Ghrelin Abstracts 1

©

The Bitter Taste Receptor Agonist Quinine Reduces Calorie Intake and Increases the Postprandial Release of Cholecystokinin in Healthy Subjects.
            (Andreozzi et al., 2015) Download
BACKGROUND/AIMS:  Bitter taste receptors are expressed throughout the digestive tract. Data on animals have suggested these receptors are involved in the gut hormone release, but no data are available in humans. Our aim is to assess whether bitter agonists influence food intake and gut hormone release in healthy subjects. METHODS:  Twenty healthy volunteers were enrolled in a double-blind cross-over study. On 2 different days, each subject randomly received an acid-resistant capsule containing either placebo or 18 mg of hydrochloride (HCl) quinine. After 60 minutes, all subjects were allowed to eat an ad libitum meal until satiated. Plasma samples were obtained during the experiment in order to evaluate cholecystokinin (CCK) and ghrelin levels. Each subject was screened to determine phenylthiocarbamide (PTC) tasting status. RESULTS:  Calorie intake was significantly lower when subjects received HCl quinine than placebo (514 ± 248 vs 596 ± 286 kcal; P = 0.007). Significantly higher CCK ΔT90 vs T0 and ΔT90 vs T60 were found when subjects received HCl quinine than placebo (0.70 ± 0.69 vs 0.10 ± 0.86 ng/mL, P = 0.026; 0.92 ± 0.75 vs 0.50 ± 0.55 ng/mL, P = 0.033, respectively). PTC tasters ingested a significantly lower amount of calories when they received HCl quinine compared to placebo (526 ± 275 vs 659 ± 320 kcal; P = 0.005), whereas no significant differences were found for PTC non-tasters (499 ± 227 vs 519 ± 231 kcal; P = 0.525). CONCLUSIONS:  This study showed that intra-duodenal release of a bitter compound is able to significantly affect calorie intake and CCK release after a standardized meal. Our results suggest that bitter taste receptor signaling may have a crucial role in the control of food intake.


 

Gastrointestinal hormones regulating appetite.
            (Chaudhri et al., 2006) Download
The role of gastrointestinal hormones in the regulation of appetite is reviewed. The gastrointestinal tract is the largest endocrine organ in the body. Gut hormones function to optimize the process of digestion and absorption of nutrients by the gut. In this capacity, their local effects on gastrointestinal motility and secretion have been well characterized. By altering the rate at which nutrients are delivered to compartments of the alimentary canal, the control of food intake arguably constitutes another point at which intervention may promote efficient digestion and nutrient uptake. In recent decades, gut hormones have come to occupy a central place in the complex neuroendocrine interactions that underlie the regulation of energy balance. Many gut peptides have been shown to influence energy intake. The most well studied in this regard are cholecystokinin (CCK), pancreatic polypeptide, peptide YY, glucagon-like peptide-1 (GLP-1), oxyntomodulin and ghrelin. With the exception of ghrelin, these hormones act to increase satiety and decrease food intake. The mechanisms by which gut hormones modify feeding are the subject of ongoing investigation. Local effects such as the inhibition of gastric emptying might contribute to the decrease in energy intake. Activation of mechanoreceptors as a result of gastric distension may inhibit further food intake via neural reflex arcs. Circulating gut hormones have also been shown to act directly on neurons in hypothalamic and brainstem centres of appetite control. The median eminence and area postrema are characterized by a deficiency of the blood-brain barrier. Some investigators argue that this renders neighbouring structures, such as the arcuate nucleus of the hypothalamus and the nucleus of the tractus solitarius in the brainstem, susceptible to influence by circulating factors. Extensive reciprocal connections exist between these areas and the hypothalamic paraventricular nucleus and other energy-regulating centres of the central nervous system. In this way, hormonal signals from the gut may be translated into the subjective sensation of satiety. Moreover, the importance of the brain-gut axis in the control of food intake is reflected in the dual role exhibited by many gut peptides as both hormones and neurotransmitters. Peptides such as CCK and GLP-1 are expressed in neurons projecting both into and out of areas of the central nervous system critical to energy balance. The global increase in the incidence of obesity and the associated burden of morbidity has imparted greater urgency to understanding the processes of appetite control. Appetite regulation offers an integrated model of a brain-gut axis comprising both endocrine and neurological systems. As physiological mediators of satiety, gut hormones offer an attractive therapeutic target in the treatment of obesity.

 

Plasma ghrelin levels and hunger scores in humans initiating meals voluntarily without time- and food-related cues.
            (Cummings et al., 2004) Download
Ghrelin is an orexigenic hormone that is implicated in meal initiation, in part because circulating levels rise before meals. Because previous human studies have examined subjects fed on known schedules, the observed preprandial ghrelin increases could have been a secondary consequence of meal anticipation. A causal role for ghrelin in meal initiation would be better supported if preprandial increases occurred before spontaneously initiated meals not prompted by external cues. We measured plasma ghrelin levels among human subjects initiating meals voluntarily without cues related to time or food. Samples were drawn every 5 min between a scheduled lunch and a freely requested dinner, and hunger scores were obtained using visual analog scales. Insulin, glucose, fatty acids, leptin, and triglycerides were also measured. Ghrelin levels decreased shortly after the first meal in all subjects. A subsequent preprandial increase occurred over a wide range of intermeal intervals (IMI; 320-425 min) in all but one subject. Hunger scores and ghrelin levels showed similar temporal profiles and similar relative differences in magnitude between lunch and dinner. One subject displayed no preprandial ghrelin increase and was also the only individual whose insulin levels did not return to baseline between meals. This finding, along with a correlation between area-under-the-curve values of ghrelin and insulin, suggests a role for insulin in ghrelin regulation. The preprandial increase of ghrelin levels that we observed among humans initiating meals voluntarily, without time- or food-related cues, and the overlap between these levels and hunger scores are consistent with a role for ghrelin in meal initiation.

Unbalanced serum leptin and ghrelin dynamics prolong postprandial satiety and inhibit hunger in healthy elderly: another reason for the "anorexia of aging".
            (Di Francesco et al., 2006) Download
BACKGROUND:  In healthy elderly, a reduction from the appetite and food intake of younger years has been defined as the "anorexia of aging," which may cause malnutrition. Leptin and ghrelin may alter the control of hunger and satiety and thus lead to anorexia. OBJECTIVE:  The aim of this study was to investigate how aging affects serum leptin and ghrelin concentrations in response to a meal and the relation of those hormones to hunger and satiety sensations. DESIGN:  We studied 8 community-dwelling elderly (x +/- SD age: 78 +/- 1 y) subjects and 8 younger (29.5 +/- 1 y) control subjects. Under fasting conditions and for 4 h after an 800-kcal mixed meal, satiety and hunger were evaluated at intervals, by using a visual analogic scale. Blood samples for leptin, ghrelin, and insulin measurements were collected at the following times: 30 min before and immediately and 30, 60, 120, and 240 min after the meal. RESULTS:  Postprandial satiety lasted significantly longer in the elderly than in the control subjects, and hunger was suppressed in the elderly throughout the observation. Fasting leptin was higher in the elderly than in the young (x +/- SE: 4.3 +/- 1.9 and 1.3 +/- 0.4 ng/mL, respectively; P < 0.05), and postprandial fluctuation was not significant. Fasting insulin also was significantly higher in the elderly than in the young (6.8 +/- 1.3 and 3.5 +/- 0.6 mU/L, respectively; P < 0.05), and the postprandial insulin rise was greater in the elderly. Fasting and postprandial ghrelin values did not differ significantly between the 2 groups. Insulin was inversely correlated with hunger and directly correlated with satiety scores. CONCLUSIONS:  In healthy elderly, anorexigenic signals prevail over orexigenic signals, and they contribute to prolonged satiety and inhibition of hunger. This condition may lead to a calorie deficit and finally to malnutrition in the elderly.

Circulating ghrelin in thyroid dysfunction is related to insulin resistance and not to hunger, food intake or anthropometric changes.
            (Giménez-Palop et al., 2005) Download
OBJECTIVE:  Ghrelin is a gastric peptide that plays a role in appetite stimulation, energy balance and possibly in insulin resistance. Hyperthyroidism is a situation where negative energy balance and insulin resistance coexist, while in hypothyroidism a positive energy balance and normal insulin sensitivity predominate. We investigated ghrelin levels and their relationship with hunger, food intake and both anthropometric and insulin resistance parameters in patients with thyroid dysfunction. DESIGN AND METHODS:  We studied 24 hyperthyroid and 17 hypothyroid patients before and after normalisation of thyroid hormone levels and their respective body mass index (BMI)-matched control group. We measured plasma ghrelin levels, homeostasis model assessment of insulin resistance (HOMA-IR) index, a hunger score, mean three-day calorie intake and anthropometric parameters. RESULTS:  In hyperthyroidism, HOMA-IR index was higher (3.21 +/- 0.60 vs 1.67 +/- 0.15 mMmU/l; P = 0.014, t test for independent data) and ghrelin levels were lower (463.6 +/- 36.4 vs 561.1 +/- 32.1 pg/ml; P = 0.041, Mann-Whitney U-test) than in its control group and both normalised after treatment (HOMA-IR: 2.28 +/- 0.38 mMmU/l; P = 0.106, t test for independent data, and ghrelin: 539.7 +/- 45.4 pg/ml; P = 0.549, Mann-Whitney U-test). Glucose, as a component of HOMA-IR index was the only predictor for ghrelin levels (beta = -0.415, P = 0.044, stepwise multiple regression analysis). In hypothyroidism, HOMA-IR index and ghrelin levels were similar to those in its control group both before and after treatment. In both thyroid dysfunction states, no correlations were observed between changes in ghrelin levels and in free T4, free T3, anthropometric parameters, total calorie intake and hunger score. CONCLUSIONS:  In thyroid dysfunction states, ghrelin levels seemed to be in relation to insulin resistance and not to energy balance and food intake regulation, as seen in other physiological and pathological states.

Loneliness predicts postprandial ghrelin and hunger in women.
            (Jaremka et al., 2015) Download
Loneliness is strongly linked to poor health. Recent research suggests that appetite dysregulation provides one potential pathway through which loneliness and other forms of social disconnection influence health. Obesity may alter the link between loneliness and appetite-relevant hormones, one unexplored possibility. We examined the relationships between loneliness and both postmeal ghrelin and hunger, and tested whether these links differed for people with a higher versus lower body mass index (BMI; kg/m(2)). During this double-blind randomized crossover study, women (N=42) ate a high saturated fat meal at the beginning of one full-day visit and a high oleic sunflower oil meal at the beginning of the other. Loneliness was assessed once with a commonly used loneliness questionnaire. Ghrelin was sampled before the meal and postmeal at 2 and 7h. Self-reported hunger was measured before the meal, immediately postmeal, and then 2, 4, and 7h later. Lonelier women had larger postprandial ghrelin and hunger increases compared with less lonely women, but only among participants with a lower BMI. Loneliness and postprandial ghrelin and hunger were unrelated among participants with a higher BMI. These effects were consistent across both meals. These data suggest that ghrelin, an important appetite-regulation hormone, and hunger may link loneliness to weight gain and its corresponding negative health effects among non-obese people.


 

Ghrelin stimulates gastric emptying and hunger in normal-weight humans.
            (Levin et al., 2006) Download
CONTEXT:  Ghrelin is produced primarily by enteroendocrine cells in the gastric mucosa and increases gastric emptying in patients with gastroparesis. MAIN OBJECTIVE:  The objective of the study was to evaluate the effect of ghrelin on gastric emptying, appetite, and postprandial hormone secretion in normal volunteers. DESIGN:  This was a randomized, double-blind, crossover study. SUBJECTS:  Subjects included normal human volunteers and patients with GH deficiency. INTERVENTION:  Intervention included saline or ghrelin (10 pmol/kg.min) infusion for 180 min after intake of a radioactively labeled omelette (310 kcal) or GH substitution in GH-deficient patients. MAIN OUTCOME MEASURES:  Measures consisted of gastric empty-ing parameters and postprandial plasma levels of ghrelin, cholecystokinin, glucagon-like peptide-1, peptide YY, and motilin. RESULTS:  The emptying rate was significantly faster for ghrelin (1.26 +/- 0.1% per minute), compared with saline (0.83% per minute) (P < 0.001). The lag phase (16.2 +/- 2.2 and 26.5 +/- 3.8 min) and half-emptying time (49.4 +/- 3.9 and 75.6 +/- 4.9 min) of solid gastric emptying were shorter during ghrelin infusion, compared with infusion of saline (P < 0.001). The postprandial peak in plasma concentration for cholecystokinin and glucagon-like peptide-1 occurred earlier and was higher during ghrelin infusion. There was no significant effect of ghrelin on plasma motilin or peptide YY. There was no difference in gastric emptying before and after GH substitution. CONCLUSION:  Our results demonstrate that ghrelin increases the gastric emptying rate in normal humans. The effect does not seem to be mediated via GH or motilin but may be mediated by the vagal nerve or directly on ghrelin receptors in the stomach. Ghrelin receptor agonists may have a role as prokinetic agents.

Ghrelin: central and peripheral implications in anorexia nervosa.
            (Méquinion et al., 2013) Download
Increasing clinical and therapeutic interest in the neurobiology of eating disorders reflects their dramatic impact on health. Chronic food restriction resulting in severe weight loss is a major symptom described in restrictive anorexia nervosa (AN) patients, and they also suffer from metabolic disturbances, infertility, osteopenia, and osteoporosis. Restrictive AN, mostly observed in young women, is the third largest cause of chronic illness in teenagers of industrialized countries. From a neurobiological perspective, AN-linked behaviors can be considered an adaptation that permits the endurance of reduced energy supply, involving central and/or peripheral reprograming. The severe weight loss observed in AN patients is accompanied by significant changes in hormones involved in energy balance, feeding behavior, and bone formation, all of which can be replicated in animals models. Increasing evidence suggests that AN could be an addictive behavior disorder, potentially linking defects in the reward mechanism with suppressed food intake, heightened physical activity, and mood disorder. Surprisingly, the plasma levels of ghrelin, an orexigenic hormone that drives food-motivated behavior, are increased. This increase in plasma ghrelin levels seems paradoxical in light of the restrained eating adopted by AN patients, and may rather result from an adaptation to the disease. The aim of this review is to describe the role played by ghrelin in AN focusing on its central vs. peripheral actions. In AN patients and in rodent AN models, chronic food restriction induces profound alterations in the « ghrelin » signaling that leads to the development of inappropriate behaviors like hyperactivity or addiction to food starvation and therefore a greater depletion in energy reserves. The question of a transient insensitivity to ghrelin and/or a potential metabolic reprograming is discussed in regard of new clinical treatments currently investigated.

A single night of sleep deprivation increases ghrelin levels and feelings of hunger in normal-weight healthy men.
            (Schmid et al., 2008) Download
Sleep loss is currently proposed to disturb endocrine regulation of energy homeostasis leading to weight gain and obesity. Supporting this view, a reduction of sleep duration to 4 h for two consecutive nights has recently been shown to decrease circulating leptin levels and to increase ghrelin levels, as well as self-reported hunger. We hypothesized that similar endocrine alterations occur even after a single night of sleep restriction. In a balanced order, nine healthy normal-weight men spent three nights in our sleep laboratory separated by at least 2 weeks: one night with a total sleep time of 7 h, one night with a total sleep time of 4.5 h and one night with total sleep deprivation (SD). On a standard symptom-rating scale, subjects rated markedly stronger feelings of hunger after total SD than after 7 h sleep (3.9 +/- 0.7 versus 1.7 +/- 0.3; P = 0.020) or 4.5 h sleep (2.2 +/- 0.5; P = 0.041). Plasma ghrelin levels were 22 +/- 10% higher after total SD than after 7 h sleep (0.85 +/- 0.06 versus 0.72 +/- 0.04 ng mL(-1); P = 0.048) with intermediate levels of the hormone after 4.5 h sleep (0.77 +/- 0.04 ng mL(-1)). Serum leptin levels did not differ between conditions. Feelings of hunger as well as plasma ghrelin levels are already elevated after one night of SD, whereas morning serum leptin concentrations remain unaffected. Thus, our results provide further evidence for a disturbing influence of sleep loss on endocrine regulation of energy homeostasis, which on the long run may result in weight gain and obesity.

 

Interaction between gastric and upper small intestinal hormones in the regulation of hunger and satiety: ghrelin and cholecystokinin take the central stage.
            (Stengel and Taché, 2011) Download
Several peptides are produced and released from endocrine cells scattered within the gastric oxyntic and the small intestinal mucosa. These peptide hormones are crucially involved in the regulation of gastrointestinal functions and food intake by conveying their information to central regulatory sites located in the brainstem as well as in the forebrain, such as hypothalamic nuclei. So far, ghrelin is the only known hormone that is peripherally produced in gastric X/A-like cells and centrally acting to stimulate food intake, whereas the suppression of feeding seems to be much more redundantly controlled by a number of gut peptides. Cholecystokinin produced in the duodenum is a well established anorexigenic hormone that interacts with ghrelin to modulate food intake indicating a regulatory network located at the first site of contact with nutrients in the stomach and upper small intestine. In addition, a number of peptides including leptin, urocortin 2, amylin and glucagon-like peptide 1 interact synergistically with CCK to potentiate its satiety signaling effect. New developments have led to the identification of additional peptides in X/A-like cells either derived from the pro-ghrelin gene by alternative splicing and posttranslational processing (obestatin) or a distinct gene (nucleobindin2/nesfatin-1) which have been investigated for their influence on food intake.

Gastric peptides and their regulation of hunger and satiety.
            (Stengel and Taché, 2012b) Download
Ingestion of food affects the secretion of hormones from specialized endocrine cells scattered within the intestinal mucosa. Upon release, these hormones mostly decrease food intake by signaling information to the brain. Although enteroendocrine cells in the small intestine were thought to represent the predominant gut-brain regulators of food intake, recent advances also established a major role for gastric hormones in these regulatory pathways. First and foremost, the gastric endocrine X/A-like cell was in the focus of many studies due to the production of ghrelin, which is until now the only known orexigenic hormone that is peripherally produced and centrally acting. Although X/A-cells were initially thought to only release one hormone that stimulates food intake, this view has changed with the identification of additional peptide products also derived from this cell, namely desacyl ghrelin, obestatin, and nesfatin-1. Desacyl ghrelin may play a counter-regulatory role to the food intake stimulatory effect of ghrelin. The same property was suggested for obestatin; however, this hypothesis could not be confirmed in numerous subsequent studies. Moreover, the description of the stomach as the major source of the novel anorexigenic hormone nesfatin-1 derived from the NUCB2 gene further corroborated the assumption that the gastric X/A-like cell products are not only stimulant but also inhibitors of feeding, thereby acting as so far unique dual regulator of food intake located in a logistically important place where the gastrointestinal tract has initial contact with food.

Yin and Yang - the Gastric X/A-like Cell as Possible Dual Regulator of Food Intake.
            (Stengel and Taché, 2012a) Download
Ingestion of food affects secretion of hormones from enteroendocrine cells located in the gastrointestinal mucosa. These hormones are involved in the regulation of various gastrointestinal functions including the control of food intake. One cell in the stomach, the X/A-like has received much attention over the past years due to the production of ghrelin. Until now, ghrelin is the only known orexigenic hormone that is peripherally produced and centrally acting to stimulate food intake. Subsequently, additional peptide products of this cell have been described including desacyl ghrelin, obestatin and nesfatin-1. Desacyl ghrelin seems to be involved in the regulation of food intake as well and could play a counter-balancing role of ghrelin's orexigenic effect. In contrast, the initially proposed anorexigenic action of obestatin did not hold true and therefore the involvement of this peptide in the regulation of feeding is questionable. Lastly, the identification of nesfatin-1 in the same cell in different vesicles than ghrelin extended the function of this cell type to the inhibition of feeding. Therefore, this X/A-like cell could play a unique role by encompassing yin and yang properties to mediate not only hunger but also satiety.


 

B-type natriuretic peptide modulates ghrelin, hunger, and satiety in healthy men.
            (Vila et al., 2012) Download
Chronic heart failure is accompanied by anorexia and increased release of B-type natriuretic peptide (BNP) from ventricular cardiomyocytes. The pathophysiological mechanisms linking heart failure and appetite regulation remain unknown. In this study, we investigated the impact of intravenous BNP administration on appetite-regulating hormones and subjective ratings of hunger and satiety in 10 healthy volunteers. Participants received in a randomized, placebo-controlled, crossover, single-blinded study (subject) placebo once and 3.0 pmol/kg/min human BNP-32 once administered as a continuous infusion during 4 h. Circulating concentrations of appetite-regulating peptides were measured hourly. Subjective ratings of hunger and satiety were evaluated by visual analog scales. BNP inhibited the fasting-induced increase in total and acylated ghrelin concentrations over time (P = 0.043 and P = 0.038, respectively). In addition, BNP decreased the subjective rating of hunger (P = 0.009) and increased the feeling of satiety (P = 0.012) when compared with placebo. There were no significant changes in circulating peptide YY, glucagon-like peptide 1, oxyntomodulin, pancreatic polypeptide, leptin, and adiponectin concentrations. In summary, our results demonstrate that BNP exerts anorectic effects and reduces ghrelin concentrations in men. These data, taken together with the known cardiovascular properties of ghrelin, support the existence of a heart-gut-brain axis, which could be therapeutically targeted in patients with heart failure and obesity.

 


 

References

Andreozzi, P, et al. (2015), ‘The Bitter Taste Receptor Agonist Quinine Reduces Calorie Intake and Increases the Postprandial Release of Cholecystokinin in Healthy Subjects.’, J Neurogastroenterol Motil, 21 (4), 511-19. PubMed: 26351252
Chaudhri, O, C Small, and S Bloom (2006), ‘Gastrointestinal hormones regulating appetite.’, Philos Trans R Soc Lond B Biol Sci, 361 (1471), 1187-209. PubMed: 16815798
Cummings, DE, et al. (2004), ‘Plasma ghrelin levels and hunger scores in humans initiating meals voluntarily without time- and food-related cues.’, Am J Physiol Endocrinol Metab, 287 (2), E297-304. PubMed: 15039149
Di Francesco, V, et al. (2006), ‘Unbalanced serum leptin and ghrelin dynamics prolong postprandial satiety and inhibit hunger in healthy elderly: another reason for the “anorexia of aging”.’, Am J Clin Nutr, 83 (5), 1149-52. PubMed: 16685059
Giménez-Palop, O, et al. (2005), ‘Circulating ghrelin in thyroid dysfunction is related to insulin resistance and not to hunger, food intake or anthropometric changes.’, Eur J Endocrinol, 153 (1), 73-79. PubMed: 15994748
Jaremka, LM, et al. (2015), ‘Loneliness predicts postprandial ghrelin and hunger in women.’, Horm Behav, 70 57-63. PubMed: 25725426
Levin, F, et al. (2006), ‘Ghrelin stimulates gastric emptying and hunger in normal-weight humans.’, J Clin Endocrinol Metab, 91 (9), 3296-302. PubMed: 16772353
Méquinion, M, et al. (2013), ‘Ghrelin: central and peripheral implications in anorexia nervosa.’, Front Endocrinol (Lausanne), 4 15. PubMed: 23549309
Schmid, SM, et al. (2008), ‘A single night of sleep deprivation increases ghrelin levels and feelings of hunger in normal-weight healthy men.’, J Sleep Res, 17 (3), 331-34. PubMed: 18564298
Stengel, A and Y Taché (2011), ‘Interaction between gastric and upper small intestinal hormones in the regulation of hunger and satiety: ghrelin and cholecystokinin take the central stage.’, Curr Protein Pept Sci, 12 (4), 293-304. PubMed: 21428875
——— (2012a), ‘Yin and Yang - the Gastric X/A-like Cell as Possible Dual Regulator of Food Intake.’, J Neurogastroenterol Motil, 18 (2), 138-49. PubMed: 22523723
——— (2012b), ‘Gastric peptides and their regulation of hunger and satiety.’, Curr Gastroenterol Rep, 14 (6), 480-88. PubMed: 23001831
Vila, G, et al. (2012), ‘B-type natriuretic peptide modulates ghrelin, hunger, and satiety in healthy men.’, Diabetes, 61 (10), 2592-96. PubMed: 22698919