Intragastric pressure during food intake: a physiological and minimally invasive method to assess gastric accommodation

Background The stomach relaxes upon food intake and thereby provides a reservoir while keeping the intragastric pressure (IGP) low. We set out to determine whether we could use IGP as a measurement for stomach accommodation during food intake. Methods In fasted healthy volunteers (n = 7–17) a manometer and an infusion catheter were positioned in the proximal stomach. After a stabilization period a nutrient drink was intragastrically infused at 15, 30 and 60 mL min^?1. To investigate the effect of impaired accommodation the effect of N^G‐monomethyl‐l ‐arginine (L‐NMMA) was examined. The volunteers scored satiation until maximum, when the experiment ended. The IGP was presented as a change from baseline (mean ± SEM) and compared with repeated measures anova . Key Results Independent on the ingestion speed, the IGP decreased initially and gradually increased thereafter. Volunteers scored maximal satiation after 699 ± 62, 809 ± 90 and 997 ± 120 mL nutrient drink infused (15, 30 and 60 mL min^?1 respectively; P < 0.01). Maximum IGP decrease was 3.4 ± 0.5 mmHg after 205 ± 28 mL, 5.1 ± 0.7 mmHg after 212 ± 46 mL, and 5.2 ± 0.7 mmHg after 296 ± 28 mL infused volume [15, 30 and 60 mL min^?1 respectively; not significant (ns)]. Post hoc analysis showed significant correlations between IGP and satiation score increase. During L‐NMMA infusion IGP was significantly increased while subjects drank significantly less (816 ± 91 vs 1032 ± 71 mL; P < 0.005). Interestingly, the correlation between IGP increase and satiation score increase did not differ after L‐NMMA treatment. Conclusions & Inferences The IGP during nutrient drink ingestion provides a minimally invasive alternative to the barostat for the assessment of gastric accommodation. These findings furthermore indicate that IGP is a major determinant of satiation.     

Diazepam reverses bombesin-induced gastric spasms and food intake reduction in the rat

Bombesin (2–16 μg/kg, i.p.) produced abnormally large gastric contractions in intact rats consisting of increases in gastric pressure and motility. The effect was antagonized by diazepam (5 mg/kg, i.p.). The same dosage of diazepam abolished bombesin-induced food intake reduction. Diazepam by itself did not increase food intake above control levels. The time course of this behavioral antagonism was followed. There was no significant difference in the intake time course of diazepam-alone and diazepam-bombesin treatments, while there was a significant difference between the saline control and the bombesin-alone treatments. Intake of the saline control, the diazepam-alone and the diazepam-bombesin treatment terminated at the same level, while the bombesin-alone remained significantly different. Additionally, swift aversion to 8 μg/kg bombesin was obtained when flavored nutrient was substituted for flavored water, suggesting that the aversion developed as a consequence of interaction with the ingested diet. Abnormalities that result from bombesin are aggravated when food is substituted for water. It is concluded that food intake reduction is due to the bombesin-produced intragastric abnormalities, and not by satiety.     

Postural changes in proximal gastric volume and pressure measured using a gastric barostat

A barostat was used to examine the effect of changes in posture on the volume and pressure in a bag positioned in the proximal stomach of 14 normal volunteers. Volumes in the supine position were compared with those in the standing, left lateral and right lateral positions at a constant pressure 2 mmHg above basal intragastric pressure. A separate series of measurements was then used to evaluate the effects of the same postural changes on pressure within the bag whilst its volume was kept constant. Changing from the supine to the left lateral position decreased bag volume by 62% when pressure was controlled; pressure increased by 60% when volume was controlled. In contrast, movement from the supine to the right lateral position resulted in a 68% increase in bag volume and a 31% fall in pressure. Moving from supine to standing had inconsistent effects on bag volume and pressure. There was a negative correlation between the magnitudes of the changes in pressure and volume (r² = 0.557). The observed effects of posture probably result from changes in the compression of the stomach by abdominal viscera and indicate that subject position must be specified and maintained constant in studies of proximal gastric motor function using a barostat.     

Obestatin – a ghrelin-associated peptide that does not hold its promise to suppress food intake and motility

Ghrelin is a gut peptide well established to induce prokinetic and appetite stimulatory actions. Obestatin is a novel 23-amino acid peptide derived from the processing of the ghrelin gene. The peptide name was in keeping with its initially reported actions to suppress food intake and digestive motility and to antagonize ghrelin's stimulatory effect through interaction with the orphan GPR-39 receptor. However, subsequently, these findings have been questioned because obestatin actions to reduce food intake and to inhibit gastrointestinal (GI) motility in vivo and in vitro have not been reproduced by several groups. Furthermore, while GPR-39 appears to be involved in gut motor functions, convergent reports showed that obestatin is not the cognate ligand for this receptor. In light of recent controversy over the effects of obestatin, the present findings from De Smet et al. provides additional evidence that obestatin does not influence food intake and GI motility in vivo and in vitro. Taken together, existing reports curtail the initial promise that obestatin is a new regulator of appetite and digestive motility. Therefore, it is proposed to rename obestatin as ghrelin-associated peptide.     

Histidyl-proline diketopiperazine decreases food intake in rats

Histidyl-proline diketopiperazine was found to suppress food intake during stress-induced eating (10⁻⁶–10⁻⁸ mol), starvation-induced eating (10⁻⁸ mol) and over an 8 h period of spontaneous eating (10⁻⁸ mol). In contrast, other cyclic piperzines failed to alter food ingestion. The suppressive effect of histidyl-proline diketopiperazine was antagonized by the enkephalin analogue, d-Ala-Met-enkephalin, in equimolar concentrations.     

Adipose tissue hormones and the regulation of food intake

Over the past decade, adipose tissue has been shown to produce numerous factors that act as hormones. Many of these act on the brain to regulate energy balance via dual effects on food intake and energy expenditure. These include well-characterised hormones such as leptin, oestrogen and glucocorticoids and novel factors such as adiponectin and resistin. This review provides a perspective on the role of these factors as lipostats.     

Intragastric distribution of a standardized meal in health and functional dyspepsia: correlation with specific symptoms

In functional dyspepsia, abnormal intragastric distribution of a test meal has been identified but has never been correlated to any symptom pattern. The aim of this study was to compare the intragastric distribution of a meal between functional dyspepsia patients and controls, and to correlate distribution with symptom patterns, using scintigraphic gastric emptying studies. In forty patients with functional dyspepsia and 29 healthy volunteers, scintigraphic planar images were obtained immediately after ingestion of a mixed radiolabelled test meal and every 20 min for 2 h. The images of the stomach were divided into proximal and distal compartments. The mean intragastric distribution was similar in patients and controls. Over the whole test, 18 (45%) and 20 (50%) patients had a distal redistribution of the solid and liquid phase of the meal, respectively, while proximal retention of these phases was found in 13 (33%) and 9 (23%) patients. Early satiety was associated with early distal redistribution of the liquid phase and fullness was associated with late proximal retention. This study shows similar intragastric distribution of a test meal in health and functional dyspepsia. Within the patient group, an association between abnormal intragastric distribution patterns and symptom profiles was found, which might be related to different pathophysiological mechanisms.     

Role of oxytocin in the control of stress and food intake

Oxytocin neurones in the hypothalamus are activated by stressful stimuli and food intake. The oxytocin receptor is located in various brain regions, including the sensory information‐processing cerebral cortex; the cognitive information‐processing prefrontal cortex; reward‐related regions such as the ventral tegmental areas, nucleus accumbens and raphe nucleus; stress‐related areas such as the amygdala, hippocampus, ventrolateral part of the ventromedial hypothalamus and ventrolateral periaqueductal gray; homeostasis‐controlling hypothalamus; and the dorsal motor complex controlling intestinal functions. Oxytocin affects behavioural and neuroendocrine stress responses and terminates food intake by acting on the metabolic or nutritional homeostasis system, modulating emotional processing, reducing reward values of food intake, and facilitating sensory and cognitive processing via multiple brain regions. Oxytocin also plays a role in interactive actions between stress and food intake and contributes to adaptive active coping behaviours.     

Centrally administered galanin-like peptide modifies food intake in the rat: a comparison with galanin

Galanin-like peptide (GALP) is a recently identified neuropeptide that shares sequence homology with the orexigenic neuropeptide, galanin. In contrast to galanin, GALP is reported to bind preferentially to the galanin receptor 2 subtype (GalR2) compared to GalR1. The aim of this study was to determine the effect of GALP on feeding, body weight and core body temperature after central administration in rats compared to the effects of galanin. Intracerebroventricular (i.c.v.) injection of GALP (1 micro g-10 micro g) significantly stimulated feeding at 1 h in both satiated and fasted Sprague-Dawley rats. However, 24 h after GALP injection, body weight gain was significantly reduced and food intake was also usually decreased. In addition, i.c.v. GALP caused a dose-related increase in core body temperature, which lasted until 6-8 h after injection, and was reduced by peripheral administration of the cyclooxygenase inhibitor, flurbiprofen (1 mg/kg). Similar to GALP, i.c.v. injection of galanin (5 micro g) significantly increased feeding at 1 h in satiated rats. However, there was no difference in food intake and body weight at 24 h, and galanin only caused a transient rise in body temperature. Thus, similar to galanin, GALP has an acute orexigenic effect on feeding. However, GALP also has an anorectic action, which is apparent at a later time. Therefore, GALP has complex opposing actions on energy homeostasis.     

Area postrema: site where cholecystokinin acts to decrease food intake

Administration of cholecystokinin (CCK) reduces food intake in rats. This effect of CCK was attenuated in rats with thermal lesions of the area postrema. This result was specific to CCK, as area postrema lesions had no effect on the reduction in food intake produced by amphetamine. The effect of the lesions was not due to changes in taste sensation as the lesioned rats showed no deficits in morphine induced conditioned taste aversions. Thus, the area postrema may be the major site where CCK acts to decrease food intake.     

Perinatal protein restriction reduces the inhibitory action of serotonin on food intake

Early malnutrition has been associated with a high risk of developing obesity, diabetes and cardiovascular diseases in adulthood. In animals, poor perinatal nutrition produces hyperphagia and persistent increased levels of serotonin (5-HT) in the brain. Inasmuch as 5-HT is directly related to the negative regulation of food intake, here we have investigated whether the anorexic effects of 5-HT are altered by protein malnutrition. Pregnant Sprague-Dawley rats were fed ad libitum either a control (20% protein) or a low-protein (8% protein) diet throughout pregnancy and lactation. At weaning, pups received a standard diet and at 35 days their feeding behaviour was evaluated after the administration of dl -fenfluramine ( dl -FEN), an anorexic compound that blocks the reuptake of 5-HT and stimulates its release. Male offspring born to protein-restricted dams exhibited significantly decreased body weight and hyperphagia compared with controls. dl -FEN dose-dependently reduced the 1 h chow intake at the onset of the dark cycle in both control and undernourished rats. However, the hypophagic effects of dl -FEN were significantly attenuated in animals submitted perinatally to protein restriction. The stimulatory action of dl -FEN on c-fos immunoreactivity within the paraventricular nucleus of the hypothalamus was also decreased in low-protein-fed rats. Further pharmacological analysis with selective 5-HT_1B and 5-HT_2C receptor agonist showed that the reduced anorexic effects of 5-HT in malnourished animals were coupled to a desensitization of 5-HT_1B receptors. These observations indicate that the hyperphagia associated with metabolic programming is at least partially related to a reduced regulatory function of 5-HT on food intake.     

Central administration of pan‐somatostatin agonist ODT8‐SST prevents abdominal surgery‐induced inhibition of circulating ghrelin,food intake and gastric emptying in rats

Background Activation of brain somatostatin receptors (sst_1–5) with the stable pan‐sst_1–5 somatostatin agonist, ODT8‐SST blocks acute stress and central corticotropin‐releasing factor (CRF)‐mediated activation of endocrine and adrenal sympathetic responses. Brain CRF signaling is involved in delaying gastric emptying (GE) immediately post surgery. We investigated whether activation of brain sst signaling pathways modulates surgical stress‐induced inhibition of gastric emptying and food intake. Methods Fasted rats were injected intracisternally (i.c.) with somatostatin agonists and underwent laparotomy and 1‐min cecal palpation. Gastric emptying of a non‐nutrient solution and circulating acyl and desacyl ghrelin levels were assessed 50 min post surgery. Food intake was monitored for 24 h. Key Results The abdominal surgery‐induced inhibition of GE (65%), food intake (73% at 2 h) and plasma acyl ghrelin levels (67%) was completely prevented by ODT8‐SST (1 μg per rat, i.c.). The selective sst₅ agonist, BIM‐23052 prevented surgery‐induced delayed GE, whereas selective sst₁, sst₂, or sst₄ agonists had no effect. However, the selective sst₂ agonist, S‐346‐011 (1 μg per rat, i.c.) counteracted the abdominal surgery‐induced inhibition of acyl ghrelin and food intake but not the delayed GE. The ghrelin receptor antagonist, [D‐Lys³]‐GHRP‐6 (0.93 mg kg^?1, intraperitoneal, i.p.) blocked i.p. ghrelin‐induced increased GE, while not influencing i.c. ODT8‐SST‐induced prevention of delayed GE and reduced food intake after surgery. Conclusions & Inferences ODT8‐SST acts in the brain to prevent surgery‐induced delayed GE likely via activating sst₅. ODT8‐SST and the sst₂ agonist prevent the abdominal surgery‐induced decrease in food intake and plasma acyl ghrelin indicating dissociation between brain somatostatin signaling involved in preventing surgery‐induced suppression of GE and feeding response.     

Calmodulin infused intracerebroventricularly enhances food intake in the cat

In the fasted cat, calmodulin (CaM) infused into the cerebral ventricle produces an increase in the normal intake of food in a dose-dependent manner. The enhancement of feeding by CaM seems to be functionally specific since the response was: (1) abolished by the simultaneous intraventricular infusion of calcineurin, a specific CaM antagonist; (2) not mimicked by another calcium binding protein, troponin C; and (3) independent of the CaM's lack of effect on body temperature and water intake. This finding opens up the dual possibility that this Ca2+ binding protein may affect receptors other than intracellularly and that CaM is involved in specific functions controlled by the brain.     

摄食控制的神经体液机制研究进展

从多种神经递质和激素对摄食行为的复杂影响,迷走神经在传递外周和中枢信号中的重要地位,以及中枢神经系统对摄食相关信息的整合作用三个方面,综述了摄食控制神经体液机制研究的一些新进展。     

RhoA in tyrosine hydroxylase neurones regulates food intake and body weight via altered sensitivity to peripheral hormones

Dopamine‐producing tyrosine hydroxylase (TH) neurones in the hypothalamic arcuate nucleus (ARC) have recently been shown to be involved in ghrelin signalling and body weight homeostasis. In the present study, we investigate the role of the intracellular regulator RhoA in hypothalamic TH neurones in response to peripheral hormones. Diet‐induced obesity was found to be associated with increased phosphorylation of TH in ARC, indicating obesity‐associated increased activity of ARC TH neurones. Mice in which RhoA was specifically knocked out in TH neurones (TH‐RhoA^?/? mice) were more sensitive to the orexigenic effect of peripherally administered ghrelin and displayed an abolished response to the anorexigenic hormone leptin. When TH‐RhoA^?/? mice were challenged with a high‐fat high‐sucrose (HFHS) diet, they became hyperphagic and gained more body weight and fat mass compared to wild‐type control mice. Importantly, lack of RhoA prevented development of ghrelin resistance, which is normally observed in wild‐type mice after long‐term HFHS diet feeding. Patch‐clamp electrophysiological analysis demonstrated increased ghrelin‐induced excitability of TH neurones in lean TH‐RhoA^?/? mice compared to lean littermate control animals. Additionally, increased expression of the orexigenic hypothalamic neuropeptides agouti‐related peptide and neuropeptide Y was observed in TH‐RhoA^?/? mice. Overall, our data indicate that TH neurones in ARC are important for the regulation of body weight homeostasis and that RhoA is both a central effector in these neurones and important for the development of obesity‐induced ghrelin resistance. The obese phenotype of TH‐RhoA^?/? mice may be a result of increased sensitivity to ghrelin and decreased sensitivity to leptin, resulting in increased food intake.     

The effect of short-term, low-dose tricyclic and tetracyclic antidepressant treatment on satiation, postnutrient load gastrointestinal symptoms and gastric emptying: a double-blind, randomized, placebo-controlled trial.

Antidepressants are commonly prescribed for patients with functional dyspepsia. However, the effect of tricyclic antidepressants on satiation and gastric emptying remains unclear, and there are no data for tetracyclic compounds. To compare the effects of nortriptyline (maximum dose: 50 mg daily) and mirtazapine (30 mg daily) vs placebo on gastric emptying, gastric satiation and postprandial symptoms after a nutrient load in healthy volunteers. Randomized, double-blind, placebo-controlled study evaluated gastric function before and after 14 days of nortriptyline (n = 13), mirtazapine (n = 13), or placebo (n = 14) in healthy volunteers. Validated methods were used to study gastric emptying ((13)C-octanoate) and satiation postnutrient drink test. The three arms were comparable with regard to age, gender, body mass index and hospital anxiety/depression scale. There were no statistically significant effects of mirtazapine or nortriptyline on gastric emptying compared to placebo (P = 0.34). Maximum tolerated volume was similar on drug and placebo (P = 0.56). Aggregate symptom score 30 min postmaximum tolerated volume after nutrient drink challenge on placebo was 132 (+/-21), vs 165 (+/-21) on mirtazapine, and 126 (+/-21) on nortriptyline 50 mg respectively (P = 0.28). Tricyclic and tetracyclic antidepressant agents do not appear to have significant effects on gastric motor or satiation postnutrient challenge in healthy individuals at the doses tested.     

Influence of the 5‐HT3 receptor antagonist ondansetron on gastric sensorimotor function and nutrient tolerance in healthy volunteers

Background Serotonin is believed to be involved in the regulation of the gastric accommodation reflex in man however which receptor subtype(s) are involved remains to be elucidated. Methods Eleven healthy subjects (nine men, age 19–30) underwent a gastric barostat and a drinking test after treatment with either placebo or ondansetron (8 mg intravenously). During the barostat protocol an intragastric flaccid bag was stepwise distended (2 mmHg increments 2 min) to determine gastric compliance and sensitivity to distention. Subsequently, the pressure level was set at intra‐abdominal pressure +2 mmHg while volume was followed before and after administration of a liquid meal (200 mL; 300 kcal). During the drink test volunteers drank at a rate of 15 mL min^?1 until maximal satiation. Results (mean ± SEM) were compared using t‐tests and mixed model analysis. Key Results Gastric compliance was not significantly altered by ondansetron (51.5 ± 5.6 vs 49.2 ± 5.2 mL mmHg^?1), neither were the pressure thresholds for first perception or discomfort. Ondansetron treatment did not affect basal gastric tone (173 ± 14 vs 156 ± 12 mL), neither did it affect the amplitude of the meal‐induced relaxation (160 ± 52 vs 131 ± 43 mL) or the maximum volume increase after the meal (264 ± 54 mL vs 234 ± 51 mL). During the drinking test the amount of liquid meal ingested at maximum satiation was significantly increased by ondansetron (784 ± 74 vs 907 ± 64 mL, P < 0.05). Conclusions & Inferences These data suggest that 5‐HT acting at 5‐HT₃ receptors is not involved in the control of gastric sensorimotor function, but contributes to the regulation of hunger and satiation in man.