Gastrointestinal Hormone Ghrelin Research Articles

The Role of Peptides in Asthma-Obesity Phenotype.

The co-occurrence of asthma and obesity is becoming an increasingly common health problem. It became clear that both diseases are closely related, since overweight/obesity are associated with an increased risk of asthma development, and more than half of the subjects with severe or difficult-to-treat asthma are obese. Currently, there are no specific guidelines for the treatment of this group of patients. The mechanisms involved in the asthma-obesity phenotype include low-grade chronic inflammation and changes in pulmonary physiology. However, genetic predispositions, gender differences, comorbid conditions, and gut microbiota also seem to be important. Regulatory peptides affect many processes related to the functioning of the respiratory tract and adipose tissue. Adipokines such as leptin, adiponectin, resistin, and the less studied omentin, chemerin, and visfatin, as well as the gastrointestinal hormones ghrelin, cholecystokinin, glucagon-like peptide-1, and neuropeptides, including substance P or neuropeptide Y, can play a significant role in asthma with obesity. The aim of this article is to provide a concise review of the contribution of particular peptides in inflammatory reactions, obesity, asthma, and a combination of both diseases, as well as emphasize their potential role in the effective treatment of the asthma-obesity phenotype in the future.

How gut hormones shape reward: A systematic review of the role of ghrelin and GLP-1 in human fMRI

The gastrointestinal hormones ghrelin and glucagon-like peptide-1 (GLP-1) have opposite secretion patterns, as well as opposite effects on metabolism and food intake. Beyond their role in energy homeostasis, gastrointestinal hormones have also been suggested to modulate the reward system. However, the potential of ghrelin and GLP-1 to modulate reward responses in humans has not been systematically reviewed before. To evaluate the convergence of published results, we first conduct a multi-level kernel density meta-analysis of studies reporting a positive association of ghrelin (Ncomb = 353, 18 contrasts) and a negative association of GLP-1 (Ncomb = 258, 12 contrasts) and reward responses measured using task functional magnetic resonance imaging (fMRI). Second, we complement the meta-analysis using a systematic literature review, focusing on distinct reward phases and applications in clinical populations that may account for variability across studies. In line with preclinical research, we find that ghrelin increases reward responses across studies in key nodes of the motivational circuit, such as the nucleus accumbens, pallidum, putamen, substantia nigra, ventral tegmental area, and the dorsal mid insula. In contrast, for GLP-1, we did not find sufficient convergence in support of reduced reward responses. Instead, our systematic review identifies potential differences of GLP-1 on anticipatory versus consummatory reward responses. Based on a systematic synthesis of available findings, we conclude that there is considerable support for the neuromodulatory potential of gut-based circulating peptides on reward responses. To unlock their potential for clinical applications, it may be useful for future studies to move beyond anticipated rewards to cover other reward facets.

Comparison of the effects of different calorie amounts of enteral nutrition in hypercatabolism associated with ghrelin-POMC in endotoxemic rats

BackgroundHypercatabolism often occurs in critically ill patients, and it increases infection rates and mortality in these patients. Enteral nutrition (EN) is commonly used in case of hypercatabolism. However, the effect of amount of calories in EN on hypercatabolism remains unexplored.ObjectiveHere, we compared the effect of low-calorie, medium-calorie and high-calorie EN on hypercatabolism in the acute phase of endotoxemia, which is associated with gastrointestinal hormones and hypothalamic neuropeptide proopiomelanocortin (POMC).MethodsOverall 84 adult male Sprague–Dawley rats were used for research. A set of rats were divided into 5 groups, Control (NS) and lipopolysaccharide (LPS) groups were fed a standard chow diet; LPS + L (LPS + 40 kcal/kg/day EN), LPS + M (LPS + 80 kcal/kg/day EN) and LPS + H (LPS + 120 kcal/kg/day EN) groups received EN through a gastric tube for 3 days. Another set of rats were used for parallel control experiment and divided into 5 groups: NS + F (saline + fasting) and LPS + F (LPS + fasting) groups were given no food, NS + L (saline + 40 kcal/kg/day EN), NS + M (saline + 80 kcal/kg/day EN) and NS + H (saline + 120 kcal/kg/day EN) groups received EN through a gastric tube for 3 days. Hypercatabolism was evaluated by assessing skeletal muscle protein synthesis and atrophy, insulin resistance, and corticosterone levels. Moreover, serum inflammatory factors, gastrointestinal hormones, hypothalamic ghrelin, growth hormone secretagogue receptor-1α, hypothalamic neuropeptide, and intestinal injury indicators were detected.ResultsLow-calorie EN effectively increased serum and hypothalamic ghrelin possibly due to slight intestinal barrier damage, thereby decreasing hypothalamic POMC expression; consequently, it alleviated rat insulin resistance, reduced blood cortisol levels and muscle atrophy, and improved the survival rate of rats in the acute phase of endotoxemia. Interestingly, with an increase in calories in enteral nutrition, the aforementioned effects did not increase.ConclusionsLow-calorie EN could effectively increase gastrointestinal hormone ghrelin by reducing intestinal damage and suppressing POMC expression to ameliorate hypercatabolism when compared with medium-calorie and high-calorie EN. Therefore Low-calorie EN may be preferred for providing EN in the acute stage of endotoxemia.

Gastrointestinal Hormones in Healthy Adults: Reliability of Repeated Assessments and Interrelations with Eating Habits and Physical Activity.

Background: Gastrointestinal hormones (GIHs) are crucial for the regulation of a variety of physiological functions and have been linked to hunger, satiety, and appetite control. Thus, they might constitute meaningful biomarkers in longitudinal and interventional studies on eating behavior and body weight control. However, little is known about the physiological levels of GIHs, their intra-individual stability over time, and their interaction with other metabolic and lifestyle-related parameters. Therefore, the aim of this pilot study is to investigate the intra-individual stability of GIHs in normal-weight adults over time. Methods: Plasma concentrations of ghrelin, leptin, GLP-1 (glucagon-like-peptide), and PP (pancreatic polypeptide) were assessed by enzyme-linked immunosorbent assay (ELISA) in 17 normal-weight, healthy adults in a longitudinal design at baseline and at follow-up six months later. The reliability of the measurements was estimated using intra-class correlation (ICC). In a second step, we considered the stability of GIH levels after controlling for changes in blood glucose and hemoglobin A1 (HbA1c) as well as self-reported physical activity and dietary habits. Results: We found excellent reliability for ghrelin, good reliability for GLP1 and PP, and moderate reliability for leptin. After considering glucose, HbA1c, physical activity, and dietary habits as co-variates, the reliability of ghrelin, GLP1, and PP did not change significantly; the reliability of leptin changed to poor reliability. Conclusions: The GIHs ghrelin, GLP1, and PP demonstrated good to excellent test–retest reliability in healthy individuals, a finding that was not modified after adjusting for glucose control, physical activity, or dietary habits. Leptin showed only moderate to poor reliability, which might be linked to weight fluctuations, albeit small, between baseline and follow-up assessment in our study sample. Together, these findings support that ghrelin, GLP1, and PP might be further examined as biomarkers in studies on weight control, with GLP1 and PP serving as anorexic markers and ghrelin as an orexigenic marker. Additional reliability studies in obese individuals are necessary to verify or refute our findings for this cohort.

Ghrelin antagonist overrides the mRNA expression of NPY in hypothalamus in feed restricted ewes.

A negative energy balance (NEB) is detrimental to reproduction in animals. A suggested link between NEB and reproductive failure is the gastrointestinal hormone ghrelin, because of the association between ghrelin and the hypothalamo-pituitary-gonadal axis. The [D-Lys3]-Growth Hormone Releasing Peptide-6 ([D-Lys3]-GHRP-6) is a ghrelin antagonist that acts on ghrelin receptors (GHS-R1). The objective of this study was to evaluate the effect of [D-Lys3]-GHRP-6 on reproduction variables in feed restricted ewes. Two experiments were conducted. Experiment I was conducted for 30 days; and Experiment II for 13 days. In both experiments the ewes (n = 18) were randomly assigned to: Control (CO): fed to meet maintenance requirements; Feed restriction (FR): 80% of maintenance restriction; or Ghrelin antagonist (GA): feed restricted and daily subcutaneous of 7.5μg/kg of [D-Lys3]-GHRP-6. Plasma was collected to measure hormones and metabolite concentration. In Experiment II, the hypothalamus and ovaries were collected on day 13. In both Experiments, sheep allocated to the FR and GA treatments decreased their body weight compared with sheep in the CO group (P < 0.06); progesterone however, did not differ between treatments (P > 0.10). Experiment I: Plasma ghrelin concentration was greater (P < 0.01) in FR and GA compared with CO ewes. Plasma non-esterified fatty acids concentration was greater (P < 0.01) in GA and FR than CO. Experiment II: Kisspeptin1-Receptor (Kiss1-R) mRNA expression was greater in FR (P < 0.01) and tended to be greater in GA (P = 0.10) compared with CO ewes. The neuro peptide-Y (NPY) mRNA expression was greater (P = 0.03) in FR than CO; and tended to be greater (P = 0.06) compared with GA ewes. Growth hormone releasing hormone (GhRH) mRNA expression was greater in GA (P = 0.04) and tended to be greater in FR (P = 0.07) compared with CO ewes. Feed restriction increased GhRH, NPY, and Kiss-R mRNA expression in hypothalamus without affecting reproductive variables.Ghrelin antagonist may prevent an increase inNPY expression in ewes.

Rikkunshito attenuates induction of epithelial-mesenchymal switch via activation of Sirtuin1 in ovarian cancer cells.

Rikkunshito, a traditional Japanese herbal medicine, improves appetite via activation of gastrointestinal hormone ghrelin pathway. The function of ghrelin is mediated by growth hormone secretagogue receptor (GHSR1a), and ghrelin has been known to possess diverse physiological functions including growth suppression of some cancer cells. Considering that increased ghrelin signaling by Rikkunshito could enhance sirtuin1 (SIRT1) activity in nervous system, we aimed to investigate the effect of Rikkunshito in ovarian cancer cells. Ovarian cancer cell lines were treated with Rikkunshito, and cellular viability, gene expressions and epithelial-mesenchymal transition (EMT) status were investigated. To investigate the involvement of SIRT1 by Rikkunshito in SKOV3 cancer cells, endogenous expression of SIRT1 was depleted using small interfering RNA (siRNA). Treatment with Rikkunshito elevated ghrelin, GHSR1a and SIRT1, while cellular viability was decreased. The treatment of Rikkunshito also inhibited cellular migration and invasion status in a dose-dependent manner, and these effects were translated to the enhanced EMT status, although the role of SIRT1 was not determined. Our study revealed a novel function of Rikkunshito in enhancing EMT status of ovarian cancer cells. Therefore, we would like to propose that Rikkunshito may be used as a novel adjunctive therapy in chemotherapy of ovarian cancer because platinum-based chemotherapy frequently used for the treatment of ovarian cancer inevitably impairs appetite.

Ghrelin Does Not Directly Stimulate Secretion of Glucagon-like Peptide-1.

The gastrointestinal hormone ghrelin stimulates growth hormone secretion and appetite, but recent studies indicate that ghrelin also stimulates the secretion of the appetite-inhibiting and insulinotropic hormone glucagon-like peptide-1 (GLP-1). To investigate the putative effect of ghrelin on GLP-1 secretion in vivo and in vitro. A randomized placebo-controlled crossover study was performed in eight hypopituitary subjects. Ghrelin or saline was infused intravenously (1 pmol/min × kg) after collection of baseline sample (0 min), and blood was subsequently collected at time 30, 60, 90, and 120 minutes. Mouse small intestine was perfused (n = 6) and GLP-1 output from perfused mouse small intestine was investigated in response to vascular ghrelin administration in the presence and absence of a simultaneous luminal glucose stimulus. Ghrelin receptor expression was quantified in human (n = 11) and mouse L-cells (n = 3) by RNA sequencing and RT-qPCR, respectively. Ghrelin did not affect GLP-1 secretion in humans (area under the curve [AUC; 0-120 min]: ghrelin infusion = 1.37 ± 0.05 min × nmol vs. saline infusion = 1.40 ± 0.06 min × nmol [P = 0.63]), but induced peripheral insulin resistance. Likewise, ghrelin did not stimulate GLP-1 secretion from the perfused mouse small intestine model (mean outputs during baseline/ghrelin infusion = 19.3 ± 1.6/25.5 ± 2.0 fmol/min, n = 6, P = 0.16), whereas glucose-dependent insulinotropic polypeptide administration, used as a positive control, doubled GLP-1 secretion (P < 0.001). Intraluminal glucose increased GLP-1 secretion by 4-fold (P < 0.001), which was not potentiated by ghrelin. Finally, gene expression of the ghrelin receptor was undetectable in mouse L-cells and marginal in human L-cells. Ghrelin does not interact directly with the L-cell and does not directly affect GLP-1 secretion.

Assessments of plasma ghrelin levels in the early stages of parkinson's disease.

Gastrointestinal symptoms are early events in Parkinson's disease (PD). The gastrointestinal hormone ghrelin was neuroprotective in the nigrostriatal dopamine system. The objective of this study was to assess ghrelin levels in the early stages of PD. Plasma was collected in the fasting state in 291 PD patients in stages 1-3 and 303 age- and sex-matched healthy controls. Additional samples were taken in the glucose response test to assess nutrition-related ghrelin levels in 20 PD patients and 20 healthy controls. The enzyme-linked immunosorbent assay was used to measure total and active plasma ghrelin levels. We reported that total and active plasma ghrelin levels were decreased in PD, although there was no difference across progressive PD stages. Postprandial ghrelin suppression and preprandial peak responses were both attenuated in PD. Plasma ghrelin levels were decreased in PD; however, this event might be irrelevant to PD progression. Ghrelin responses to meals were also impaired in PD. © 2017 International Parkinson and Movement Disorder Society.

Oral Treatment with the Ghrelin Receptor Agonist HM01 Attenuates Cachexia in Mice Bearing Colon-26 (C26) Tumors.

The gastrointestinal hormone ghrelin reduces energy expenditure and stimulates food intake. Ghrelin analogs are a possible treatment against cancer anorexia-cachexia syndrome (CACS). This study aimed to investigate whether oral treatment with the non-peptidergic ghrelin receptor agonist HM01 counteracts CACS in colon-26 (C26) tumor-bearing mice. The C26 tumor model is characterized by pronounced body weight (BW) loss and muscle wasting in the absence of severe anorexia. We analyzed the time course of BW loss, body composition, muscle mass, bone mineral density, and the cytokines interleukin-6 (IL-6) and macrophage-inhibitory cytokine-1 (MIC-1). Moreover, we measured the expression of the muscle degradation markers muscle RING-finger-protein-1 (MuRF-1) and muscle atrophy F-box (MAFbx). After tumor inoculation, MIC-1 levels increased earlier than IL-6 and both cytokines were elevated before MuRF-1/MAFbx expression increased. Oral HM01 treatment increased BW, fat mass, and neuronal hypothalamic activity in healthy mice. In tumor-bearing mice, HM01 increased food intake, BW, fat mass, muscle mass, and bone mineral density while it decreased energy expenditure. These effects appeared to be independent of IL-6, MIC-1, MuRF-1 or MAFbx, which were not affected by HM01. Therefore, HM01 counteracts cachectic body weight loss under inflammatory conditions and is a promising compound for the treatment of cancer cachexia in the absence of severe anorexia.

Pup sex and body mass of rats raised in different lactation litter sizes affect ghrelin and peptide-YY concentrations

Introduction: Previous studies have established that litter size during lactation influences body size and adiposity in male rat pups, but female pups and appetite-regulatory hormones have not been studied in this way. Gastrointestinal hormones ghrelin and peptide-YY (PYY) have roles in appetite regulation: high ghrelin levels signal hunger high PYY levels signal satiety. Both hormones are also associated with altered body mass and body composition. Previous findings (SRF 2014) demonstrated that lactation litter size affected levels of appetite hormones in gastrointestinal tissue, but not in plasma. Observed changes in hormone concentrations may have been further influenced by significant differences in pup body size between small and large litters, thus additional data analysis accounting for body masses presented here aims to establish the effects on male and female pups being suckled and raised in different sized litters. Methods: Male and female littermates from small (n=4), control (n=8) and large (n=12) litter sizes were studied at weaning, with litter sizes adjusted Results and discussion: Pups raised in smaller litters were significantly larger (P<0.001). No differences were found in measured concentrations of either ghrelin or PYY in plasma between the litter sizes. Correcting for body mass revealed that large pups raised in small litters had the least circulating ghrelin (P=0.002) and PYY (P<0.001). Analysing by pup sex further revealed that although plasma ghrelin concentrations were only significantly lower in these larger males (P=0.023), PYY levels were significantly lower in both the males (P=0.011) and females (P=0.032). This work highlights the importance of taking into consideration factors such as body mass and sex when investigating hormones that affect body composition.

Potential new role of the GHSR-1a-mediated signaling pathway in cardiac remodeling after myocardial infarction (Review).

The gastrointestinal hormone ghrelin has important cardiovascular protective effects, however, its specific mechanisms are not yet completely understood. Recent studies have shown that the ghrelin receptor, growth hormone secretagogue receptor type 1a (GHSR-1a), regulates cell proliferation, apoptosis and inflammation-related signaling pathways. In human aortic endothelial cells, ghrelin activates NO production through AMP-activated protein kinase (AMPK) and Akt activation, and these effects can be blocked by knockdown of GHSR-1a. Obese mice have been found to exhibit an increased GHSR-1a content and expression in the heart, associated with an increase in phosphatidylinositol 3-kinase (PI3K) content and an increase AKT content and phosphorylation. Furthermore, GHSR-1a expression was observed to be increased in heart failure after myocardial infarction (MI) in rats. Given such complexity in GHSR-1a signaling and crosstalk with the AMPK and PI3K/Akt signaling pathways, both of which are well-known factors involved in cardiac remodeling after MI, we speculate that GHSR-1a signaling may play a regulatory role in cardiac protection and hope to identify new drugs targets. However, to date, no direct association between GHSR-1a and cardiac remodeling has been found. Therefore, further studies are required.

Ghrelin increases the motivation to eat, but does not alter food palatability.

Homeostatic eating cannot explain overconsumption of food and pathological weight gain. A more likely factor promoting excessive eating is food reward and its representation in the central nervous system (CNS). The anorectic hormones leptin and insulin reduce food reward and inhibit related CNS reward pathways. Conversely, the orexigenic gastrointestinal hormone ghrelin activates both homeostatic and reward-related neurocircuits. The current studies were conducted to identify in rats the effects of intracerebroventricular ghrelin infusions on two distinct aspects of food reward: hedonic valuation (i.e., "liking") and the motivation to self-administer (i.e., "wanting") food. To assess hedonic valuation of liquid food, lick motor patterns were recorded using lickometry. Although ghrelin administration increased energy intake, it did not alter the avidity of licking (initial lick rates or lick-cluster size). Several positive-control conditions ruled out lick-rate ceiling effects. Similarly, when the liquid diet was hedonically devalued with quinine supplementation, ghrelin failed to reverse the quinine-associated reduction of energy intake and avidity of licking. The effects of ghrelin on rats' motivation to eat were assessed using lever pressing to self-administer food in a progressive-ratio paradigm. Ghrelin markedly increased motivation to eat, to levels comparable to or greater than those seen following 24 h of food deprivation. Pretreatment with the dopamine D1 receptor antagonist SCH-23390 eliminated ghrelin-induced increases in lever pressing, without compromising generalized licking motor control, indicating a role for D1 signaling in ghrelin's motivational feeding effects. These results indicate that ghrelin increases the motivation to eat via D1 receptor-dependent mechanisms, without affecting perceived food palatability.

Ghrelin, peptide YY and their hypothalamic targets differentially regulate spontaneous physical activity

Recent studies suggest that spontaneous physical activity (SPA) may be under the non-conscious control of neuroendocrine circuits that are known to control food intake. To further elucidate endocrine gut–brain communication as a component of such circuitry, we here analyzed long-term and acute effects of the gastrointestinal hormones ghrelin and PYY 3-36 as well as their hypothalamic neuropeptide targets NPY, AgRP and POMC (alpha-MSH), on locomotor activity and home cage behaviors in rats. For the analysis of SPA, we used an automated infrared beam break activity measuring system, combined with a novel automated video-based behavior analysis system (HomeCageScan (HCS)). Chronic (one-month) peripheral infusion of ghrelin potently increased body weight and fat mass in rats. Such positive energy balance was intriguingly not due to an overall increased caloric ingestion, but was predominantly associated with a decrease in SPA. Chronic intracerebroventricular infusion (7 days) of ghrelin corroborated the decrease in SPA and suggested a centrally mediated mechanism. Central administration of AgRP and NPY increased food intake as expected. AgRP administration led to a delayed decrease in SPA, while NPY acutely (but transiently) increased SPA. Behavioral dissection using HCS corroborated the observed acute and transient increases of food intake and SPA by central NPY infusion. Acute central administration of alpha-MSH rapidly decreased food intake but did not change SPA. Central administration of the NPY receptor agonist PYY 3-36 transiently increased SPA. Our data suggest that the control of spontaneous physical activity by gut hormones or their neuropeptide targets may represent an important mechanistic component of energy balance regulation.

Plasma ghrelin and oxyntomodulin concentrations in lactating dairy cows receiving abomasal soybean oil, corn starch, and casein infusions

The effects of increased postruminal supply of casein, corn starch, and soybean oil on plasma concentrations of the gastrointestinal hormones ghrelin and oxyntomodulin (OXM) were investigated. Four mid-lactation Holstein cows were used in a 4 × 4 Latin square. Treatments were continuous abomasal infusions (23 h/d) for 7 d of water, soybean oil (500 g/d), corn starch (1100 g/d), or casein (800 g/d). Jugular vein plasma was obtained every 30 min for 7 h on days 1 and 7. Soybean oil and casein infusion decreased preprandial plasma ghrelin concentration by approximately 20% on both d (time-by-treatment P < 0.10); however, dry matter intake (DMI) was depressed only after 7 d of oil infusion. Infusion of soybean oil, corn starch, or casein did not change the plasma OXM concentration ( P > 0.20 ). The present data indicate that plasma ghrelin concentration is depressed immediately before feeding by the postruminal infusion of soybean oil and casein, but it is not affected during the postprandial period. Plasma ghrelin concentration was not altered ( P > 0.20), pre- or postfeeding, by increased postruminal supply of corn starch. In addition, plasma OXM concentration did not respond ( P > 0.20 ) to postruminal nutrient infusion. In conclusion, a decrease in DMI when fat is infused could be partially explained by the decrease in prefeeding plasma ghrelin concentration, but a decrease in prefeeding plasma ghrelin concentration is not always associated with a decrease in DMI, as observed for the infusion of casein. Plasma OXM concentration was not affected by postruminal infusion of macronutrients.

Ghrelin and peptide YY (PYY) profiles in gastrointestinal tissues and the circulation of the rat during pregnancy and lactation

Plasma and tissue profiles of gastrointestinal hormones ghrelin and peptide YY (PYY) were investigated in different female rat reproductive states. Neither plasma nor tissue ghrelin concentrations were suppressed during pregnancy despite elevated leptin. The highest concentrations of stomach ghrelin were measured in late pregnancy. PYY concentrations in plasma, descending colon and rectum tissues were increased ( P < 0.001) throughout pregnancy and lactation. PYY peaked at day 5 of lactation in plasma, as well as descending colon and rectum tissues (proestrus vs day 5 of lactation: 25 ± 3.0 pmol/l vs 55 ± 8.0 pmol/l; 85 ± 4.5 pmol/g wwt vs 418 ± 45.0 pmol/g wwt; 23 ± 3.0 pmol/g wwt vs 78 ± 9.1 pmol/g wwt). This PYY peak was temporally associated with the luteinizing hormone peak on day 1 of lactation. Following weaning, dam adiposity and plasma leptin increased whereas ghrelin stomach peptide decreased. Relative PYY concentrations in the tissues of the gut varied in the different states suggesting regional alterations taking place in the colon. The ascending colon produced the highest concentrations in non-pregnant rats, the descending colon the highest concentrations during lactation with the pregnant rats and the dams postweaning in a transition state between. It is unclear what role the increased PYY in various tissues observed has during pregnancy and lactation as it would be expected to be reduced in these states of greatly increased appetite. PYY may have an influence on maternal dietary adaptation, intestinal hypertrophy and weight gain during pregnancy and lactation although it is still unclear precisely how it acts.

Effect of viscosity on appetite and gastro-intestinal hormones

In previous studies we showed that higher viscosity resulted in lower ad libitum intake and that eating rate is an important factor. In this study we aimed to explore the effect of viscosity on the gastro-intestinal hormones ghrelin, CCK-8 and GLP-1. Thirty-two subjects (22 ± 2 y, BMI 21.9 ± 2.2 kg/m 2) participated in this cross-over study. Subjects received a fixed amount of a chocolate flavored milk-based liquid or semi-solid product similar in energy density and macronutrient composition. Before intake and 15, 30, 60 and 90 min thereafter, appetite was rated and blood was drawn to determine glucose, CCK-8, active ghrelin, desacyl ghrelin and GLP-1 concentrations. After the last blood withdrawal, subjects were offered a chocolate cake meal to consume ad libitum. In the appetite ratings we observed a small effect showing that the semi-solid product is apparently considered as more satisfying than the liquid. There was a significant product effect for fullness ( p 0.03), desire to eat ( p 0.04), appetite something sweet ( p 0.002) and prospective consumption ( p 0.0009). We observed no clear effect of viscosity on gastro-intestinal hormones. Only for desacyl ghrelin there was a significant product effect ( p 0.004). Concentrations were consistently higher after intake of the semi-solid product. Ad libitum intake of the chocolate cake was 102 ± 55 g after the liquid and 96 ± 46 g after the semi-solid product (ns). The results of our study show a similar response of the gastro-intestinal hormones CCK-8, ghrelin and GLP-1 after a fixed preload of a liquid and semi-solid product similar in energy- and macronutrient composition.

Low fasting PYY3-36 levels in healthy women with high dietary restraint.

The gastrointestinal hormones ghrelin and PYY3-36 are released peripherally and act on the central nervous system to signal hunger and satiety, respectively. Atypical levels of Ghrelin and PYY3-36 have been reported in obesity and in those with clinically disordered eating, and may contribute to the types of eating behaviours seen in these pathologies. However, a causal relationship cannot be inferred. In this study, we examined fasting PYY3-36 and Ghrelin levels in healthy normal weight non-eating-disordered women grouped by differences in eating behaviors, categorized using Three-Factor Eating Questionnaire (TFEQ) scores of dietary restraint and disinhibition. Differences in fasting plasma levels of ghrelin, PYY3-36, leptin and glucose were contrasted between 60 healthy women classified as either low or high TFEQ-restraint (LR vs. HR) and with low or high TFEQ-disinhibition (LD vs. HD). All blood sampling took place in the morning following an overnight fast. Blood plasma samples were frozen to −70 °C and later analyzed using Radioimmunoassay methods. Controlling for BMI, HR women had similar fasting levels of ghrelin, leptin and glucose compared to LR women, but significantly lower fasting levels of PYY3-36 [ F (1, 58)=8.4, p =0.005]. There were no TFEQ-disinhibition effects or TFEQ-restraint×TFEQ-disinhibition interactions. Healthy women with high dietary restraint have low fasting levels of the satiety GI hormone PYY3-36, and potential reasons for this finding are discussed.

Gut–Brain Axis: Regulation of Glucose Metabolism

Obesity and type II diabetes mellitus have reached epidemic proportions. From this perspective, knowledge about the regulation of satiety and food intake is more important than ever. The gut releases several peptides upon feeding, which affect hypothalamic pathways involved in the regulation of satiety and metabolism. Within the hypothalamus, there are complex interactions between many nuclei of which the arcuate nucleus is considered as one of the most important hypothalamic centres that regulates food intake. The neuropeptides, which are present in the hypothalamus and are involved in regulating food intake, also play a key role in regulating glucose metabolism and energy expenditure. In synchrony with the effects of those neuropeptides, gastrointestinal hormones also affect glucose metabolism and energy expenditure. In this review, the effects of the gastrointestinal hormones ghrelin, cholecystokinin, peptide YY, glucagon-like peptide, oxyntomodulin and gastric inhibitory polypeptide on glucose and energy metabolism are reviewed. These gut hormones affect glucose metabolism at different levels: by altering food intake and body weight, and thereby insulin sensitivity; by affecting gastric delay and gut motility, and thereby meal-related fluctuations in glucose levels; by affecting insulin secretion, and thereby plasma glucose levels, and by affecting tissue specific insulin sensitivity of glucose metabolism. These observations point to the notion of a major role of the gut-brain axis in the integrative physiology of whole body fuel metabolism.

The Neurobiology of Obesity

Obesity is an energy balance regulation dysfunction thatleads to an excessive fat deposition, which increases the riskfor cardiovascular, respiratory, and metabolic diseases, inparticular when such deposition occurs within the abdomi-nal cavity. The high prevalence of obesity and its costlyco-morbidities has significantly contributed to intensify ef-forts to understand obesity, which is currently at the fore-front of biochemical, biomolecular, and neurobiological re-search. We now confront the tremendous challenge ofpreventing obesity and developing effective treatments.In the last 15 years, research has generated many impor-tant discoveries, including those of adipose tissue-derivedhormones such as leptin and adiponectin, those of the gas-trointestinal tract hormones such as ghrelin, and the deter-mination of numerous central and peripheral circuitries in-volved in energy balance regulation. The neurobiology ofobesity represents a rapidly growing research field that hasprovedtobeessentialintheunderstandingoftheetiologyofobesity. The brain plays a major role in energy balanceregulation as it exerts controls on both food intake andenergy expenditure (Figure 1). Three brain entities are par-ticularly important in these controls, namely the hypothal-amus, the dorsal vagal complex, and the reward system,which are inter-related structures capable of controllingenergy intake as well as thermogenesis. Brain systems con-trolling energy intake and energy expenditure have beendivided into anabolic and catabolic systems, each systemcomprising different types of neurons capable of controllingenergy intake as well as energy expenditure. These neuronsrelease various molecules that include neuropeptide Y, ag-outi-related peptide, melanin-concentrating hormone, theendocannabinoids, -melanocyte-stimulating hormone, co-caine- and amphetamine-regulated transcript, corticotropin-releasing factor, thyrotropin-releasing hormone, and seroto-nin. These neurosystems are modulated by short- and long-termsignalsthatreportonthestatusoftheenergystoresandenergy fluxes. Whereas leptin and insulin are recognized asthe main long-term signals, the gastrointestinal hormonesghrelin, peptide tyrosine-tyrosine, cholecystokinin, and glu-cagon-like peptide 1 are known as short-term signals thatinform about the nutritional status. The way an organismregulates energy balance is in large part a function of itsgenes and the environment. One energy expenditure com-ponent, which is perhaps not so important in human ener-getics but which is undoubtedly relevant in laboratory ro-dents used by most neurobiologists of obesity, is brownadipose tissue thermogenesis, the activity of which dependson factors activating the sympathetic nervous system. Theextraordinary thermogenic power of brown adipose tissue isattributable to uncoupling protein 1, a mitochondrial proteinuniquely found in brown adipose tissue.It is within the mission of the Merck Frosst/CIHR Re-search Chair in Obesity to provide continuing educationabout the best possible knowledge on obesity to scientists,physicians, health professionals, as well as to the public atlarge, regarding the causes, complications, treatment, andprevention of obesity. In this regard, the purpose of theannual symposium is to summarize evidence regarding im-portant topics related to obesity and to propose novel obe-sity research directions. Since its creation in 1997, theMerck Frosst/CIHR Research Chair in Obesity has held sixinternational symposia devoted entirely to obesity research.The first symposium of the series, entitled “The UncouplingProteins and Obesity,” was held in 1998 (1). The secondsymposium, which was organized the following year, wasoriented toward “The New Biology of Adipose Tissue” (2).In 2000, the third symposium was entitled “The Pon-derostat: From Behavior to Neural Substrates” (3) and fo-cused on the mechanisms whereby energy balance is regu-lated. The fourth symposium, organized in November 2002and entitled “Complications of Obesity: The InflammatoryLink,” summarized the latest most important findings on themechanisms underlying the link between obesity and itscomplications such as diabetes and cardiovascular diseases(4). In 2003, the fifth symposium brought a comprehensiveview on the “Role of Gene Regulation in Obesity and itsComplications” (5) and, specifically, on the regulation ofperoxisome proliferator-activated receptors, prostaglandin