Lack of interaction between peripheral injection of CCK and obestatin in the regulation of gastric satiety signaling in rodents

Obestatin is a new peptide for which anorexigenic effects were recently reported in mice. We investigate whether peripheral injection of obestatin or co-injection with cholecystokinin (CCK) can modulate food intake, gastric motor function (intragastric pressure and emptying) and gastric vagal afferent activity in rodents. Obestatin (30, 100 and 300 microg/kg, i.p.) did not influence cumulative food intake for the 2h post-injection in rats or mice nor gastric emptying in rats. In rats, obestatin (300 microg/kg) did not modify CCK (1 microg/kg, i.p.)-induced significant decrease in food intake (36.6%) and gastric emptying (31.0%). Furthermore, while rats injected with CCK (0.3 microg/kg, i.v.) displayed gastric relaxation, no change in gastric intraluminal pressure was elicited by obestatin (300 microg/kg, i.v.) pre- or post-CCK administration. In in vitro rat gastric vagal afferent preparations, 20 units that had non-significant changes in basal activity after obestatin at 30 microg responded to CCK at 10 ng by a 182% increase. These data show that obestatin neither influences cumulative food intake, gastric motility or vagal afferent activity nor CCK-induced satiety signaling.     

Effect of centrally administered apelin-13 on gastric emptying and gastrointestinal transit in mice

Apelin, as the endogenous ligand for the APJ, regulates many biological functions, including blood pressure, neuroendocrine, drinking behavior, food intake and colonic motility. The present study was designed to investigate the effect of central apelin-13 on gastric emptying and gastrointestinal transit in mice. Intracerebroventricular (i.c.v.) injection of apelin-13 (3 and 10 μg/mouse) decreased gastric emptying rate by 10.9% and 17.1%. This effect was significantly antagonized by the APJ receptor antagonist apelin-13(F13A) and the opioid receptor antagonist naloxone, respectively. However, intraperitoneal (i.p.) injection of apelin-13 (10-100 μg/mouse) did not affect gastric emptying. Apelin-13 (0.3, 1 and 3 μg/mouse, i.c.v.) inhibited gastrointestinal transit by 16.8%, 23.4% and 19.2%. Apelin-13(F13A) and naloxone could also reverse this antitransit effect induced by apelin-13. Taken together, these results suggest that i.c.v. injected apelin-13 inhibits gastric emptying and gastrointestinal transit and it seems that APJ receptor and opioid receptor might be involved in these processes.     

Novel actions of proadrenomedullin N-terminal 20 peptide (PAMP).

Poadrenomedullin N-terminal 20 peptide (PAMP) is a hypotensive peptide derived from the precursor of adrenomedullin. We identified novel actions of proadrenomedullin N-terminal 20 peptide (PAMP) on blood glucose, food intake and gastric emptying after exogenous administration. PAMP elevated blood glucose levels after central injection in fasted mice. PAMP had affinity for bombesin (BN) receptor and the hyperglycemic effect of PAMP was blocked by a BN antagonist, indicating that the elevation of blood glucose after central administration of PAMP was mediated by BN receptor. Centrally administered PAMP inhibited food intake and gastric emptying in fasted conscious mice. However, studies using a BN antagonist and BN receptor knockout mice suggested that the inhibitory effects of PAMP on feeding and gastric emptying were mediated not via BN receptor but via another receptor specific for PAMP. In the present review, we summarize these effects of PAMP and report other novel actions of PAMP on body temperature and oxygen consumption. In addition, the mechanism underlying the cardiovascular functions of PAMP is discussed.     

Intracerebroventricular administration of MK-801 increases food intake through mechanisms independent of gastric emptying

Systemic or hindbrain administration of MK-801, a noncompetitive N-methyl-D-aspartate receptor antagonist, increases meal size. To examine whether MK-801 enhances intake by increasing gastric emptying, we administered MK-801 (2.0 microg/3.0 microl) into the fourth ventricle [intracerebroventricular (ICV)] and measured feeding and gastric emptying of 5-ml NaCl or 15% sucrose loads. In a parallel experiment, we examined food intake and gastric emptying following intraperitoneal (IP) injection of MK-801 (100 microg/kg). MK-801, either IP or ICV, increased 30-min sucrose intake compared with control (12.3 +/- 0.7 vs. 9.8 +/- 0.5 and 16.6 +/- 2.0 vs. 10.7 +/- 0.7 ml, for IP and ICV administration, respectively). Also, IP MK-801 increased 5-min gastric emptying of NaCl (4.13 +/- 0.1 ml emptied) and sucrose (3.11 +/- 0.1 ml emptied) compared with control (3.75 +/- 0.2 and 2.28 +/- 0.1 ml emptied for NaCl and sucrose loads, respectively). In contrast, ICV MK-801 did not alter NaCl emptying (3.82 +/- 0.1 ml emptied) compared with control (3.82 +/- 0.3 ml emptied) and actually reduced gastric emptying of sucrose (2.1 +/- 0.2 and 2.94 +/- 0.1 ml emptied, for MK and vehicle, respectively). These data confirm previous results that systemic as well as hindbrain injection of MK-801 increases food intake. However, because ICV MK-801 failed to increase gastric emptying, these results indicate that MK-801 increases food intake through mechanisms independent of altered gastric emptying.     

Mouse pancreatic polypeptide modulates food intake, while not influencing anxiety in mice

This study was designed to investigate the effects of synthetic mouse pancreatic polypeptide (mPP) on feeding and anxiety in mice. The intracerebroventricular (i.c.v.) injection of mPP (0.003-3 nmol) dose-dependently increased food intake. A significant increase was observed 20 min after i.c.v. injection and continued for 4 h. The intraperitoneal (i.p.) injection of mPP (0.03-30 nmol) dose-dependently decreased food intake. A significant decrease was observed 20 min after i.p. injection and continued for 4 h. In the elevated plus maze test, the i.c.v. injection of mPP (0.003-3 nmol) did not affect anxiety behavior. These results suggest that mPP modulates food intake and the Y4 receptor in the brain may contribute to the regulation of feeding, whereas appearing not to influence anxiety in mice.     

Proadrenomedullin N-terminal 20 peptide (PAMP) inhibits food intake and gastric emptying in mice

We found that proadrenomedullin N-terminal 20 peptide (PAMP) decreased dose-dependently (3-30 nmol/mouse) food intake after intra-third cerebroventricular administration in fasted ddY mice. Gastric emptying also was delayed after central injection of PAMP. In our previous study, PAMP was demonstrated to elicit hyperglycemia via bombesin (BN) receptor. Then, we examined whether the effects of PAMP on feeding and gastric emptying were induced through BN receptor. Surprisingly, PAMP-induced reductions in feeding and gastric emptying rate were not blocked by a BN antagonist, [D-Phe(6), Leu-NHEt(13), des-Met(14)]-BN (6-14). PAMP suppressed feeding in mice lacking gastrin-releasing peptide receptor or BN receptor subtype-3. These results indicate that centrally administered PAMP inhibits food intake, involving the delayed gastric emptying, not through BN receptors but through selective PAMP receptor.     

Duodenum electrical stimulation delays gastric emptying, reduces food intake and accelerates small bowel transit in pigs

Duodenum electrical stimulation (DES) has been shown to delay gastric emptying and reduce food intake in dogs. The aim of this study was to investigate the effects of DES on gastric emptying, small bowel transit and food intake in pigs, a large animal model of obesity. The study consisted of three experiments (gastric emptying, small bowel transit, and food intake) in pigs implanted with internal duodenal electrodes for DES and one or two duodenal cannulas for gastric emptying and small bowel transit. We found that (i) gastric emptying was dose-dependently delayed by DES of different stimulation parameters; (ii) small bowel transit was significantly accelerated with continuous DES in proximal intestine but not with intermittent DES; (iii) DES significantly reduced body weight gain with 100% duty cycle (DC), but not with DES with 40% DC. A marginal difference was noted in food intake among 100% DC session, 40% DC session, and control session. DES with long pulses energy-dependently inhibits gastric emptying in pigs. DES with appropriate parameters accelerates proximal small bowel transit in pigs. DES reduces body weight gain in obese pigs, and this therapeutic effect on obesity is mediated by inhibiting gastric emptying and food intake, and may also possibly by accelerating intestinal transit. DES may have a potential application to treat patients with obesity.     

The TRPA1 Agonist,Methyl Syringate Suppresses Food Intake and Gastric Emptying

Transient receptor potential channel ankryn 1 (TRPA1) expressed in the gastrointestinal tract is associated with gastric motility, gastric emptying, and food intake. In this study, we investigated the effects of methyl syringate, a specific and selective TRPA1 agonist, on food intake, gastric emptying, and gut hormone levels in imprinting control region (ICR) mice. The administration of methyl syringate suppressed cumulative food intake and gastric emptying. In addition, treatment with ruthenium red (RR), a general cation channel blocker, and HC-030031, a selective TRPA1 antagonist, inhibited methyl syringate-induced reduction of food intake and delayed gastric emptying in ICR mice. Methyl syringate also increased plasma peptide YY (PYY) levels, but not glucagon-like peptide-1 (GLP-1) levels. The elevation in PYY was blocked by treatment with RR and HC-030031. The present findings indicate that methyl syringate regulates food intake and gastric emptying through a TRPA1-mediated pathway and, by extension, can contribute to weight suppression.     

Gastric Electrical‐Stimulation Effects on Canine Gastric Emptying,Food Intake,and Body Weight

Objective: It has been reported that electrical stimulation at the distal stomach can disrupt intrinsic gastric electrical activity and delay gastric emptying. Gastric dysrhythmia and impaired gastric emptying are associated with upper gastrointestinal symptoms and weight loss. The purpose of this study was to evaluate the effect of low‐frequency/long‐pulse gastric electrical stimulation (GES), at proximal and distal stomach, on canine gastric emptying, food intake, and body weight. Research Methods and Procedures: Eight dogs were surgically implanted with four pairs of electrodes along the greater curvature and a gastric tube at the dependent part of the stomach. Liquid gastric emptying at baseline, during proximal and distal GES at 6 cycles per minute, was assessed first by a dye dilution technique. Proximal and distal GES were then randomly delivered during feeding for 10 consecutive days, and food intake and body weight were recorded daily. Results: There was no significant difference in gastric emptying parameters among the various sessions. The mean daily food consumption was significantly reduced during both sessions of GES, resulting in significant immediate weight loss. Percentage weight loss was comparable between both sessions of GES. Discussion: Short‐term GES significantly reduced canine food intake and weight. This effect may not be related to changes in gastric emptying. GES may have a potential role in the treatment of obesity.     

Blockade of central GLP-1 receptors prevents CART-induced hypophagia and brain c-Fos expression

Central administration of both CART and GLP-1 reduces feeding and increases c-Fos in brain areas associated with food intake. To determine whether aspects of CART's effects were mediated through GLP-1's action, we examined whether the GLP-1 receptor antagonist des-His1-Glu9-exendin-4 (EX) blocked CART-induced feeding inhibition, and c-Fos activation. An i.c.v. dose of 100 microg EX blocked the feeding inhibitory action of 1 microg of CART i.c.v. and prevented CART-induced c-Fos expression at multiple hindbrain and hypothalamic sites. These data suggest that i.c.v. CART administration activates a central release of GLP-1 to inhibit feeding and produce widespread neural activation.     

Species-specific effects of bombesin on gastric emptying and neurohypophyseal secretion

Previous reports have demonstrated that systemic injection of cholecystokinin (CCK) in rats produces dose-related decreases in food intake, increases in neurohypophyseal secretion of oxytocin (OT), and decreases in gastric emptying. The present studies determined whether systemic injection of bombesin (BBS), another peptide that potently reduces food intake in rats, had similar effects on OT secretion and gastric emptying. Although BBS produces a dose-dependent inhibition of food intake, even very high doses did not significantly affect plasma OT levels and only slightly decreased rates of gastric emptying. Consequently, despite their similar inhibitory effects on food intake, BBS does not appear to activate the same network of central nervous system pathways as does CCK in rats. However, parallel studies in monkeys demonstrated that systemic injection of BBS was effective in stimulating neurohypophyseal secretion of vasopressin rather than OT, in a pattern both qualitatively and quantitatively analogous to the effects of CCK in this species. Together with previous findings that BBS more potently inhibits gastric emptying in primates than in rats, these results therefore also suggest the presence of significant species differences in the central mechanisms by which BBS acts to reduce food intake.     

Roles of pancreatic polypeptide in regulation of food intake

Pancreatic polypeptide (PP) is produced in pancreatic islets of Langerhans and released into the circulation after ingestion of a meal. Peripherally administered PP suppresses food intake and gastric emptying. On the other hand, central administration of PP elicits food intake and gastric emptying. Therefore, PP actions on food intake may be, in part, attributable to gastric emptying. PP transgenic mice exhibit decreases in both food intake and gastric emptying rate that were clearly reversed by anti-PP antiserum. PP is an anorexigenic signal in the periphery and an orexigenic signal in the central nervous system.     

Leptin inhibits gastric emptying in rats: role of CCK receptors and vagal afferent fibers

Leptin regulates energy homeostasis and body weight by balancing energy intake and expenditure. It was recently reported that leptin, released into the gut lumen during the cephalic phase of gastric secretion, is capable of initiating intestinal nutrient absorption. Vagal afferent neurons also express receptors for both CCK and leptin, which are believed to interact in controlling food intake. The present study was undertaken to investigate the central and peripheral effects of leptin on gastric emptying rate. Under anesthesia, male Sprague-Dawley rats (250-300 g) were fitted with gastric Gregory cannulas (n=12) and some had additional cerebroventricular cannulas inserted into their right lateral ventricles. Following recovery, the rate of gastric emptying of saline (300 mOsm/kg H(2)O) was determined after instillation into the gastric fistula (3 ml, 37 degrees C, containing phenol red, 60 mg/l as a non-absorbable dilution marker). Gastric emptying rate was determined from the volume and phenol red concentrations recovered after 5 min. Leptin, injected intraperitoneally (i.p.; 10, 30, 60, 100 microg/kg) or intracerebroventricularly (i.c.v.; 5, 15 microg/rat) 15 min before the emptying, delayed gastric emptying rate of saline at the dose of 30 microg/kg or 15 microg/rat (p<0.001). When CCK(1) receptor blocker L-364,718 (1 mg/kg, i.p.), CCK(2) receptor blocker L-365,260 (1 mg/kg, ip) or adrenergic ganglion blocker bretylium tosylate (15 mg/kg, i.p.) was administered 15 min before ip leptin (30 microg/kg) injections, leptin-induced delay in gastric emptying was abolished only by the CCK(1) receptor blocker (p<0.001). However, the inhibitory effect of central leptin on gastric emptying was reversed by adrenergic blockade, but not by either CCK antagonists. Our results demonstrated that leptin delays gastric emptying. The peripheral effect of leptin on gastric motility appears to be mediated by CCK(1) receptors, suggesting the release of CCK and the involvement of vagal afferent fibers. On the other hand, the central effect of leptin on gastric emptying is likely to be mediated by adrenergic neurons. These results indicate the existence of a functional interaction between leptin and CCK receptors leading to inhibition of gastric emptying and short-term suppression of food intake, providing an additional feedback control in producing satiety.     

Leptin-like effects of MTII are augmented in MSG-obese rats

To evaluate whether MTII, a melanocortin receptor 3/4 agonist, is working in hypophagic and hypothermogenic obese model, we measured food intake, body weight, oxygen consumption, and fat mass following intracerebroventricular (i.c.v.) infusion of MTII in monosodium glutamate (MSG)-induced obese rats. MTII, or artificial cerebrospinal fluid (aCSF), was infused into i.c.v. with an osmotic minipump for 1 week. MSG-obese rats were induced by neonatal injection of MSG. Five-month-old MSG rats were characterized by hypophagia, lower oxygen consumption, hyperleptinemia, and obesity compared to age-matched control rats. The infusion of MTII decreased their food intake, visceral fat, and body weight in MSG-obese rats compared with aCSF-infused rats. The oxygen consumption was increased by MTII treatment in MSG-obese rats compared with aCSF as well as pair fed (PF) rats. Interestingly, these leptin-like effects of MTII were greater in MSG-obese rats than in controls, which might be related to the increased expression of melanocortin receptor 4 (MC4R) in the hypothalamus of MSG-obese rats. Our results suggested that both anorexic and thermogenic mechanisms were activated by MTII in the MSG-obese rats and contributed to the decrease in body weight and fat mass. Moreover, there was a sensitization to MTII caused by upregulation of the melanocortin receptor in the MSG-obese rats.     

Colon electrical stimulation: potential use for treatment of obesity

Obesity is one of the most prevalent health problems in the United States. Current therapeutic strategies for the treatment of obesity are unsatisfactory. We hypothesized the use of colon electrical stimulation (CES) to treat obesity by inhibiting upper gastrointestinal motility. In this preliminary study, we aimed at studying the effects of CES on gastric emptying of solid, intestinal motility, and food intake in dogs. Six dogs, equipped with serosal colon electrodes and a jejunal cannula, were randomly assigned to receive sham-CES or CES during the assessment of: (i) gastric emptying of solids, (ii) postprandial intestinal motility, (iii) autonomic functions, and (iv) food intake. We found that (i) CES delayed gastric emptying of solids by 77%. Guanethidine partially blocked the inhibitory effect of CES on solid gastric emptying; (ii) CES significantly reduced intestinal contractility and the effect lasted throughout the recovery period; (iii) CES decreased vagal activity in both fasting and fed states, increased the sympathovagal balance and marginally increased sympathetic activity in the fasting state; (iv) CES resulted in a reduction of 61% in food intake. CES reduces food intake in healthy dogs and the anorexigenic effect may be attributed to its inhibitory effects on gastric emptying and intestinal motility, mediated via the autonomic mechanisms. Further studies are warranted to investigate the therapeutic potential of CES for obesity.     

Activation of prostaglandin E receptor EP4 subtype suppresses food intake in mice

Prostaglandin (PG) E2, a bioactive lipid produced in the brains of various mammals, decreases food intake after central administration. We examined which of four distinct subtypes of PGE2 receptors (EP1-EP4) mediated the anorexigenic action of PGE2 using highly selective ligands. PGE2 at a dose of 0.1-10 nmol/mouse decreased food intake after intracerebroventricular (i.c.v.) administration in a dose-dependent manner in fasted mice. A centrally administered EP4 agonist, ONO-AE1-329 at a dose of 1-10 nmol/mouse mimicked the anorexigenic action by PGE2. The anorexigenic action of PGE2 or EP4 agonist was ameliorated by EP4 antagonist ONO-AE3-208 at a dose of 10 nmol/mouse. Thus, activation of PGE2-EP4 signaling in the central nervous system suppresses food intake. The EP4 agonist at a dose of 10 nmol/mouse delayed gastric emptying and elevated blood glucose.     

Obestatin对血浆ghrelin和nesfatin-1水平及胃排空的影响

目的:探讨侧脑室注射obestatin对大鼠血浆酰基化ghrelin、去酰基化ghrelin、nesfatin-1水平的影响以及对胃排空的调控。方法:侧脑室注射obestatin,采用酶免疫测定(EIA)法检测血浆酰基化ghrelin、去酰基化ghrelin、nesfatin-1水平以及胃排空率的变化。结果:侧脑室分别注射0.1、0.3或1.0 nmol obestatin,大鼠血浆酰基化ghrelin、去酰基化ghrelin以及nesfatin-1水平无显著改变(P0.05),且酰基化ghrelin与去酰基化ghrelin比率无显著改变(P0.05);侧脑室注射obestatin,大鼠摄食量无显著改变,但胃排空率明显增加(P0.05);胃排空率明显延迟(P0.05)。与侧脑室注射1.0 nmol Obestatin组相比,注射1.0 nmol Obestatin+CRF,大鼠摄食量无显著改变,胃排空率明显延迟(P0.05)。各组摄食量及进入十二指肠内食物量无明显差异(P0.05)。结论:中枢obestatin促进大鼠的胃排空,可能与h/r CRF通路有关。     

High fat maintenance diet attenuates hindbrain neuronal response to CCK

Rats maintained on a high fat diet reduce their food intake less in response to exogenous cholecystokinin (CCK) than rats maintained on a low fat diet. In addition, inhibition of gastric emptying by CCK is markedly attenuated in rats maintained on a high fat diet. Both inhibition of food intake and gastric emptying by CCK are mediated by sensory fibers in the vagus nerve. These fibers terminate on dorsal hindbrain neurons of the nucleus of the solitary tract and area postrema. To determine whether diet-induced changes in the control of feeding and gastric emptying are accompanied by altered vagal sensory responsiveness, we examined dorsal hindbrain expression of Fos-like immunoreactivity (Fos-li) following intraperitoneal CCK injection of rats maintained on high fat or low fat diets. Following CCK, there were numerous Fos-li nuclei in the area postrema and in the commissural and medial subnuclei of the nucleus of the solitary tract of rats maintained on a low fat diet. However, Fos-li was absent or rare in the brains of rats maintained on a high fat diet. These data suggest that the vagal sensory response to exogenous CCK is reduced in rats maintained on a high fat diet. Our results also are consistent with our previous findings that CCK-induced reduction of food intake and gastric emptying are both attenuated in rats maintained on a high fat diet. In addition our results support the hypothesis that attenuation of CCK-induced inhibition of food intake and gastric emptying may be due to diet-induced diminution of vagal CCK responsiveness.     

Suppression of food intake by a complement C3a agonist [Trp5]-oryzatensin(5-9)

[Trp5]-oryzatensin(5-9) (WPLPR), an agonist peptide for complement C3a receptor, has been designed based on the C-terminal region of ileum-contracting peptide oryzatensin derived from rice protein. We previously reported that WPLPR has anti-analgesic and anti-amnesic activities after central or oral administration. In this study, we found a novel function of WPLPR on food intake. WPLPR suppressed food intake after intracerebroventricular or intraperitoneal (i.p.) administration at a dose of 3-30 nmol/mouse or 30-300 mg/kg, respectively, in fasted mice. Orally administered WPLPR at a dose of 300 mg/kg also decreased food intake. WPLPR decreased gastric emptying after i.p. injection at a dose of 300 mg/kg. The anorexigenic activity of WPLPR was blocked by cyclooxygenase inhibitor or antagonist for prostaglandin (PG) E receptor EP4 subtype. These results suggest that WPLPR decreases food intake through PGE2 production followed by EP4 receptor activation.