolites [ketone bodies, free fatty acids (FFAs), insulin, leptin, glucose, and cholecystokinin (CCK)], and measures of hunger and satiety at baseline, 8 wk after weight loss with a very-low-energy diet, and 1 wk after weight maintenance.. Weight loss led to a reduction in postprandial CCK secretion (P = 0.016). However, when subjects were ketotic (elevated circulating beta-hydroxybutyrate concentrations), CCK secretion was sustained at concentrations before weight loss. After weight loss, there were reduced postprandial FFA concentrations (P = 0.0005). The presence of ketosis sustained FFA to concentrations before weight loss (P = 0.60).. Rapid weight loss of approximately 10% of initial body weight results in a reduction in postprandial CCK and FFA concentrations.

Topics: Adaptation, Physiological; Adult; Anthropometry; Body Mass Index; Cholecystokinin; Eating; Fatty Acids, Nonesterified; Gastrointestinal Tract; Humans; Hunger; Insulin; Ketone Bodies; Ketosis; Leptin; Male; Middle Aged; Nutritional Physiological Phenomena; Obesity; Peptide Hormones; Postprandial Period; Satiation; Signal Transduction; Weight Loss

Obesity has a heritable component; however, the heterogeneity of obesity complicates dissection of its genetic background. In this study, we therefore focused on eating patterns as specific traits within obesity. These traits have a heritable component; genes associated with a specific eating pattern have not yet been reported at the population level. In this study, we determined whether genetic variations in cholecystokinin (CCK) and leptin genes underlie specific eating patterns. We selected obese individuals showing extreme snacking behavior or use of excessive portion sizes from a large population-based sample (n = 17,357) from the Prospect-EPIC (European Prospective Study into Cancer and Nutrition) study. Using allele-specific PCRs, we tested several single nucleotide polymorphisms in the candidate genes and performed haplotype analysis. Obese carriers of common allelic variations in leptin or the leptin receptor gene had an increased risk to display extreme snacking behavior. In contrast, obese carriers of common allelic variations in CCK had an increased risk to eating increased meal sizes. In conclusion, we identified common allelic variants specifically associated with distinctly different eating patterns, namely extreme snacking behavior or excessive portion size.

Topics: Aged; Blood Pressure; Body Mass Index; Body Size; Cholecystokinin; Feeding Behavior; Female; Genetic Variation; Humans; Leptin; Middle Aged; Netherlands; Obesity; Polymerase Chain Reaction; Polymorphism, Single Nucleotide; Postmenopause; Premenopause; Receptors, Cell Surface; Receptors, Leptin; Smoking

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

Oleoyl-estrone (OE) decreases appetite, maintains energy expediture, induces lipolysis (sparing protein), and decreases cholesterolemia and insulin resistance. Rimonabant (SR141716) is a cannabinoid-receptor inhibitor that decreases appetite and mobilizes fat. We studied whether their combination improves their slimming effects. Male overweight rats received daily gavages of 5.3 mg/kg OE, 10 mg/kg rimonabant, or both drugs during 10 days. Body weight and composition, energy balance, adipose tissue weight, and serum hormones and metabolites were measured. OE halved food intake and maintained energy expenditure at the expense of body fat. Rimonabant effects on appetite and energy balance were less marked, resulting in lower lipid mobilization. OE and rimonabant followed the OE pattern, with no additive or synergic effects. Glycemia was maintained, but OE decreased insulin, GLP-1, and cholesterol, whilst rimonabant increased cholecystokinin and cholesterol, and decreased NEFA. Both drugs decreased leptin and triacylglycerols; ghrelin was unchanged. The results hint at different mechanisms of action of both drugs: we can assume that OE effects do not involve the cannabinoid pathway. OE does not seem to act, either, after 10 days, through the secretion of ghrelin or the intestinal appetite-controlling peptides tested.

Topics: Animals; Anti-Obesity Agents; Appetite; Blood Glucose; Cholecystokinin; Cholesterol; Drug Synergism; Drug Therapy, Combination; Eating; Energy Metabolism; Estrone; Fatty Acids, Nonesterified; Ghrelin; Glucagon-Like Peptide 1; Insulin; Leptin; Male; Obesity; Oleic Acids; Overweight; Peptide Hormones; Piperidines; Pyrazoles; Rats; Rats, Wistar; Rimonabant; Triglycerides

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

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

Interactions between gastrointestinal signals are a part of integrated systems regulating food intake (FI). We investigated whether cholecystokinin (CCK)-8 and urocortin systems potentiate each other to inhibit FI and gastric emptying (GE) in fasted mice. Urocortin 1 and urocortin 2 (1 microg/kg) were injected ip alone or with CCK (3 microg/kg) in lean, diet-induced obese (DIO) or corticotropin-releasing factor receptor-2 (CRF(2))-deficient mice. Gastric vagal afferent activity was recorded from a rat stomach-vagus in vitro preparation. When injected separately, urocortin 1, urocortin 2, or CCK did not modify the 4-h cumulative FI in lean mice. However, CCK plus urocortin 1 or CCK plus urocortin 2 decreased significantly the 4-h FI by 39 and 27%, respectively, compared with the vehicle + vehicle group in lean mice but not in DIO mice. Likewise, CCK-urocortin-1 delayed GE in lean but not DIO mice, whereas either peptide injected alone at the same dose had no effect. CCK-urocortin 2 suppression of FI was observed in wild-type but not CRF(2)-deficient mice. Gastric vagal afferent activity was increased by intragastric artery injection of urocortin 2 after CCK at a subthreshold dose, and the response was reversed by devazepide. These data establish a peripheral synergistic interaction between CCK and urocortin 1 or urocortin 2 to suppress FI and GE through CRF(2) receptor in lean mice that may involve CCK modulation of gastric vagal afferent responsiveness to urocortin 2. Such synergy is lost in DIO mice, suggesting a resistance to the satiety signaling that may contribute to maintain obesity.

Topics: Animals; Cholecystokinin; Drug Synergism; Eating; Gastric Emptying; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Models, Biological; Obesity; Peptide Fragments; Rats; Receptors, Corticotropin-Releasing Hormone; Satiation; Signal Transduction; Stomach; Urocortins; Vagus Nerve

The Clock gene is a core component of the circadian clock in mammals. We show here that serum levels of triglyceride and free fatty acid were significantly lower in circadian Clock mutant ICR than in wild-type control mice, whereas total cholesterol and glucose levels did not differ. Moreover, an increase in body weight induced by a high-fat diet was attenuated in homozygous Clock mutant mice. We also found that dietary fat absorption was extremely impaired in Clock mutant mice. Circadian expressions of cholecystokinin-A (CCK-A) receptor and lipase mRNAs were damped in the pancreas of Clock mutant mice. We therefore showed that a Clock mutation attenuates obesity induced by a high-fat diet in mice with an ICR background through impaired dietary fat absorption. Our results suggest that circadian clock molecules play an important role in lipid homeostasis in mammals.

Topics: Animals; Cholecystokinin; Circadian Rhythm; CLOCK Proteins; Dietary Fats; Fatty Acids; Gene Expression Regulation; Homeostasis; Mice; Mice, Mutant Strains; Obesity; Receptor, Cholecystokinin A; Trans-Activators; Triglycerides

Topics: Cholecystokinin; Dietary Fats; Ghrelin; Glucagon-Like Peptide 1; Humans; Obesity; Peptide Hormones; Postprandial Period

Both obesity and diabetes are associated with an increased incidence of gallstones. Recent animal and human data from our laboratory suggest that insulin resistance is associated with increased gallbladder volume and/or impaired gallbladder emptying. Pioglitazone is a thiazolidinedione that has been shown to improve insulin resistance. Therefore, we tested the hypothesis that pioglitazone would improve insulin resistance, decrease resting gallbladder volume and improve gallbladder response to neurotransmitters in insulin-resistant obese mice fed a 25% carbohydrate diet.. Twenty eight-week-old insulin-resistant obese (Lep(ob)) mice fed a 25% carbohydrate diet for 4 weeks. Half of the animals had 0.3 g/kg pioglitazone added to their diet. At 12 weeks all animals were fasted and underwent cholecystectomy. Gallbladder volume and weight were measured, and fresh gallbladders were placed in a muscle bath to assess response to acetylcholine (ACh 10(-5)M), neuropeptide Y (NPY 10(-8,-7,-6)M) and cholecystokinin (CCK 10(-10,-9,-8,-7)M). Serum glucose and insulin were measured, and HOMA Index, a measure of insulin resistance, was calculated.. Fasting serum insulin and HOMA Index were significantly decreased (P < 0.03), but gallbladder volume was significantly increased (P < 0.03) in the pioglitazone treated group. Pioglitazone did not alter gallbladder weight or response to ACh, NPY, or CCK.. These data suggest that in insulin-resistant obese mice pioglitazone 1) lowers insulin-resistance, 2) increases resting gallbladder volume, and 3) does not alter gallbladder response to neurotransmitters. Therefore, we conclude that pioglitazone, while improving insulin resistance, paradoxically increases gallbladder volume and, thereby, may increase the propensity for gallstone formation by enhancing gallbladder stasis.

Topics: Acetylcholine; Age Factors; Animals; Blood Glucose; Cholecystokinin; Cholinergic Agents; Dietary Carbohydrates; Female; Gallbladder; Gallstones; Hypoglycemic Agents; Insulin; Insulin Resistance; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Neuropeptide Y; Obesity; Organ Size; Peptide Fragments; Pioglitazone; Thiazolidinediones

The capacity to adjust energy intake in response to changing energy requirements is a defining feature of energy homeostasis. Despite the identification of leptin as a key mediator of this process, the mechanism whereby changes of body adiposity are coupled to adaptive, short-term adjustments of energy intake remains poorly understood. To investigate the physiological role of leptin in the control of meal size and the response to satiety signals, and to identify brain areas mediating this effect, we studied Koletsky (fa(k)/fa(k)) rats, which develop severe obesity due to the genetic absence of leptin receptors. Our finding of markedly increased meal size and reduced satiety in response to the gut peptide cholecystokinin (CCK) in these leptin receptor-deficient animals suggests a critical role for leptin signaling in the response to endogenous signals that promote meal termination. To determine if the hypothalamic arcuate nucleus (ARC) (a key forebrain site of leptin action) mediates this leptin effect, we used adenoviral gene therapy to express either functional leptin receptors or a reporter gene in the area of the ARC of fa(k)/fa(k) rats. Restoration of leptin signaling to this brain area normalized the effect of CCK on the activation of neurons in the nucleus of the solitary tract and area postrema, key hindbrain areas for processing satiety-related inputs. This intervention also reduced meal size and enhanced CCK-induced satiety in fa(k)/fa(k) rats. These findings demonstrate that forebrain signaling by leptin, a long-term regulator of body adiposity, limits food intake on a meal-to-meal basis by regulating the hindbrain response to short-acting satiety signals.

Topics: Animals; Cholecystokinin; Eating; Feeding Behavior; Genetic Therapy; Homeostasis; Humans; Leptin; Male; Neurons; Obesity; Prosencephalon; Proto-Oncogene Proteins c-fos; Rats; Rats, Inbred Strains; Receptors, Cell Surface; Receptors, Leptin; Recombinant Fusion Proteins; Rhombencephalon; Satiety Response; Signal Transduction

Scintigraphic gastric emptying studies are far from conclusive in obesity. The aim was to investigate gastric emptying and CCK release in weight-stable obese subjects on their usual diet and to study the impact of factors known to determine gastric emptying. Patients entering a weight reduction program were asked to participate in a study examining gastric emptying by scintigraphy and CCK release in response to a meal with questionnaires on feelings of satiety. Forty-five patients (9 M, 36 F) with a mean (SD) BMI of 37.0 (4.0) kg/m2 entered the study. The mean T50 (emptying of 50%) of fluids was 20.7 (10.3) min, and that of solids 141.9 (168.3) min. The percentage emptying of solids was 34.5 (19.9)%/hr. CCK values peaked within 42 min and paralleled the subjective ratings of satiety but did not correlate with gastric emptying. Five of 45 subjects (11%) had very prolonged gastric emptying of solids; they showed higher caloric intakes and higher insulin levels. They did not differ in CCK values and ratings of satiety but scored higher in being active and awake. Without these five subjects the T50 of solids was 94.3 (36.1) min, and the percentage of emptying 37.9 (18.4)%/hr. Liquid emptying was faster and solid emptying similar compared with those of normal-weight individuals. Height, fat-free mass, and waist-hip circumference were positively related to solid emptying. In weight-stable obese subjects liquid emptying was faster and solid emptying similar to those in normal-weight subjects. Higher caloric intakes and insulin levels were present in subjects with prolonged solid emptying; they also appeared more vigilant. Body size and composition were the only determinants suggesting a faster solid emptying in taller and muscular subjects or in subjects with more intraabdominal fat.

Topics: Adult; Body Weight; Cholecystokinin; Female; Gastric Emptying; Humans; Male; Middle Aged; Obesity; Radionuclide Imaging; Satiety Response; Time Factors

Leptin is produced by adipocytes and causes satiety by regulating hypothalamic neurotransmission and energy expenditure. Leptin functions through the active long form of its receptor, which is expressed throughout the gastrointestinal tract, including the vagal neurons concerned with small intestinal motility. However, the role of leptin in small intestinal motility is poorly understood. Therefore, we hypothesized that leptin-deficient (Lepob) obese mice would have altered small intestinal response to neurotransmitters and transit time.. Responses of jejunal and ileal segments from lean control and leptin-deficient obese animals to acetylcholine (ACh) and cholecystokinin (CCK) were determined in an organ bath. In addition, gastric emptying was determined as the amount of gavaged liquid diet remaining in the stomach after 1 h, and intestinal transit time was determined by calculating the geometric center (GC) of passage of a fluorescent-labeled marker.. Leptin deficiency resulted in increased jejunal responses to CCK (P <0.05) and a similar response to ACh compared to lean controls. Also, gastric emptying (97% versus 91%, P <0.001) in obese mice was greater. Overall small intestinal transit (GC) in obese mice was decreased (7.3 versus 8.4, P <0.05) even though proximal transit was increased (5.3 versus 1.5, P <0.06).. These studies indicate that leptin-deficient (Lepob) obese mice have an increased jejunal response to CCK as well as an increased proximal intestinal transit, but an overall decrease in small intestinal transit.

Topics: Acetylcholine; Animals; Cholecystokinin; Gastric Emptying; Gastrointestinal Motility; Gastrointestinal Transit; Intestine, Small; Leptin; Male; Mice; Mice, Inbred C57BL; Models, Animal; Neurotransmitter Agents; Obesity

Leptin receptors are present in the jejunum, ileum, and vagal neurons. Leptin increases duodenal secretion of cholecystokinin (CCK) and acts with CCK on vagal mechanoreceptors in the regulation of small intestinal motility. We have demonstrated that leptin-deficient (Lepob) obese mice have increased jejunal and normal ileal responses to CCK. Therefore, we hypothesized that leptin administration alters small intestinal motility observed in leptin-deficient obese mice.. Twelve-week-old female leptin-deficient (Lepob) obese mice received either saline (n=12) or 5 microg/g leptin ip (n=12) injections daily. After 4 weeks, jejunal and ileal segments were harvested, mounted in an organ bath, and reacted with acetylcholine (ACh, 10(-5)M) and CCK (10(-8,-7,-6)M). Data were expressed as N/cm2 and compared by ANOVA and Student's t test.. The average body weights in the leptin-treated group were significantly decreased compared to those of the saline-treated group (34 versus 49 g, P <0.01). Jejunal responses to ACh within each group were significantly decreased (P <0.05) when compared to ileal responses. No significant differences in responses to ACh were observed between groups. Jejunal responses to 10(-7,-6)M CCK in the leptin-treated group were significantly greater than those in the saline-treated group. Ileal responses in the leptin group were similarly increased at all CCK concentrations.. These data suggest that daily leptin administration for 4 weeks in leptin-deficient (Lepob) obese mice increases jejunal and ileal responses to CCK and does not alter responses to ACh. Therefore, we conclude that regulation of small intestinal motility may be influenced by synergistic action of cholecystokinin and leptin.

Topics: Acetylcholine; Animals; Cholecystokinin; Female; Gastrointestinal Motility; In Vitro Techniques; Injections, Intraperitoneal; Intestine, Small; Leptin; Mice; Mice, Inbred C57BL; Models, Animal; Neurotransmitter Agents; Obesity; Peptide Hormones

Ghrelin and cholecystokinin (CCK) are gastrointestinal hormones regulating feeding. Both transmitted via the vagal afferent, ghrelin elicits starvation signals, whereas CCK induces satiety signals. We investigated the interaction between ghrelin and CCK functioning in short-term regulation of feeding in Otsuka Long-Evans Tokushima fatty (OLETF) rats, which have a disrupted CCK type A receptor (CCK-AR), and their lean littermates, Long-Evans Tokushima Otsuka (LETO) rats. Intravenous administration of ghrelin increased 2-h food intake in both OLETF and LETO rats. Because OLETF rats are CCK insensitive, iv-administered CCK decreased 2-h food intake in LETO, but not in OLETF, rats. Although preadministration of CCK to LETO rats blocked food intake induced by ghrelin, CCK preadministration to OLETF rats did not affect ghrelin-induced food intake. Conversely, preadministration of ghrelin to LETO rats blocked feeding reductions induced by CCK. In electrophysiological studies, once gastric vagal afferent discharges were altered by ghrelin or CCK administration, they could not be additionally affected by serial administrations of either CCK or ghrelin, respectively. The induction of Fos expression in the hypothalamic arcuate nucleus by ghrelin was also attenuated by CCK preadministration. Using immunohistochemistry, we also demonstrated the colocalization of GH secretagogue receptor (GHS-R), the cellular receptor for ghrelin, with CCK-AR in vagal afferent neurons. These results indicate that the vagus nerve plays a crucial role in determining peripheral energy balance. The efficiency of ghrelin and CCK signal transduction may depend on the balance of their respective plasma concentration and/or on interactions between GHS-R and CCK-AR.

Topics: Afferent Pathways; Animals; Cholecystokinin; Electrophysiology; Energy Intake; Feeding Behavior; Ghrelin; Obesity; Peptide Hormones; Rats; Rats, Mutant Strains

Obesity is associated with diabetes and gallstone formation. Obese leptin-deficient (Lepob) and leptin-resistant (Lepdb) mice are hyperglycemic and have enlarged gallbladders with diminished response in vitro to cholecystokinin (CCK) and acetylcholine (ACh). Whether this phenomenon is secondary to hyperosmolar myocytes and/or decreased neuromuscular transmission remains unclear. We hypothesize that myocytes from Lepob and Lepdb obese mice would not respond normally to neurotransmitters.. Cholecystectomy was performed on 39 lean, 19 Lepob, and 20 Lepdb 12-week-old female mice. The gallbladder was divided and enzymatically digested. Half of each gallbladder's myocytes had contraction induced by CCK (10(-8) mol/L, n = 38) or ACh (10(-5) mol/L, n = 40).. Body weights, gallbladder volumes, and serum glucoses were greater for Lep(ob) and Lepdb mice compared to controls (P < .001). Resting myocyte lengths from Lepob and Lepdb mice were 93% and 91% of the length of controls (P < .001). In response to CCK, lean myocytes shortened 6% (P < .01), while myocytes from obese mice demonstrated no shortening. None of the myocytes demonstrated significant shortening with ACh.. These data suggest that gallbladder myocytes from obese mice are (1) foreshortened and (2) have a diminished response to cholecystokinin. We conclude that altered leptin and/or increased glucose may foreshorten myocytes and decrease response to cholecystokinin.

Topics: Acetylcholine; Animals; Blood Glucose; Body Weight; Cholecystokinin; Diabetes Mellitus; Female; Gallbladder; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Muscle Contraction; Myocytes, Smooth Muscle; Obesity

Anorexia-associated malnutrition is a severe complication that increases mortality in peritoneal dialysis (PD) patients. Ghrelin is a recently-discovered orexigenic hormone with actions in brain and stomach. We analyzed, in 42 PD patients, the possible relationship between ghrelin and appetite regulation with regard to other orexigens [neuropeptide Y (NPY), NO3] and anorexigens [cholecystokinin (CCK), leptin, glucose-dependent insulinotropic peptide (GIP), tumor necrosis factor alpha (TNFalpha)]. All orexigens and anorexigens were determined in plasma. Eating motivation was evaluated using a visual analog scale (VAS). The patients were divided into three groups: those with anorexia (n = 12), those with obesity associated with high intake (n = 12), and those with no eating behavior disorders (n = 18). A control group of 10 healthy volunteers was also evaluated. Mean plasma levels of ghrelin were high (3618.6 +/- 1533 mg/mL), with 36 patients showing values above the normal range (< 2600 mg/mL). Patients with anorexia had lower ghrelin and NPY levels and higher peptide-C, CCK, interleukin-1 (IL-1), TNFalpha, and GIP levels than did the other patients. Patients with anorexia also had an early satiety score and low desire and pleasure in eating on the VAS and diet survey. We observed significant positive linear correlations between ghrelin and albumin (r = 0.43, p < 0.05), prealbumin (r = 0.51, p < 0.05), transferrin (r = 0.4, p < 0.05), growth hormone (r = 0.66, p < 0.01), NO3 (r = 0.36, p < 0.05), and eating motivation (VAS). At the same time, negative relationships were observed between blood ghrelin and GIP (r = -0.42, p < 0.05), insulin (r = -0.4, p < 0.05), leptin (r = -0.45, p < 0.05), and creatinine clearance [r = -0.33, p = 0.08 (nonsignificant)]. Ghrelin levels were not related to Kt/V or to levels of CCK and cytokines. Ghrelin plasma levels are elevated in PD patients. Uremic patients with anorexia show relatively lower ghrelin plasma levels than the levels seen in obese patients or in patients with normal appetite. The role of ghrelin in appetite modulation is altered in uremic PD patients, and that alteration is possibly associated with disorders in insulin and growth hormone metabolism.

Topics: Adult; Aged; Anorexia; Appetite Regulation; Blood Proteins; Cholecystokinin; Cytokines; Eating; Female; Gastric Inhibitory Polypeptide; Ghrelin; Humans; Leptin; Male; Middle Aged; Neuropeptide Y; Nitric Oxide; Nutritional Status; Obesity; Peptide Hormones; Peritoneal Dialysis

Cholecystokinin (CCK), glucose dependent insulinotropic peptide (GIP), and glucagon-like peptide 1 (GLP-1) regulate satiety as enterogastrons and incretins. They also directly affect the satiety centers. Therefore, these peptides may participate in the pathogenesis of eating disorders. CCK, GIP, and GLP-1 secretion were studied in 13 adolescent girls suffering from simple obesity, 13 girls with anorexia nervosa, and 10 healthy girls. Each girl was subjected to an oral glucose tolerance test (OGTT) and standard meal test. Blood was collected before stimulation and at 15, 30, 60, and 120 min. The concentrations of all peptides were determined by RIA commercial kits. Fasting and postprandial levels of these peptides as well as integrated outputs were measured. High postprandial levels of CCK observed in the girls with anorexia may aggravate the course of this disease by intensifying nausea and vomiting. Low postprandial level of GLP-1 in girls with simple obesity may be responsible for excessive ingestion of food and weaker inhibition of gastric emptying, which also leads to obesity.

Topics: Adolescent; Anorexia Nervosa; Child; Cholecystokinin; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Humans; Male; Obesity; Peptide Fragments; Protein Precursors; Radioimmunoassay

Although the results of dynamic ultrasonography (DUS) are similar to those of dynamic cholescintigraphy (DCS) in the study of gallbladder function, the methodology required for this technique is laborious and sometimes complex. The aim of this study was to investigate the reliability of a simple method of DUS to evaluate gallbladder function using DCS as a reference.. Gallbladder function was studied using DUS and DCS in 80 consecutive patients with clinical findings compatible with gallbladder dysfunction. For DUS the ellipsoid method was used with measurement of three gallbladder diameters (transversal, longitudinal and anteroposterior) in basal conditions and after applying a cholecystokinetic stimulus (meal test); gallbladder emptying of less than 50% was considered abnormal. In DCS intravenous cholecystokinin (CCK) (0.40 IDU/kg in 20 minutes) was used as stimulus and an ejection fraction < or = 40% was considered abnormal.. In 15 patients (19%; 95% CI, 11-29%) abnormal gallbladder response was found using DUS. The ejection fraction in the entire group of patients studied was 48 26.2%. Ejection fraction was abnormal in 41 patients (51%; 95% IC, 40-63%) with a value of 25 8.5% and was normal in 39 patients (49%; 95% IC, 40-63%) with a value of 71.5 14.5%. The correlation coefficient between the values of gallbladder emptying calculated with DUS and the ejection fraction obtained with DCS was 0.199 (p = 0.079). When patients were divided according to gallbladder emptying measured by DUS and the ejection fraction obtained with DCS the concordance was very low (k = 0.065; EE = 0.085).. DUS performed using a simple technique lacks diagnostic value in gallbladder dysfunction when DCS is taken as a reference test

Topics: Adult; Aged; Cholecystokinin; Computer Systems; Female; Gallbladder; Gallbladder Emptying; Humans; Male; Middle Aged; Obesity; Radionuclide Imaging; Reproducibility of Results; Ultrasonography

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

In obese patients, jejunoileal bypass (JIB) has been used to induce weight reduction. Changes in the neuroendocrine system may be affected by the JIB-operation, because the proximal small intestinal mucosa has a rich supply of endocrine cells and peptidergic nerves.. In 37 obese patients operated with JIB 1-30 years ago, small intestinal biopsies were taken at the duodeno-jejunal flexure, proximal to the anastomosis and from 5 unoperated obese persons and 20 normal weight patients. The tissue specimens were processed for immunocytochemical demonstration of cells/nerves containing: gastrin, cholecystokinin (CCK), secretin, gastric inhibitory peptide (GIP), motilin, somatostatin, serotonin, glicentine, peptide YY (PYY), neurotensin, vasoactive intestinal peptide (VIP), substance P, neuropeptide Y (NPY) and galanin. The number of different endocrine cell-types were counted per unit length of mucosa, and the density of the peptidergic nerves was assessed semiquantitatively according to a schematic scale.. JIB-patients had an increased density of CCK and somatostatin cells in the duodenal mucosa. The CCK cells displayed a changed reaction pattern, with a greater cell number reacting with an antiserum directed towards a non-amidated mid-sequence of procholecystokinin compared with the other groups. In obese unoperated patients, the density of PYY and secretin cells was decreased compared with the JIB-patients and the density of the GIP cells compared with both other groups.. JIB induces an up-regulation of somatostatin and CCK precursor-containing cells in the duodenal mucosa. The time duration after the JIB did not seem to influence the results.

Topics: Adolescent; Adult; Aged; Cell Count; Cholecystokinin; Duodenum; Enteroendocrine Cells; Female; Follow-Up Studies; Gastrins; Hormones; Humans; Jejunoileal Bypass; Male; Middle Aged; Obesity; Somatostatin; Somatostatin-Secreting Cells; Time Factors

Obesity is a polygenic disorder that is associated with gallstone disease. We have previously shown that leptin deficiency in obese mice correlates with decreased gallbladder motility, suggesting that leptin plays a role in the link between gallstone disease and obesity. However, most obese humans are leptin-resistant, and relatively few are leptin-deficient. To confirm that leptin dysfunction is responsible for impaired gallbladder motility in obese mice, we hypothesized that leptin-resistant obese mice (Lep(db)) would have abnormal gallbladder motility while obese mice with intact leptin function (Agouti Yellow, A(y)) would have normal gallbladder motility.. Eighteen lean control (C57BL/6J), 10 A(y) and 12 Lep(db) female mice were fasted overnight, weighed, and livers and gallbladders were harvested. Liver weights and gallbladder volumes were measured. Gallbladder contractile responses (N/cm(2)) to acetylcholine (10(-5)M), neuropeptide Y (10(-8,-7,-6) M) and cholecystokinin (10(-10,-9,-8,-7)M) were determined in muscle bath chambers. Results were analyzed by analysis of various (ANOVA) and with the Mann-Whitney Rank Sum Test.. Both Agouti yellow (A(y)) and leptin-resistant (Lep(db)) obese mice had body weights, liver weights and gallbladder volumes that were significantly greater (P < 0.01) than lean control mice. Leptin-resistant obese mice had gallbladder responses to acetylcholine, neuropeptide Y and cholecystokinin that were significantly less (P < 0.01) than both lean control and Agouti yellow obese mice.. These data suggest that (1). leptin-resistant obese mice (Lep(db)) have abnormal gallbladder motility and (2). obese mice with normal leptin metabolism (A(y)) have normal gallbladder response to neurotransmitters. We conclude that leptin represents a link between obesity, gallbladder motility and gallstone formation.

Topics: Acetylcholine; Animals; Cholecystokinin; Female; Gallbladder Emptying; Leptin; Mice; Mice, Obese; Neuropeptide Y; Neurotransmitter Agents; Obesity

This review focuses on the satiating effect of cholecystokinin (CCK) in humans. Current evidence supports a role for the peptide as a physiological satiety factor. The therapeutic potential of CCK analogs cannot be estimated until further studies are performed that demonstrate the efficacy of analogs for decreasing body weight, and the safety of CCK when administered chronically. Because the brain-gut axis is so important in the normal control of food intake, a great deal of caution is needed, particularly with agents that will presumably be taken for prolonged periods. Even so, at present it seems likely that we will see the introduction of CCK analogs or CCK antagonists as a new class of appetite-modulating agents in the not-too-distant future.

Topics: Anti-Obesity Agents; Cholecystokinin; Eating; Humans; Obesity; Receptors, Cholecystokinin; Satiety Response

CCK is a satiety neuropeptide. Animal studies have shown that both acute and chronic exposure to nicotine results in weight loss which is associated with an increase in hypothalamic CCK and that CCK antagonists ameliorate symptoms of nicotine withdrawal. A major detriment to smoking cessation, especially in women, is the fear of gaining weight. These observations suggested that genetic variants in the CCK gene might be a possible risk factor for smoking.. To test this hypothesis we examined the association of the C-45T promoter polymorphism in the Sp1 binding region of the CCK gene with smoking and BMI in two independent groups of subjects.. Group 1 consisted of 191 Caucasian women participating in an obesity study. The T allele was present in 15% of women who had never smoked, 20% of ex-smokers, and 58% of current smokers, P < or = 0.0014. The T allele was present in 26.8% of ever-smokers (ex-smokers + current smokers). There was no association with BMI. Group 2 consisted of 725 parents of twins from the Minnesota Twin and Family Study of substance abuse. Logistic regression analysis showed that a diagnosis of nicotine dependence was significantly associated with the T allele (P < or = 0.002) and with gender (males > females) (P < or = 0.001), but not with BMI (P < or = 0.68). The T allele was present in 15.9% of parents who had never smoked and 24.7% of ever-smokers, very similar to the results for group 1.. These results are consistent with a role of the CCK gene as a risk factor for smoking.

Topics: Adult; Alleles; Body Weight; Chi-Square Distribution; Cholecystokinin; Female; Genetic Predisposition to Disease; Genotype; Humans; Male; Middle Aged; Models, Biological; Obesity; Polymorphism, Genetic; Regression Analysis; Reproducibility of Results; Smoking; Tobacco Use Disorder; White People

Topics: Anti-Obesity Agents; Cholecystokinin; Humans; Obesity; Weight Loss

Obesity occurs in 60% of women after menopause and is characterized by an excess of adipose tissue that depends on several orexigenic (neuropeptide Y (NPY) stimulates carbohydrate ingestion, galanin stimulates fat intake) and anorectic (leptin, cholecystokinin (CCK)) factors. Both leptin and insulin can reduce hypothalamic NPY production and secretion. Behavior related to the consumption of food is probably attributed to the NPY-galanin signalling route. We investigated basal levels of serum leptin, CCK, galanin and NPY in 16 non-obese premenopausal women, in 15 obese premenopausal women (body mass index (BMI) 34.6 +/- 1.3 SD) and in ten obese postmenopausal women (BMI 34.7 +/- 1.5 SD) to determine the relationship between obesity, menopause and these neuropeptides. Obese premenopausal women had three-fold elevations of serum leptin (32.1 +/- 3.2 ng/ml) in comparison to non-obese premenopausal women (10.3 +/- 1.5 ng/ml), but similar levels to those in obese postmenopausal women (35.3 +/- 4.1 ng/ml). In all 44 patients and in both sub-groups of premenopausal and postmenopausal women, serum leptin exhibited a strong positive correlation with BMI (r = 0.8692, p < 0.0001; r = 0.8803, p = 0.0001; r = 0.8184, p = 0.0001, respectively). Serum galanin values showed a statistically significant increment in the obese postmenopausal group (51.1 +/- 8.1 pg/ml) compared to both premenopausal groups: the non-obese (34.9 +/- 5.8 pg/ml) and the obese (36.0 +/- 5.5 pg/ml). Non-obese menstruating women demonstrated NPY levels (175.0 +/- 12.8 pg/ml) significantly higher than those of obese premenopausal women (126.0 +/- 12.1 pg/ml) and obese postmenopausal women (138.1 +/- 15.4 pg/ml). CCK values showed no differences between non-obese and obese pre- and postmenopausal groups. Basal insulin values were elevated in both obese groups compared to non-obese premenopausal women. Significantly increased leptin and galanin levels in postmenopausal obese women coupled with decreased NPY levels revealed some changes in the neuropeptides regulating eating behavior, which may be the reason for the onset of postmenopausal obesity.

Topics: Body Mass Index; Cholecystokinin; Female; Follicle Stimulating Hormone; Galanin; Humans; Insulin; Leptin; Luteinizing Hormone; Menopause; Neuropeptide Y; Obesity; Postmenopause; Premenopause

Obesity is an important factor predisposing to type 2 diabetes mellitus, especially for postmenopausal women. Experimental studies provided evidences that leptin, cholecystokinin (CCK), galanin (GAL), neuropeptide Y (NPY) and insulin are involved in feeding behaviour. The aim of the study was to evaluate their possible relationships in obese and diabetic women. Three groups of postmenopausal women (FSH > 30 mIU/ml) were evaluated: 8 diabetic (mean age 56.6 +/- 6.9 y, BMI 29.8 +/- 5.3 kg/m2), 10 obese non-diabetic (mean age 49.6 +/- 5.4 y, BMI 36.0 +/- 3.7 kg/m2) and 12 non-diabetic controls (mean age 52.7 +/- 3.5 y, BMI 27.3 1.9 kg/m2). For each patient BMI and WHR were measured and calculated. Blood samples were collected at 8:00 a.m. after an overnight fast. Plasma concentrations of FSH, leptin, CCK, GAL, NPY and insulin were determined using commercial RIA kits. Mean plasma NPY concentration was significantly higher in diabetic women than in controls (190.1 pg/ml +/- 85.4 vs 120.4 +/- 36.6). Compared to controls, mean plasma leptin level was significantly higher in obese non-diabetic women (32.9ng/ml +/- 9.2 vs 18.9 +/- 9.1). No significant differences were found between obese non-diabetic and diabetic women. In diabetic subjects positive correlations were found between: CCK and leptin (r= 0.8295; P= 0.011), CCK and insulin (r=0.7832; P=0.022), leptin and insulin (r=0.9302; P=0.001). In obese subjects a positive correlation between WHR and GAL (r= 0.6624; P= 0.037) and a negative between GAL and insulin (r= -0.6795; P= 0.031) were found. In controls positive correlations were found between WHR and CCK (r=0.6412; P=0.025), GAL and insulin (r=0.630; P=0.028) and negative between CCK and NPY (r = -0.6505; P= 0.022). Our results, ie higher mean plasma NPY levels in postmenopausal diabetic women and positive correlation of CCK with leptin and insulin, may suggest the role of these neuropeptides in metabolic disorders leading to type 2 diabetes mellitus.

Topics: Body Constitution; Body Mass Index; Cholecystokinin; Diabetes Mellitus; Diabetes Mellitus, Type 2; Female; Galanin; Humans; Insulin; Leptin; Middle Aged; Neuropeptide Y; Neuropeptides; Obesity

The cardinal feature of individuals with Prader-Willi syndrome (PWS) is severe hyperphagia-mediated obesity resulting from a faulty satiety mechanism. PWS is the most common genetic cause of marked obesity. Cholecystokinin (CCK) is a 33-amino-acid peptide found in high levels in the gut and brain involved in mediating the satiety response to meals. Free fatty acids (FFA) are responsible for the stimulation of CCK release after a fatty meal, and CCK and plasma FFA levels rise in tandem in normal individuals. Fasting plasma CCK levels were measured by radio-immunoassay in 33 PWS subjects with a mean age of 22.2 years +/- 8.1 years and 24 obese control subjects without a known cause of their obesity with a mean age of 28.7 years +/- 12.9 years. Consistent with previous findings, neither fasting plasma FFA levels (617.5 versus 486.8 microm/mL) or CCK levels (21.0 versus 19.1 pg/mL) were significantly different in PWS or control subjects, respectively. However, there was a significant correlation between fasting plasma FFA and CCK levels in obese subjects (r = 0. 64, P < 0.01), this correlation was completely lacking in PWS subjects (r = -0.06, P = 0.79). This difference in correlation coefficients constitutes a large effect. There were no significant effects observed for genetic subtypes (15q11-q13 deletion or maternal disomy 15), body mass index, percentage of fat, plasma levels of insulin, C-peptide, glucagon or leptin, age, or gender on CCK levels in our PWS subjects. These results suggest that differences in the peripheral CCK response to FFA levels may be a factor contributing to the altered satiety response in PWS subjects.

Topics: Adolescent; Adult; Cholecystokinin; Fatty Acids, Nonesterified; Female; Humans; Male; Obesity; Prader-Willi Syndrome

Circulating peptide leptin which is the product of the ob gene is known to provide feedback information on the size of fat stores to central OB-receptors that control food intake. Recently, leptin messenger RNA and leptin protein have been detected in gastric epithelium and leptin was found to be released by CCK into circulation but the physiological role of this gastric leptin remains unknown. As CCK has been reported to protect gastric mucosa against various noxious agents, we designed the study to determine the influence of leptin and CCK on the gastroprotection and the control of food intake and to compare them with classic gastroprotective substance, prostaglandin E2, in rats with acute gastric mucosal lesions induced by topical application of 75% ethanol. Four series of Wistar rats (A, B, C and D) were used to determine; A) the effects of various doses of leptin (0.1-10 microg/kg) given intraperitoneally (i.p.) on ethanol-induced gastric lesions, gastric blood flow (GBF) and plasma levels of immunoreactive leptin; B) the effects of various doses of CCK-8 (0.1-10 microg/kg i.p.) on ethanol-induced gastric lesions, GBF and plasma levels of leptin; C) the effects of various doses of PGE2 (12.5--100 microg/kg) given intragastrically (i.g.) on ethanol-induced gastric lesions and GBF and D) the influence of leptin, CCK and PGE2 on the intake of liquid meal in rats. Rats were anesthetized with ether 1 h after i.g. administration of 75% ethanol to measure the GBF using H2-gas clearance technique and blood samples were withdrawn for the measurement of plasma leptin levels by radioimmunoassay (RIA). Food intake was assessed in separate group of rats fasted 18 h and then fed with liquid caloric meal. Leptin, CCK and PGE2 reduced dose-dependently gastric lesions induced by 75% ethanol, the dose reducing these lesions by 50% (ED50) being, respectively, 1 microg/kg, 5 microg/kg and 20 microg/kg. The protective effects of leptin, CCK-8 and PGE2 were accompanied by significant attenuation of the fall of the GBF caused by ethanol. Leptin and CCK reduced also dose-dependently the food intake while PGE2 was not effective. Leptin and CCK resulted a dose-dependent increment in the plasma leptin levels. We conclude that: 1) exogenous leptin and CCK, causing similar increments in plasma immunoreactive leptin levels, protect dose-dependently gastric mucosa against the damage provoked by 75% ethanol; 2) Leptin and CCK afford similar gastroprotective activity to that attaine

Topics: Adipose Tissue; Animals; Cholecystokinin; Digestive System; Dinoprostone; Eating; Ethanol; Gastrointestinal Diseases; Leptin; Male; Obesity; Prostaglandins; Proteins; Rats; Rats, Wistar

The present study evaluates long-term effects of the CCK-agonist caerulein and the CCK-A antagonist loxiglumide in obese and lean Zucker rats. Caerulein and loxiglumide altered food intake neither in obese nor in lean rats. By as yet unknown mechanisms, however, weight increase was accelerated by loxiglumide and reduced by caerulein in obese and lean rats. Caerulein increased pancreatic weight only in lean but not in obese rats. Thus, obese rats show a resistance of pancreatic CCK-A receptors. The failure of CCK-agonist and -antagonist to alter food intake suggests that this CCK-resistance is not responsible for obesity in the genetically altered rats.

Topics: Animals; Body Weight; Ceruletide; Cholecystokinin; Drug Resistance; Eating; Female; Male; Obesity; Organ Size; Pancreas; Proglumide; Rats; Rats, Zucker; Receptor, Cholecystokinin A; Receptors, Cholecystokinin; Satiety Response

Topics: Cholecystokinin; Energy Metabolism; Humans; Insulin; Obesity; Uncoupling Agents

Otsuka Long-Evans Tokushima Fatty (OLETF) rats develop obesity, hyperglycemia, and non-insulin-dependent diabetes mellitus and do not express cholecystokinin A (CCK-A) receptors, the receptor subtype mediating the satiety actions of CCK. In short-term feeding tests, male OLETF rats were completely resistant to exogenous CCK, and their response to bombesin was attenuated. Comparisons of liquid meal consumption in OLETF and control Long-Evans Tokushima (LETO) rats demonstrated that 1) OLETF rats had greater intakes during 30-min scheduled daytime meals and significantly larger and fewer spontaneous night-time meals and 2) although the initial rates of licking were the same, OLETF rats maintained the initial rate longer and the rate at which their licking declined was slower. In 24-h solid food access tests, OLETF rats consumed significantly more pellets than LETO controls, and this increase was attributable to significant increases in meal size. Together, these data are consistent with the interpretation that the lack of CCK-A receptors in OLETF rats results in a satiety deficit leading to increases in meal size, overall hyperphagia, and obesity.

Topics: Animals; Body Weight; Bombesin; Cholecystokinin; Circadian Rhythm; Eating; Glucose; Male; Obesity; Rats; Rats, Inbred Strains; Receptor, Cholecystokinin A; Receptors, Cholecystokinin; Satiation

To investigate whether total body fat mass or fat distribution and associated metabolic disturbances in glucose and lipid metabolism influence the well known gallstone pathogenetic factors in obese subjects in order to explain why some obese subjects develop gallstones and some do not.. Cross sectional study of gallstone pathogenetic factors, body composition, fat distribution, glucose and lipid metabolism.. 57 healthy overweight subjects (aged 26-64y, body mass index (BMI) 30-45 kg/m2).. Total and intra-abdominal fat masses were measured by dual X-ray absorptiometry and abdominal CT scanning, respectively. The lithogenic index was measured in aspirated bile. The gallbladder volume was determined by ultrasound and the gallbladder ejection fraction% by dynamic cholescintigraphy. Plasma cholecystokinin (CCK) concentrations during a meal were measured with a specific radioimmunoassay. Insulin sensitivity was measured by the Minimal Model and glucose tolerance by an oral glucose tolerance test (OGTT). Serum lipid concentrations were measured by standard methods.. The gallbladder volume in the fasting state increased with increasing intra-abdominal fat mass (P=0.006) and was increased in subjects with impaired glucose tolerance (41 vs 27 ml, P=0.001). The lithogenic index was > 1 in all subjects and correlated with total fat mass (P=0.04).. Gallstone pathogenesis in obesity seems to be influenced by the total body fat mass and its regional distribution possibly via mutual association with the glucose tolerance.

Topics: Abdomen; Absorptiometry, Photon; Adipose Tissue; Adult; Blood Glucose; Body Composition; Cholecystokinin; Cholelithiasis; Cohort Studies; Cross-Sectional Studies; Dietary Fats; Fasting; Female; Gallbladder; Glucose Intolerance; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Lipids; Male; Middle Aged; Obesity; Tomography, X-Ray Computed

Satiety plays an important role in weight control. The meaning of fasting hormone levels and satiety feelings, and how post-absorptive changes after meals high in carbohydrate regulate appetite remains to be demonstrated.. Prospective metabolic study with 25 non-diabetic obese women at the Energy Metabolism Research Unit of the Department of Nutrition Sciences, University of Alabama at Birmingham. We analyzed fasting and postprandial ratings of hunger-satiety and values of various metabolic parameters (serum glucose and insulin, plasma cholecystokinin, respiratory quotient) during controlled weight loss. The postprandial measures were assessed following a test meal providing 320 kcal and yielding a food quotient of 0.89.. In the fasting state, there was no correlation between hunger-satiety ratings and any of the measured metabolic parameters. Under postprandial conditions, satiety was positively related to glucose (p=0.002) and insulin (p=0.002) responses to the test meal. In multivariate analysis including glucose, insulin, cholecystokinin, hunger-satiety ratings and respiratory quotient, insulin was the only independent predictor of satiety in the postprandial state.. These data suggest an association between the endogenous insulin response and feelings of postprandial satiety. Insulin's satiation properties, which could well be mediated by other hormones, may represent a primary factor of food intake regulation after meals relatively high in carbohydrate.

Topics: Adult; Blood Glucose; Cholecystokinin; Energy Intake; Fasting; Female; Food; Humans; Hunger; Insulin; Middle Aged; Multivariate Analysis; Obesity; Oxygen Consumption; Prospective Studies; Satiation; Weight Loss

Neuropeptides play an important role in the integration of dietary signals. Cholecystokinin (CCK) has been implicated in regulating ingestive behavior, particularly satiety. The primary objective of this study was to examine whether the hyperphagia characteristic of obese (fa/fa) rats involves impaired neural CCK secretion. Dynamic release of CCK at the hypothalamic paraventricular nucleus (PVN) of age-matched lean (Fa/Fa) and obese Zucker rats was determined using push-pull perfusion. The gavage of a 10.3-kcal (6 ml) liquid diet during lights off was followed by increased CCK release in lean rats (from 13.6 +/- 1.1 to 22.1 +/- 1.4 fmol in the 1st postprandial period and 18.4 +/- 2.5 fmol in the 2nd postprandial period). An identical meal load resulted in no postprandial increase in CCK release in obese rats, despite the fact that high-K+ artificial cerebrospinal fluid evoked CCK outflow in all animals. Intubation of 6 ml of nonnutritive 1% carboxymethylcellulose had no effect. These results are consistent with the suggestion that hypothalamic CCK plays a physiological role in satiety, and they demonstrate that obese Zucker rats have blunted hypothalamic CCK release in response to dietary cues.

Topics: Animals; Cholecystokinin; Darkness; Eating; Energy Intake; Hyperphagia; Light; Male; Obesity; Paraventricular Hypothalamic Nucleus; Postprandial Period; Rats; Rats, Zucker; Thinness; Time Factors

The fat mouse strain exhibits a late-onset obesity syndrome associated with a mutation in the gene encoding carboxypeptidase E (CPE). CPE plays a central role in the biosynthesis of many regulatory peptides. Therefore, we examined the processing of procholecystokinin (proCCK) in the brain (neurons) and small intestine (endocrine cells) of fat/fat mice. In the brain, bioactive CCK was markedly reduced (7.9+/-1.0 pmol/g in fat/fat mice vs. 82.5+/-11.2 pmol/g in controls), but the concentration of the CPE substrate, glycylarginine-extended CCK, was elevated 105-fold. In contrast, the concentration of bioactive CCK in intestinal endocrine cells was unaffected. Endocrine cell processing was, nevertheless, altered with a 33-fold increase in glycyl-arginine-extended CCK. Interestingly, although total proCCK products were normal in the brain they were elevated 3-fold in the intestine, indicating that biosynthesis is upregulated in endocrine cells but not neurons to compensate for the processing defect. These results demonstrate that the CPE mutation differentially affects CCK processing in these two cell types. Intestinal CCK synthesis more closely resembles progastrin processing, suggesting the presence of an endocrine-specific biosynthetic regulatory mechanism not present in neurons.

Topics: Animals; Brain; Carboxypeptidase H; Carboxypeptidases; Cholecystokinin; Enteroendocrine Cells; Heterozygote; Mice; Mice, Mutant Strains; Neurons; Obesity; Protein Precursors; Protein Processing, Post-Translational

To measure leptin, insulin and cholecystokinin (CCK) concentrations in obese women on calorie restriction and to determine their correlation with hunger-satiety ratings. Although it has been proposed to play a role in appetite regulation, the effects of physiological concentrations of these hormones on hunger-satiety in humans have not yet been well established.. Prospective metabolic study. A two week 'wash-in period' followed by a three-week observation period, during which each subject underwent six measurements of satiety, blood parameters and body weight.. Energy Metabolism Research Unit, Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, Alabama, USA.. 22 moderately to severely overweight women (mean age: 45 +/- 8 y; body mass index (BMI): 33 +/- 6 kg/m2).. Energy restriction, in the form of a 3.3 MJ (800 kcal) diet during five weeks.. Fasting blood levels of leptin, insulin, glucose and CCK, fasting hunger-satiety scores and body weight.. The mean (+/- s.d.) fasting serum leptin concentration at the beginning of the observation period was 26.1 +/- 15.9 ng/ml (range: 6.7-59.8 ng/ml). Leptin concentrations correlated positively with body weight (P < 0.0001). Furthermore, reductions in body weight were associated with decreases in fasting leptin levels (P = 0.002). Leptin concentrations correlated with serum levels of insulin (P = 0.0001) and CCK (P = 0.06), but in multivariate analysis including insulin, CCK and glucose, only leptin had a significant relationship with satiety (P = 0.04). This relationship was linear.. These results confirm the association between leptin levels, body weight and serum insulin. We also showed that higher serum leptin levels correlated with greater feelings of fullness, a relationship which was not blunted in the more obese subjects. These findings suggest that leptin is a satiety hormone that reduces appetite, even in obese individuals, and that weight gain must be due to other factors, overriding this feed-back regulation.

Topics: Adult; Appetite; Black People; Body Weight; Cholecystokinin; Female; Humans; Hunger; Insulin; Leptin; Middle Aged; Obesity; Prospective Studies; Proteins; Satiety Response; White People

Topics: Animals; Cholecystokinin; Gastric Mucosa; Gastrointestinal Hormones; Humans; Leptin; Neurotransmitter Agents; Obesity; Proteins

Topics: Cholecystokinin; Humans; Hypothalamus; Lipoprotein Lipase; Neuropeptides; Obesity

Obese Zucker rats are less sensitive to the satiety effect of CCK than lean litter mates. The present studies further characterised this CCK resistance. Subcutaneous injection of the CCK agonist caerulein dose-dependently decreased food intake in Zucker obese and lean rats whereas the CCK-B agonist gastrin-17 did not. Caerulein at 4 microg/kg, which resulted in CCK plasma bioactivity slightly above postprandial levels, decreased food intake in lean rats but not in obese rats. The decrease in food intake was also more marked at higher caerulein doses (20-100 microg/kg) in lean versus obese rats. In lean animals the satiety effects of the "near physiological" 4 microg/kg caerulein dose was abolished after blockade of vagal afferents with capsaicin, whereas the effects of higher caerulein doses were not. CCK-stimulated amylase secretion from pancreatic acini and binding capacity of 125I-labelled CCK-8 were decreased in obese versus lean rats. The CCK-A antagonist loxiglumide at 20 mg/kg, a dose which abolished the action of all caerulein doses on food intake, failed to alter the food intake either in obese or in lean rats when given without an agonist. The results suggest that the satiety effects of "near physiological" doses of caerulein in lean rats are mediated by vagal afferents whereas pharmacological doses act via non-vagal mechanisms. The differences in CCK's satiety effect between lean and obese rats may be due to differences in CCK-receptor binding and action at peripheral vagal sites. However, the failure of the CCK-A antagonist to increase food intake questions whether any of the effects of exogenous CCK are of physiological relevance.

Topics: Amylases; Animals; Capsaicin; Cholecystokinin; Eating; Female; Injections, Subcutaneous; Male; Obesity; Proglumide; Rats; Rats, Zucker; Receptors, Cholecystokinin

In order to assess the possible role of carboxypeptidase E (Cpe) in pro-CCK processing, tissues from the Cpe(fat)/Cpe(fat) mice were analyzed for CCK content and molecular forms using specific RIAs directed against different portions of the prohormone. Levels of amidated CCK were decreased by about 74% in whole brain of Cpe(fat)/Cpe(fat) mice in comparison to control mice, while levels of amidated CCK in intestine were only reduced by about 36%. In contrast, using an antiserum specific for CCK Gly Arg Arg, Cpe(fat)/Cpe(fat) mice brain had about 13-fold higher levels of this peptide relative to controls, while levels were identical in mutant and control duodenal tissue. This study demonstrates a regional difference in the involvement of Cpe in pro-CCK processing. The accumulation of CCK Gly Arg Arg in Cpe(fat)/Cpe(fat) brains provides definitive proof that the dibasic cleavage of the carboxyl terminus of pro CCK occurs on the carboxyl terminal of the dibasic, between the Arg and Ser as well as confirming that amidated CCK 8 in brain originates from CCK 8 Gly Arg Arg rather than from larger amidated peptides like CCK 22 or CCK 33. The Cpe(fat)/Cpe(fat) mouse phenotype obviously involves multiple endocrine defects, however, it is tempting to speculate that this severe CNS deficiency in CCK 8 may be related to the adult-onset obesity seen in this mutant mouse.

Topics: Animals; Brain; Carboxypeptidase H; Carboxypeptidases; Cholecystokinin; Duodenum; Mice; Mice, Mutant Strains; Obesity; Point Mutation; Protein Precursors

A radioimmunoassay has been developed for the determination of ARL 15849XX, a cholecystokinin-8 (CCK-8) analogue, in dog plasma. The method incorporates solid-phase sample extraction and is suitable for the determination of the analyte at picogram per millilitre concentrations. The antiserum was raised in Suffolk-cross sheep following primary and booster immunisations with an immunogen prepared by conjugating ARL 16935XX, an analogue of ARL 15849KF, to bovine serum albumin. The radioligand was prepared by the no-carrier-added 125I iodination of a non-sulphated derivative, ARL 15745XX. The solid-phase extraction procedure, carried out using ion-exchange aminopropyl and octadecyl sorbents sequentially, was introduced to remove matrix interferences in the plasma and to enhance the method sensitivity. The calibration range is 20-1000 pg ml-1, using a 1 ml sample of undiluted dog plasma.

Topics: Amino Acid Sequence; Animals; Calibration; Chemistry Techniques, Analytical; Cholecystokinin; Cross Reactions; Dogs; Drug Stability; Molecular Sequence Data; Obesity; Radioimmunoassay; Receptor, Cholecystokinin A; Receptors, Cholecystokinin; Reproducibility of Results; Sensitivity and Specificity

Clinical as well as experimental studies in insulinopenic diabetes mellitus have demonstrated abnormal pancreatic exocrine responses to cholecystokinin (CCK). In the present study, we examined pancreatic exocrine and endocrine function in the recently developed genetically diabetic Otsuka Long-Evans Tokushima fatty (OLETF) rats and compared them with those in the control Long-Evans Tokushima Otsuka (LETO) rats of the same age. Stepwise increasing doses of CCK octapeptide (CCK-8; 0.027-7.0 nmol.kg-1.h-1) evoked a characteristic biphasic dose-response curve for pancreatic juice and protein output in the LETO rats, whereas the OLETF rats were totally insensitive to CCK-8 stimulation. However, the responsiveness and the sensitivity to both carbamylcholine and secretin were similar in the two groups. Intraduodenal infusion of casein (500 mg/h) failed to stimulate pancreatic exocrine secretion in the OLETF rats despite a greater CCK response than in the LETO rats (peak response: 8.43 +/- 0.97 vs 5.12 +/- 0.30 pmol/l in LETO, P < 0.01). Intravenous infusion of CCK-8 (4.4 nmol.kg-1.20 min-1) caused a significant increase in serum insulin concentrations and a concomitant decrease in glucose levels in the LETO rats but not in the OLETF rats. On the other hand, an intravenous bolus injection of 1.1 mmol/kg glucose caused a greater insulin release in the OLETF rats than in the LETO rats. In contrast, gastric acid secretion in the OLETF rats was significantly high in basal and in response to intravenous infusion of CCK-8 compared with that in the LETO rats. Four subcutaneous injections of 20 micrograms/kg caerulein at hourly intervals over 3 h induced acute pancreatitis in the LETO rats but did not elicit any significant increase in serum amylase or lipase activities and pancreatic wet weight or histological evidence of acute pancreatitis in the OLETF rats. These results indicate that the exocrine and endocrine pancreas of the recently developed genetically diabetic OLETF rats are totally and specifically insensitive to exogenous and endogenous CCK stimulation, whereas parietal cells in these rats are sensitive to CCK stimulation.

Topics: Acute Disease; Animals; Carbachol; Caseins; Ceruletide; Cholecystokinin; Duodenum; Gastric Acid; Glucose; Injections; Insulin; Islets of Langerhans; Male; Obesity; Pancreas; Pancreatitis; Rats; Rats, Inbred Strains; Secretin; Sincalide

Cholecystokinin 33 (CCK) was infused intravenously to eight healthy obese women and 10 healthy lean women of the same age, in doses that elicited plasma cholecystokinin concentrations in the physiological range. The effect of these infusions after a standardised banana 'shake' (preload) on food intake and satiety signals was compared with the effect of saline infusions in the same subjects. For the whole group food intake (mean (SEM)) (282 (29 g)) was significantly less during CCK than during saline (346 (31) g, p < 0.05). Hunger feelings tended to be less during CCK infusions. Examination of the separate subgroups showed no differences between lean and obese subjects in the satiety effects of CCK. In conclusion, under the conditions of this study, CCK significantly decreases food intake in humans, and this effect is similar for lean and obese subjects.

Topics: Adult; Cholecystokinin; Eating; Female; Humans; Hunger; Obesity; Satiation; Time Factors

Topics: Bulimia; Cholecystokinin; Diet, Reducing; Energy Intake; Humans; Obesity; Satiation

This work expands recent observations that Otsuka Long-Evans Tokushima Fatty (OLETF) rats show little or no pancreatic expression of the cholecystokinin (CCK)-A receptor gene. We examined whether the CCK-A and -B receptor genes were expressed in the brain (hypothalamus) of OLETF rats in comparison with control (Long-Evans Tokushima Otsuka = LETO) rats. CCK-A receptor mRNA was detected in the hypothalamus of LETO rats but not OLETF rats. The CCK-B receptor gene was expressed in the hypothalamus in both strains. Cerebroventricular administration of CCK-8 sulfate inhibited daily food intake in LETO rats, but not in OLETF rats. These results show that in OLETF rats the absence of CCK-A receptor gene expression in the hypothalamus results in hyperphagia because of lack of satiety.

Topics: Animals; Base Sequence; Cholecystokinin; Diabetes Insipidus; Hyperphagia; Hypothalamus; Male; Molecular Sequence Data; Obesity; Polymerase Chain Reaction; Rats; Rats, Mutant Strains; Receptor, Cholecystokinin A; Receptors, Cholecystokinin; Satiation; Sincalide

Disturbed satiety mechanisms may contribute to obesity. There has been speculation that cholecystokinin (CCK) and pancreatic polypeptide (PP) are involved in the regulation of satiety. We have therefore investigated whether there are differences between healthy lean and healthy non-diabetic obese volunteers in plasma CCK or PP release after a neuropeptidergic stimulation with bombesin and after infusion of a mixed meal. There were no differences in plasma CCK between groups either basally or in response to either form of stimulation. However, the plasma PP concentrations after the meal were significantly less in obese (2845 +/- 404 pM.min) than in lean subjects (5569 +/- 997 pM.min), whereas the plasma PP concentrations during bombesin were similar in both groups. We tested two other groups of nine obese and lean subjects to determine whether a disturbed vagal function could be the cause of the diminished plasma PP in obese persons, by studying the effect of modified sham feeding (MSF) on plasma PP. However, there were no significant differences in the plasma PP response to MSF between lean and obese subjects. We conclude that there are no differences between lean and obese persons in plasma CCK secretion in response to infusion of the neuropeptide bombesin or to ingestion of a mixed meal. However, the plasma PP after a mixed meal, is markedly diminished in obese subjects. This could not be attributed to a disturbed vagal cephalic stimulation.

Topics: Adult; Blood Glucose; Bombesin; Cholecystokinin; Female; Food; Humans; Kinetics; Male; Obesity; Pancreatic Polypeptide

Cholecystokinin (CCK) inhibits gastric emptying and may exert satiety effects in several species, including humans. Because the effects of physiological doses of CCK on satiety in humans is unclear, the satiety effects of CCK-33 in physiological levels in lean and obese subjects were studied.. CCK-33 was infused intravenously to 32 healthy men or women (14 obese, all women; 18 lean, 4 men and 14 women) in doses that elicited plasma CCK concentrations in the physiological range. The effects of these infusions on feelings of hunger, wish to eat, fullness, and prospective feeding intentions were measured on visual analogue scales and compared with saline during a 1-hour infusion period.. The CCK infusions induced significant decreases in hunger feelings, wish to eat, and prospective feeding intentions (P < 0.05), whereas fullness tended to be increased (P = 0.054). No clear differences between lean and obese subjects were observed apart from a more marked decrease in fullness and increase in prospective feeding intentions during the 1-hour saline infusion in the lean group (P < 0.05).. CCK infusion leading to physiological plasma levels significantly increases satiety in humans.

Topics: Adult; Cholecystokinin; Female; Humans; Infusions, Intravenous; Male; Obesity; Osmolar Concentration; Reference Values; Satiety Response

Based on a large number of studies in various species, cholecystokinin (CCK) is considered to function as an important regulator of satiety. The present study was undertaken to determine the relationship between hunger score and basal and postprandial plasma CCK secretion, in six obese subjects before and after weight loss with modified fasting. Modified fasting (modifast, 240 kcal/day) for ten weeks induced a mean weight loss of 23 kg. The hunger score was reduced by about 75%. However, basal and plasma CCK release induced by 80 kcal of modifast were not different before and after ten weeks of modifast treatment. Thus, the reduction of hunger during modified fasting is not mediated by circulating CCK.

Topics: Adult; Cholecystokinin; Diet, Reducing; Energy Intake; Female; Humans; Hunger; Male; Obesity; Weight Loss

CCK-33 was infused intravenously to groups of 9 lean and 9 obese volunteers in doses that elicited plasma CCK concentrations in the physiological range. The effect of these infusions on food intake and satiety signals was compared with the effect of saline infusions in the same subjects. Food intake (486 +/- 52 g; mean +/- S.E.M.) was slightly, but not significantly decreased (553 +/- 55 g after saline), and hunger and fullness feelings after eating were unaffected, in both of the two groups. We conclude that the infusion of CCK-33 to plasma levels comparable to those observed after a fatty meal does not have a major effect on food intake and postprandial hunger feelings.

Topics: Adult; Cholecystokinin; Eating; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Obesity; Satiation

Topics: Cholecystokinin; Cholelithiasis; Dietary Fats; Gallbladder; Humans; Muscle Contraction; Obesity

Plasma concentrations of regulatory peptides were monitored in groups of obese and normal-weight subjects following modified sham feeding and a liquid fatty meal. Following modified sham feeding a significant increase in immunoreactive cholecystokinin (CCK) in plasma was recorded in both groups. In the obese subjects, however, the concentrations following sham feeding were significantly lower than in normal-weight subjects, and the initial part of the response was negative. Basal and modified sham feeding stimulated immunoreactive pancreatic polypeptide (PP) concentrations in plasma did not differ between the groups. After the liquid fatty meal plasma CCK concentrations increased similarly in both groups. In contrast immunoreactive neurotensin and somatostatin concentrations following the meal were lower in the obese group, and a changed concentration-time pattern for somatostatin was observed in the obese group. Postprandial concentrations of PP and immunoreactive gastrin were not different in the groups. The results indicate that the plasma concentration patterns of CCK, somatostatin and NT are disarranged in obesity. The changes may promote rapid propulsion and absorption of ingested food, and facilitate deposition of fat in adipose tissue in obesity and thus may be of pathophysiological importance.

Topics: Adult; Blood Glucose; Cholecystokinin; Female; Food; Gastrins; Humans; Middle Aged; Neurotensin; Obesity; Pancreatic Polypeptide; Radioimmunoassay; Somatostatin

Cholecystokinin (CCK) is a neuropeptide which is present in brain and intestine and which stimulates gall bladder contraction and pancreatic secretion. Additional studies have demonstrated an appetite-suppressing effect of CCK in vivo. These data have aroused speculation that the physiology of this hormone could be relevant in the pathogenesis of the mouse obesity mutations ob on chromosome 6 and db on chromosome 4. In order to determine whether abnormalities of this hormone could be the primary defect in these obesity mutations, we have used three separate approaches to map the mouse Cck gene to distal chromosome 9, where it is part of a syntenic group between mouse chromosome 9 and human chromosome 3. These data therefore exclude cholecystokinin as the etiologic factor in the pathogenesis of any of the known mouse obesity syndromes. In order to exclude the possibility that there are differences in mutant animals in the level of CCK RNA, we have used an S1 nuclease protection assay as well as a novel radioimmunoassay that detects the CCK precursor, to show that there are no gross differences in CCK mRNA or protein precursor levels between ob/ob and wild-type animals.

Topics: Alleles; Animals; Blotting, Southern; Cholecystokinin; Chromosome Mapping; Cricetinae; Crosses, Genetic; DNA; Gene Expression; Hybrid Cells; Mice; Mice, Inbred Strains; Models, Genetic; Mutation; Obesity; Polymorphism, Restriction Fragment Length; Protein Precursors; Radioimmunoassay; Rats; RNA, Messenger

Children with Prader-Willi syndrome (PWS) are characterized by obesity, hyperphagia, hypogonadism, and mental retardation with underlying hypothalamic dysfunction and are known to have blunted or absent pancreatic polypeptide (PP) secretion in response to protein meals. In this communication, adults (26 +/- 3 years of age) with PWS were compared with age-matched normal obese and normal weight controls in regards to plasma glucose, insulin, PP, cholecystokinin (CCK), cholesterol, and triglyceride after a high protein meal. Compared with normal weight controls, adults with PWS showed a smaller and delayed rise in plasma insulin, and relatively smaller and delayed PP elevation whereas obese controls revealed hyperglycemia, markedly higher insulin, and moderately higher PP, cholesterol, and triglyceride levels than those with PWS. There was a small increment of CCK levels after a protein meal in all groups of adults. After a protein meal, the molar ratio of PP to CCK doubled in normal weight and PWS groups, and this ratio tripled in the normal obese group, suggesting no reduced PP secretion in PWS in response to CCK stimulation. PP hyposecretion in PWS thus appears to be a part of multiple endocrinopathy associated with hypothalamic dysfunction.

Topics: Adult; Cholecystokinin; Cholesterol; Dietary Proteins; Female; Humans; Insulin; Male; Obesity; Pancreatic Polypeptide; Prader-Willi Syndrome; Triglycerides

Populations eating low-fat or low-fat, high-fiber diets have lower mortality rates for many cancers and coronary heart disease. The importance of nutrient composition in the lumen on absorption and on function of the gastrointestinal tract as a factor in the development of these diseases has not been studied. We investigated the plasma levels of gut-CNS peptide hormones in lean and obese Dutch women fed a high-fat meal and administered cholecystokinin (CCK). After a high-fat meal the increase in plasma CCK was similar in lean and obese women. CCK administration significantly decreased insulin release in lean and obese women, decreased glucagon release in obese women, but caused a rapid increase in plasma glucagon in lean women. Although the CCK response was similar to a fat meal in lean and obese women, differences in the control of peptide hormone release occurred in response to fat meals and CCK administration.

Topics: beta-Endorphin; Cholecystokinin; Cholesterol; Coronary Disease; Diet; Diet, Vegetarian; Dietary Fiber; Female; Gastrins; Glucagon; Humans; Insulin; Lipids; Middle Aged; Neoplasms; Obesity; Risk Factors

Topics: Animals; Cholecystokinin; Esophagus; Gastric Acid; Gastric Emptying; Gastrins; Humans; Intestine, Small; Obesity; Stomach

We previously found that massively obese patients respond with less gastric acid secretion in response to vagal stimulation. This is compatible with the described association between experimental obesity and altered vagal function in the rat. To confirm this observation, the pancreatic and biliary responses to vagal stimulation were examined in nine nondiabetic obese patients against a background secretin infusion of 15 CU x h-1, and monitored after a subsequent injection of 75 IDU of cholecystokinin. Two separate marker perfusion systems were used in the stomach and duodenum, respectively, and blood samples were drawn for hormone analyses. In contrast to controls having normal body weight, the obese patients failed to respond with increments of pancreatic enzyme secretion and duodenal bile acids after stimulation with modified sham feeding. Cholecystokinin stimulated the pancreatic secretion of trypsin, amylase, and lipase, the emptying of bile acids, and the release of gastrin, but the patients' responses were only half that of the controls. In the resting state the obese had higher outputs of bile and pancreatic enzymes and higher plasma levels of pancreatic polypeptide compared with controls, but the pancreatic bicarbonate secretion rate was not different. The almost complete suppression of the basal gastric acid secretion by a low dose of intravenous (IV) secretin in controls did not occur in the obese. We conclude that massive obesity is associated with a reduced pancreatic and biliary response to vagal stimulation. Compared with controls, the digestive functions of the obese patients seem to be less sensitive to stimulation by exogenous cholecystokinin.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Bile; Blood Glucose; Cholecystokinin; Female; Gastric Acid; Humans; Insulin; Male; Middle Aged; Obesity; Pancreas; Vagus Nerve

Topics: Animals; beta-Endorphin; Brain; Cholecystokinin; Endorphins; Hypothalamus; Mice; Neuropeptides; Neurotransmitter Agents; Obesity

Cholecystokinin (CCK) and Bombesin (BBS) are two neuropeptides which induce changes in monoamines in the brain after peripheral administration. A vagal mediation of these effects was investigated since the satiety responses to both peptides are affected differently by vagotomy. This work was performed on genetically obese and lean Zucker rats and on "cafeteria-fed" and lean Sprague-Dawley rats as the effects of the peptides are dissimilar in these different groups. Vagotomy either inhibited or potentiated the peptide-induced effects, or created new variations. With CCK, the inhibition occurred mainly in the serotonergic system and in the Zucker strain, while new effects appeared in the dopaminergic system of lean rats of both strains. With bombesin, vagotomy inhibited the effects in the dopaminergic system in all lean rats, while new effects were observed in the serotonergic system in the Zucker strain. These data enable the differentiation of the mechanisms of action of both peptides and their selective effects, according to the strain of rat and the presence or absence of obesity.

Topics: Animals; Body Weight; Bombesin; Brain; Cholecystokinin; Female; Neurotransmitter Agents; Obesity; Rats; Rats, Inbred Strains; Rats, Zucker; Vagotomy

The effect of jejunoileal bypass in lean and obese Zucker rats on a number of enteroendocrine cell types was investigated 5 weeks following surgery to remove 80 percent of the small bowel from continuity. The endocrine cells containing somatostatin, cholecystokinin, gastric inhibitory polypeptide, enteroglucagon and neurotensin were investigated. In control rats enteroglucagon cell number was decreased in obese compared to lean animals (5 +/- 1 vs 11 +/- 1 cells/mm). Following jejunoileal bypass the enteroglucagon cell population increased two-fold in both the functional and bypassed bowel in obese rats but was not elevated in lean animals. A significant increase in the number of cholecystokinin cells in the bypassed loop of the jejunum in both lean and obese bypassed rats was observed. The cholecystokinin cell population was also markedly elevated in the functional jejunum of obese but not lean bypassed rats. Only small changes were noted in cell numbers of gastric inhibitory polypeptide, somatostatin and neurotensin containing cells, suggesting that individual cell types have specific stimuli for proliferation. Epithelial height, a measure of intestinal adaptation, was similar in lean and obese rats in both the control and bypassed states, but weight loss in obese bypassed animals was significantly greater than that of lean bypassed rats. The hyperinsulinemia of obese rats was only partially normalized by jejunoileal bypass. These data indicate that jejunoileal bypass has effects on specific enteroendocrine cells which differ between lean and obese Zucker rats, and between individual cell types.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Cholecystokinin; Gastric Inhibitory Polypeptide; Glucagon-Like Peptides; Ileum; Jejunoileal Bypass; Jejunum; Neurotensin; Obesity; Rats; Rats, Zucker; Somatostatin

The regulation of energy reserves is modified by both the autonomic nervous system and the hormonal milieu. The activity of the two limbs of the autonomic nervous system shows a reciprocal response to stimulation or damage in either the ventromedial or the lateral hypothalamus. Ventromedial hypothalamic lesions decrease the activity of the sympathetic nervous system and increase the activity of the vagus nerve. Lateral hypothalamic lesions, on the other hand, increase the activity of the sympathetic nervous system. Central neurotransmitters involved in energy balance include the monoamines, amino acids, and peptides. Removal of adrenal steroids by adrenalectomy reverses or attenuates all forms of obesity by reducing food intake and possibly by increasing energy expenditure. Acute insulin injections increase food intake, but chronic injections may reduce it. A model showing the reciprocal relation of sympathetic activity to energy reserves is presented.

Topics: Animals; Autonomic Nervous System; Cats; Chickens; Cholecystokinin; Dogs; Eating; Endocrine Glands; Energy Metabolism; Glucocorticoids; Gonadal Steroid Hormones; Growth Hormone; Haplorhini; Humans; Hyperphagia; Hypothalamus; Hypothalamus, Middle; Insulin; Mice; Neurotransmitter Agents; Obesity; Paraventricular Hypothalamic Nucleus; Rats; Satiation; Thyroid Hormones; Vagus Nerve

Evidence suggests that the satiety responses to peripherally administered CCK are mediated by a CNS component(s). Since CCK concentrations in the hypothalamus can change with degree of hunger, they may also be involved in the feeding response to peripherally administered CCK. Six-hr fasted rats were administered saline or 2 micrograms/kg CCK-8 and half were allowed to eat a meal. They were sacrificed after a meal or after the fast and hypothalamic content of CCK was measured by RIA. In rats injected with CCK, compared with those injected with saline, CCK concentrations were decreased in the ventromedial hypothalamus (VMH, 39 vs. 47 pg/mg tissue, p less than 0.004) and dorsomedial hypothalamus (17 vs. 21 pg/mg, p less than 0.009) and increased in the lateral hypothalamus (28 vs. 19 pg/mg, p less than 0.01). CCK concentrations in fed compared with fasted rats were higher in the VMH (47 vs. 39 pg/mg, p less than 0.002) and in obese compared with lean rats CCK concentrations were higher in the paraventricular nucleus (48 vs. 38 pg/mg, p less than 0.05), suprachiasmatic nucleus (46 vs. 34 pg/mg, p less than 0.008) and VMH (52 vs. 34 pg/mg, p less than 0.001). Since peripheral injections of CCK influenced concentrations of CCK in hypothalamic areas associated with feeding, these results provide evidence that the feeding response to peripherally injected CCK may be mediated by changes in CCK content of specific brain areas.

Topics: Animals; Brain; Cholecystokinin; Fasting; Female; Hypothalamus; Obesity; Olfactory Bulb; Pituitary Gland; Radioimmunoassay; Rats; Rats, Zucker; Tissue Distribution

The interactions between cholecystokinin (CCK) and brain monoamines have been investigated. The data found in the literature are quite dissimilar. Several reasons for these disparities have been suggested. We have sought to test some of them, such as the strain of rat, the nutritional state (by the use of two models of obesity), the length of the peptide (CCK 8 and CCK 33), the route of administration (i.p. and i.c.v.) and the time of sacrifice. We indeed found all these experimental conditions to be the cause of differential effects on brain monoamines and metabolites. However, by repeating the same experiments several times, we did not always obtain the same variations, even under the same conditions. In addition to the different parameters tested, another source of variability exists, possibly due to the molecule itself or to seasonal variations.

Topics: Animals; Biogenic Amines; Brain Chemistry; Cholecystokinin; Female; Injections, Intraperitoneal; Injections, Intraventricular; Obesity; Rats; Rats, Inbred Strains; Rats, Zucker

In order to study the mechanisms influencing bile acid pool size and cholesterol saturation index of fasting gall bladder bile, eight obese volunteers were placed on a low calorie diet for six weeks, and given intramuscular injections of a pharmacological dose of cholecystokinin octapeptide (CCK-OP, 5 micrograms) at mealtimes for half that period (alternating order). During CCK-OP administration, postprandial emptying of the gall bladder (mean +/- SEM) increased from 58 +/- 11% to 82 +/- 5% (p less than 0.005), and small intestinal transit time decreased from 205 +/- 27 to 178 +/- 26 minutes (NS). Bile acid pool size decreased from 4.6 +/- 0.3 to 3.1 +/- 0.3 mmol (p less than 0.001), while fractional turnover rate for chenodeoxycholic acid increased from 0.23 +/- 0.02 to 0.36 +/- 0.03 per day (p less than 0.005), suggesting an increase in recycling frequency of the pool. Synthesis rate was unchanged (0.43 +/- 0.08 vs 0.44 +/- 0.07 mmol/day), suggesting a new steady state. The cholesterol saturation index of fasting gall bladder bile increased in all subjects from 1.3 +/- 0.1 to 1.6 +/- 0.1 (p less than 0.005). Fasting gall bladder volume was reduced from 29 +/- 4 to 20 +/- 7 ml (p less than 0.01). Fractional turnover rate on the two regimens correlated with gall bladder emptying (n = 16, r = 0.61, p less than 0.01), but not with small intestinal transit time (r = 0.07, NS). Bile acid pool size correlated with fractional turnover rate (r = -0.73, p less than 0.005) and with cholesterol saturation index (r = -0.56, p less than 0.025). These findings suggest that CCK influences bile acid kinetics and cholesterol saturation index of fasting gall bladder in man; and that these effects of CCK are mainly mediated via alterations in gall bladder emptying rather than through alterations in small intestinal transit rate.

Topics: Adult; Bile; Bile Acids and Salts; Cholecystokinin; Cholesterol; Diet, Reducing; Female; Gallbladder; Gastrointestinal Motility; Humans; Kinetics; Male; Middle Aged; Obesity

Cholecystokinin (CCK) is a peripheral and central mediator of short-term satiety. When given i.p., CCK decreases food intake in previously fasted rats for a period of 30 min. The effect has been previously shown to be abolished by vagotomy and more specifically by severing of vagal sensory rootlets. These studies were designed to determine the effects on rat feeding behavior, and in particular CCK-satiety, of the sensory neurotoxin capsaicin. In neonates, capsaicin selectively and permanently destroys unmyelinated sensory fibers including those in the vagus nerve. Rat neonates were treated with capsaicin, 50 mg/kg or vehicle, and surviving females studied at 8-10 weeks of age. The weights, 24-h food intake, and feeding responses to insulin were the same in adult capsaicin treated (Cap Rx) and vehicle treated (Veh Rx) rats. CCK (8 micrograms/kg i.p.) reduced 30 min food intake 61 +/- 18% in Veh Rx animals (mean +/- S.D., P less than 0.01). In capsaicin denervated animals, CCK also significantly reduced 30 min food intake from 5.09 +/- 1.10 to 3.92 +/- 0.84 g (P less than 0.01), but the mean reduction, 23 +/- 6%, was significantly less than in Veh Rx rats (P less than 10(-4]. A separate group of females, similarly treated as neonates with capsaicin or vehicle, were subjected to bilateral lesioning of the ventromedial hypothalamus. Both Cap Rx and Veh Rx animals gained significantly and equally more than non-lesioned controls. 24 h vagal transport of substance P was reduced 70% in age matched capsaicin treated animals compared to controls. These studies demonstrate that peripheral CCK-satiety is partly mediated by capsaicin sensitive fibers, presumably in the vagus nerve. Substance P is one possible transmitter mediating this reflex. Further conclusions are that active inhibition of an intact peripheral CCK-stimulated reflex arc is not necessary for full expression of central inducers of feeding, e.g., insulin or lesioning of the ventromedial hypothalamus, and that destruction of these fibers does not alter long-term weight regulation in rats receiving a normal diet.

Topics: Aging; Animals; Animals, Newborn; Biological Transport; Capsaicin; Cholecystokinin; Fasting; Feeding Behavior; Insulin; Obesity; Rats; Rats, Inbred Strains; Satiation; Satiety Response; Somatostatin; Substance P; Vagus Nerve; Ventromedial Hypothalamic Nucleus

Obesity as a common disorder of lipid metabolism might be caused by defective hypothalamic control as demonstrated by ventromedial lesions or the effect of cholecystokinin application. The hypothalamic proopiomelanocorticotropin is the precursor of hormonal fragments affecting fat mobilisation, the endocrine pancreas and gastrointestinal functions.

Topics: Animals; beta-Endorphin; Cholecystokinin; Eating; Endorphins; Glucagon; Humans; Hypothalamic Diseases; Insulin; Intestinal Absorption; Lipid Mobilization; Lipids; Lipolysis; Obesity; Pro-Opiomelanocortin; Receptors, Opioid; Satiety Response; Vagus Nerve

Cholecystokinin (CCK) has been shown to produce satiety not only in a variety of animal species but in man as well. In healthy humans, CCK reduces appetite and activation arising from the preparation of a meal, inhibits intake of liquid food in both non-obese and obese subjects, and decreases the intake of solid food. The closely related caerulein produces a similar reduction of solid food consumption in lean and, as suggested by preliminary results, in obese man. There is good evidence that the satiety effect of CCK depends on its inhibition of gastric emptying and the consequent gastric distension. In healthy man, the same dose of caerulein found to reduce food intake also slows gastric emptying of a semisolid meal. This effect seems to be relayed into the brain by afferent vagal fibers as in animals; selective gastric vagotomy blocks the satiety effect while pharmacological antagonism of vagal motor effects or lesions in the ventro-medial hypothalamus do not. Ongoing studies suggest that gastric vagotomy also blocks the satiety effects of caerulein in man. A critical role for CCK in the control of human feeding behavior seems certain.

Topics: Ceruletide; Cholecystokinin; Electroencephalography; Feeding Behavior; Female; Gastric Emptying; Humans; Male; Obesity; Psychomotor Performance; Satiation; Vagotomy

The CCK- and secretin stimulated pancreatic volume, bicarbonate and enzyme secretion was investigated before and during fasting for 20 days in 12 obese subjects. Pancreatic function tests were performed at the start of the fasting period and on the 10th and 20th day. In an additional and comparable group of 8 obese patients plasma concentrations of cholecystokinin (CCK), gastrin and insulin as well as metabolic parameters (bicarbonate, beta-OH-butyrate and free fatty acids) have been measured before and during total fasting. During three weeks of total fasting the average overweight of the patients undergoing pancreatic function tests was reduced from 49 to 31% (-11.5 +/- 1,5 kg). A significant reduction of volume, bicarbonate, trypsin and amylase secretion occurred already after 10 days of total fasting. After 20 days these parameters were further significantly reduced compared to the 10th day. All mentioned parameters were found at the lower limit of the normal range at the end of the fasting period at 20 days. The only exception being lipase secretion; the decrease of this enzyme was not significant at the 5% level. No significant reduction of basal plasma concentrations could be observed for CCK and gastrin during the course of total fasting. The plasma insulin levels were significantly reduced after 7 days whereas at 10 and 20 days insulin concentration was not significantly lowered compared to day 1. A small but significant decrease in the blood bicarbonate concentration could be observed after 7 days of fasting which remained constant up to the end of the study.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 3-Hydroxybutyric Acid; Adult; Amylases; Bicarbonates; Cholecystokinin; Fasting; Fatty Acids, Nonesterified; Female; Gastrins; Gastrointestinal Hormones; Humans; Hydroxybutyrates; Insulin; Male; Middle Aged; Obesity; Pancreatic Function Tests

Gastrin/CCK immunoreactivity appears to be widely distributed throughout the mammalian CNS, being most abundant in the cerebral cortex [Vanderhaeghen et al. 1975; Straus et al. 1977; Beinfeld et al. 1981]. Besides its putative role as a co-transmitter in dopaminergic neurotransmission [Hökfelt et al. 1980], cholecystokinin is apparently involved in the central regulation of appetite and satiety [Gibbs et al. 1973; Antin et al. 1975; Parret and Batt 1980; Smith 1980; Smith and Gibbs 1981] Furthermore, it has been shown that the brain concentration of the peptide is decreased in genetically obese mice as compared to non-obese animals [Strauss and Yalow 1979]. The sand rat (Psammomys obesus) is a desert rodent which tends to become diabetic when it is fed with normocaloric diet and restricted in movement [Haines et al. 1965; Hahn et al. 1971]. However, the usefulness of this animal as a paradigm of diabetes is now being revised, since because in its typical expression this metabolic dysfunction appears to be an obesity syndrome [Rice and Robertson 1980]. Therefore, it seems to be necessary to study the distribution of gastrin/CCK-immunoreactive nerve cells in the brain of normal and diabetic (obese) sand rats to get further information about mechanism underlying the development of this form of diabetes.

Topics: Animals; Arvicolinae; Cell Count; Cerebral Cortex; Cholecystokinin; Diabetes Mellitus; Gastrins; Immunoenzyme Techniques; Neurons; Obesity; Rabbits

The concentration of cholecystokinin (the octapeptide, CCK-8), bombesin, and neurotensin was measured by radioimmunoassay in the cortex, hypothalamus and diencephalon of brains from lean, genetically obese and hypothalamic (VMH) obese rodents. Highest concentration of CCK-8 was found in the cortex whereas highest concentrations of bombesin and neurotensin were in the hypothalamus. When food was provided ad libitum, there was no difference in concentration of any of these peptides between lean and the respective genetically obese mice (ob/ob) and fatty (fa/fa) rats, or between lean and hypothalamic (VMH lesioned) obese rats. Adrenalectomy, which arrested the progression of obesity in both ob/ob and fatty rats, did not result in significant change in concentration of any of the three peptides studied in comparison with the respective sham-operated animals. Though significant differences in cholecystokinin and bombesin concentrations were detectable in some instances between adrenalectomized lean and adrenalectomized obese rats, these differences did not appear to be related to fall in food intake or slowing of body weight gain. Thus a variety of manipulations which altered the nutritional plane of the experimental rodents was not accompanied by significant changes in brain concentrations of cholecystokinin, bombesin or neurotensin.

Topics: Adrenal Glands; Animals; Appetite Regulation; Bombesin; Brain Chemistry; Cerebral Cortex; Cholecystokinin; Diencephalon; Female; Hypothalamus; Mice; Mice, Obese; Neurotensin; Obesity; Peptides; Rats; Rats, Inbred Strains; Rats, Zucker; Starvation; Ventromedial Hypothalamic Nucleus

Plasma cholecystokinin (CCK) rose significantly after a 15-min liquid test meal in six normal controls and six obese patients, both before and after a jejunoileal bypass operation. Post-prandial rises in the obese patients were virtually unaffected by the operation, and tended to be higher in the obese patients than in the normal controls. It is therefore concluded that hormonal CCK is unlikely to be a mediator of satiety signals from the digestive tract in obese persons.

Topics: Adult; Appetite Regulation; Cholecystokinin; Eating; Female; Humans; Ileum; Jejunum; Male; Middle Aged; Obesity

Topics: Appetite Depressants; Cholecystokinin; Humans; Male; Obesity; Satiation; Satiety Response

Cholecystokinin (CCK), one of the peptides secreted by the gastrointestinal tract during a meal, stimulates release of enzymes into pancreatic juice and is a trophic hormone for the pancreas. Administration of CCK also decreases food intake, and obese rats have been shown to have a higher threshold than lean rats for this apparent effect on satiety. In this study experiments were designed to compare the sensitivity of obese and lean rats to the effects of CCK octapeptide (CCK-8) on pancreatic structure and exocrine function. In both growing and adult Zucker rats DNA content of the pancreas from obese rats was decreased compared with that from lean rats [2.42 +/- 0.21 vs. 3.07 +/- 0.18 mg (P less than 0.01) and 2.46 +/- 0.25 vs. 3.01 +/- 0.19 mg (P less than 0.05), respectively], and in adult obese rats this was accompanied by decreased pancreas size on both absolute weight and percent of body weight bases. In adult obese Bar Harbor mice, although DNA content of the pancreas was also decreased [1.70 +/- 0.10 vs. 2.41 +/- 0.11 mg (P less than 0.01)], pancreas weight was not different (0.30 +/- 0.01 vs. 0.32 +/- 0.01 g). In young rats growth of the pancreas was stimulated by 2 micrograms/kg CCK-8 administered subcutaneously or 100 mg/kg of a trypsin inhibitor administered orally twice daily for 2 wk. Although both treatments increased weight and DNA and protein content of the pancreas, the increases in DNA and protein content were smaller in obese than lean rats, indicating a decreased responsiveness to both trophic agents. Administration of CCK-8 stimulated smaller increases in pancreatic juice volume and amylase release in obese compared with lean rats, indicating decreased pancreatic exocrine function in response to CCK. In adults the CCK-8 dose-response curve for amylase release from dispersed pancreatic acini of obese rats was similar to that of lean rats, indicating normal sensitivity in vitro. Thus, in obese rats and mice DNA content of the pancreas is decreased when compared with that of lean rats and mice, and this is accompanied by decreased in vivo responses to CCK in obese rats.

Topics: Animals; Body Weight; Cholecystokinin; DNA; Eating; Obesity; Organ Size; Pancreas; Proteins; Rats; Rats, Zucker; RNA; Trypsin Inhibitors

Topics: Animals; Aurothioglucose; Brain; Cerebral Cortex; Cholecystokinin; Gold; Hypothalamus; Male; Mice; Mice, Inbred C3H; Obesity; Olfactory Bulb; Receptors, Cell Surface; Receptors, Cholecystokinin

Topics: Animals; Cerebral Cortex; Cholecystokinin; Mice; Mice, Obese; Obesity; Rats; Receptors, Cell Surface; Receptors, Cholecystokinin

Topics: Animals; Blood Glucose; Cholecystokinin; Female; Insulin; Obesity; Rats; Rats, Mutant Strains; Rats, Zucker; Triglycerides

Levels of gastrin-cholecystokinin-like immunoreactivity were measured in three brain regions (cortex, diencephalon, brainstem) and the pituitary gland in groups of genetically obese Zucker rats and their non-obese littermates. The obese animals had significantly increased body weights and significantly lowered brain weights. However, levels of gastrin-cholecystokinin-like immunoreactivity were not different between the two groups in any of the regions measured. These results contrast with a recent report [11] in which ob/ob mice were found to have decreased levels of cholecystokinin in their brains.

Topics: Animals; Body Weight; Brain Chemistry; Brain Stem; Cerebral Cortex; Cholecystokinin; Diencephalon; Gastrins; Male; Obesity; Organ Size; Pituitary Gland; Radioimmunoassay; Rats; Rats, Inbred Strains; Species Specificity; Tissue Distribution

Cholecystokinin (CCK, 20% pure) inhibited liquid food intake in obese and lean male mice after 1.5 and 4.5 hr of food deprivation. CCK decreased meal size without changing the duration of the postprandial intermeal interval. The inhibition of food intake was relatively specific. The largest dose of CCK tested (40 U/kg) had no effect on water intake in lean mice and it merely changed the pattern of intake in obese mice. Obese mice were as sensitive as lean mice to the satiating effect of CCK after 1.5 hr and 4.5 hr of food deprivation. Since CCK decreased meal size in obese mice and since obese mice were normally sensitive to CCK, CCK could be the circulating satiety factor that Coleman [4] postulated was deficient in obese mice. The results, however, only indicate that CCK could be the deficient factor. Other experiments are required to prove the point.

Topics: Animals; Cholecystokinin; Feeding Behavior; Food Deprivation; Male; Mice; Mice, Inbred Strains; Obesity

Topics: Animals; Cholecystokinin; Drinking Behavior; Feeding Behavior; Female; Obesity; Rats; Rats, Zucker; Satiation; Sincalide

Topics: Animals; Cholecystokinin; Circadian Rhythm; Feeding Behavior; Female; Obesity; Rats; Rats, Zucker; Satiation; Sincalide

Topics: Animals; Appetite Regulation; Cholecystokinin; Endorphins; Enkephalins; Gastrointestinal Hormones; Glucagon; Humans; Mice; Obesity; Secretin; Vasoactive Intestinal Peptide

Topics: Animals; Body Weight; Bombesin; Cholecystokinin; Eating; Female; Male; Obesity; Peptides; Rats; Weaning

The hyperphagia characteristic of some types of obesity may result from a deficiency in one or more components of the systems controlling satiety which in rats may include the gastrointestinal hormone cholecystokinin (CCK). Obesity may also influence responsivity to often used central nervous system (CNS)-acting drugs and combination of drugs. In these experiments it was shown that: (1) Zucker fatty rats were less sensitive than lean to intraperitoneal injections of 20 U/kg CCK after a 6-hr fast and when reduced were less sensitive than lean and less sensitive than when obese to injections of 5 U/kg CCK; (2) Although fatties were equally sensitive as leans to injections of 0.5 and 1.0 mg/kg d-amphetamine sulfate, when reduced, they were less sensitive; (3) Injections of 1.25 and 2.5 mg/kg diazepam produced smaller increases in food intake after a 6-hr fast in fatty and reduced fatty than lean rats; (4) Combination of diazepam with cholecystokinin in both fatty and lean rats produced feeding similar to that following injection of carrier; and (5) A similar additive effect was obtained in both fatty and lean rats when diazepam was combined with amphetamine; however, the fatty appeared to be more sensitive to the amphetamine than the diazepam effect. Thus the Zucker fatty rat appears to be less sensitive to these chemicals which affect food intake, which supports the contention that their CNS is generally less responsive.

Topics: Animals; Body Weight; Cholecystokinin; Dextroamphetamine; Diazepam; Drug Interactions; Feeding Behavior; Female; Male; Obesity; Rats; Time Factors

Under certain conditions, exogenously administered cholecystokinin (CCK) or its COOH-terminal octapeptide can terminate feeding and cause behavioral satiety in animals. Furthermore, high concentrations of CCK are normally found in the brains of vertebrate species. It has thus been hypothesized that brain CCK plays a role in the control of appetite. To explore this possibility, a COOH-terminal radioimmunoassay was used to measure concentrations of CCK in the cerebral cortex, hypothalamus, and brain stem of rats and mice after a variety of nutritional manipulations. CCK, mainly in the form of its COOH-terminal octapeptide, was found to appear in rat brain shortly before birth and to increase rapidly in cortex and brain stem throughout the first 5 wk of life. Severe early undernutrition had no effect on the normal pattern of CCK development in rat brain. Adult rats deprived of food for up to 72 h and rats made hyperphagic with highly palatable diets showed no alterations in brain CCK concentrations or distribution of molecular forms of CCK as determined by Sephadex gel filtration of brain extracts. Normal CCK concentrations were also found in the brains of four strains of genetically obese rodents and in the brains of six animals made hyperphagic and obese by surgical or chemical lesioning of the ventromedial hypothalamus. It is concluded that despite extreme variations in the nutritional status of rats and mice, CCK concentrations in major structures of the brain are maintained with remarkable constancy.

Topics: Aging; Animals; Appetite Regulation; Brain Stem; Cerebral Cortex; Cholecystokinin; Feeding Behavior; Female; Food Deprivation; Hypothalamus; Mice; Nutrition Disorders; Nutritional Physiological Phenomena; Obesity; Rats; Satiety Response

Bile salt pool size and kinetics were evaluated in 8 morbidly obese women before and following jejunoileal bypass. The results indicate that following jejunoileal bypass pool sizes of both chenodeoxycholate and cholate decrease, turnover rates increase, and the rates of bile salt synthesis increase. Influenced by pool size, hepatic synthesis and the degree of malabsorption, the daily bile salt loss may actually decrease in time. Chenodeoxycholate is more efficiently absorbed than cholate in both the preoperative and postoperative states. In spite of greater cholate synthetic capabilities, in this malabsorptive state the chenodeoxycholate pool decreases less than the cholate pool. Although all patients received an identical surgical procedure, the effect on bile salt kinetics and pool sizes varied in these patients. Since some of the postoperative complications may be related to the degree of interference with bile salt metabolism, the individual patient's capacity for increased hepatic synthesis of bile salts and increased reabsorption of bile salts from the remaining small bowel may vary the clinical postoperative course.

Topics: Adult; Bile Acids and Salts; Chenodeoxycholic Acid; Cholecystokinin; Cholic Acids; Female; Humans; Ileum; Jejunum; Kinetics; Middle Aged; Obesity; Radioactive Tracers

Topics: Amylases; Animals; Carbamates; Cholecystokinin; Choline; Dinitrophenols; Epinephrine; Evaluation Studies as Topic; Fasting; Female; Homozygote; Hydrogen-Ion Concentration; Hyperglycemia; Kinetics; Maltose; Methods; Mice; Obesity; Pancreas; Phenotype; Secretin; Spectrophotometry; Time Factors

Topics: Animals; Cholecystokinin; Gastrins; Gastrointestinal Hormones; Hyperglycemia; In Vitro Techniques; Insulin; Insulin Secretion; Islets of Langerhans; Obesity; Secretin; Secretory Rate

Topics: Blood Glucose; Cholecystokinin; Diazoxide; Drug Antagonism; Fatty Acids, Nonesterified; Glucose; Glycerol; Humans; Infusions, Parenteral; Injections, Intravenous; Insulin; Insulin Secretion; Islets of Langerhans; Kinetics; Obesity; Radioimmunoassay; Secretin