ORCID Profile
0000-0002-7086-5865
Current Organisation
University of Adelaide
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Publisher: MDPI AG
Date: 26-11-2019
DOI: 10.3390/NU11122882
Abstract: We would like to thank Drs [...]
Publisher: Public Library of Science (PLoS)
Date: 18-08-2015
Publisher: MDPI AG
Date: 21-01-2021
Abstract: High amylose wheat (HAW) contains more resistant starch than standard amylose wheat (SAW) and may have beneficial effects on gastrointestinal health. However, it is currently unclear whether these effects differ according to the level of HAW included in the diet or between males and females. Male and female C57BL/6 mice (n = 8/group/sex) were fed SAW65 (65% SAW control), HAW35 (35% HAW), HAW50 (50% HAW) or HAW65 (65% HAW) diet for eight weeks. Female but not male, mice consuming any amount of HAW exhibited accelerated gastric emptying compared to SAW65 group. In both sexes, relative colon weights were higher in the HAW65 group compared to SAW65 group and in females, relative weights of the small intestine and cecum were also higher in the HAW65 group. In females only, colonic expression of Pyy and Ocln mRNAs were higher in the HAW65 group compared to HAW35 and HAW50 groups. In both sexes, mice consuming higher amounts of HAW (HAW50 or HAW65) had increased fecal bacterial load and relative abundance of Bacteroidetes phylum and reduced relative abundance of Firmicutes compared to SAW65 group. These data are consistent with a beneficial impact of HAW on gastrointestinal health and indicate dose-dependent and sex-specific effects of HAW consumption.
Publisher: MDPI AG
Date: 05-03-2021
DOI: 10.3390/NU13030844
Abstract: Gastrointestinal vagal afferents (VAs) play an important role in food intake regulation, providing the brain with information on the amount and nutrient composition of a meal. This is processed, eventually leading to meal termination. The response of gastric VAs, to food-related stimuli, is under circadian control and fluctuates depending on the time of day. These rhythms are highly correlated with meal size, with a nadir in VA sensitivity and increase in meal size during the dark phase and a peak in sensitivity and decrease in meal size during the light phase in mice. These rhythms are disrupted in diet-induced obesity and simulated shift work conditions and associated with disrupted food intake patterns. In diet-induced obesity the d ened responses during the light phase are not simply reversed by reverting back to a normal diet. However, time restricted feeding prevents loss of diurnal rhythms in VA signalling in high fat diet-fed mice and, therefore, provides a potential strategy to reset diurnal rhythms in VA signalling to a pre-obese phenotype. This review discusses the role of the circadian system in the regulation of gastrointestinal VA signals and the impact of factors, such as diet-induced obesity and shift work, on these rhythms.
Publisher: Elsevier BV
Date: 09-2014
Publisher: Society for Neuroscience
Date: 04-12-2013
DOI: 10.1523/JNEUROSCI.3846-13.2013
Abstract: Food intake is coordinated to cellular metabolism by clock gene expression with a master clock in the suprachiasmatic nucleus synchronized by light exposure. Gastric vagal afferents play a role in regulating food intake, but it is unknown whether they exhibit circadian variation in their mechanosensitivity. We aimed to determine whether gastric vagal afferents express clock genes and whether their response to mechanical stimuli oscillates throughout the light/dark cycle. Nodose ganglia were collected from 8-week-old female C57BL/6 mice every 3 h starting at lights off (1800 h) to quantify Bmal1 , Per1 , Per2 , and Nr1d1 mRNA by qRT-PCR. Additionally in vitro single-fiber recordings of gastric vagal mechanoreceptors were taken at all time points. Per1 , Per2 , Bmal1 , and Nr1d1 mRNA is expressed in the nodose ganglia and levels oscillated over a 24 h period. In mice fed ad libitum , gastric content was 3 times higher at 0000 h and 0300 h than 1200 h. The response of tension receptors to 3 g stretch was reduced by up to 70% at 2100 h, 0000 h, and 0300 h compared with 1200 h. Gastric mucosal receptor response to stroking with a 50 mg von Frey hair was 3 times greater at 1200 h and 1500 h than the response at 0000 h. Similar findings were obtained in mice fasted for 6 h or maintained in darkness for 3 d before study. Therefore, these changes do not result from food intake or the light/dark cycle. Thus, gastric vagal mechanoreceptors display circadian rhythm, which may act to control food intake differentially at different times of the day.
Publisher: BMJ
Date: 10-2005
Publisher: Cambridge University Press (CUP)
Date: 2011
Publisher: Elsevier BV
Date: 12-2004
DOI: 10.1053/J.GASTRO.2004.08.061
Abstract: Visceral mechanoreceptors are critical for perceived sensations and autonomic reflex control of gastrointestinal function. However, the molecular mechanisms underlying visceral mechanosensation remain poorly defined. Degenerin/epithelial Na+ channel (DEG/ENaC) family ion channels are candidate mechanosensory molecules, and we hypothesized that they influence visceral mechanosensation. We examined the influence of the DEG/ENaC channel ASIC1 on gastrointestinal mechanosensory function, on gastric emptying, and on fecal output. We also compared its role in gastrointestinal and somatic sensory function. To assess the role of ASIC1 we studied wild-type and ASIC1-/- mice. Reverse-transcription polymerase chain reaction (RT-PCR) and Western blot analysis determined expression of ASIC1 messenger RNA and protein in vagal and spinal sensory ganglia. Colonic, gastroesophageal, and cutaneous afferent fibers were characterized by functional subtype and their mechanical stimulus-response relationships were determined. Gastric emptying was determined by using a 13CO2 breath test. Behavioral tests assessed somatic mechanical and thermal sensitivity. ASIC1 was expressed in sensory ganglia and was lost after disruption of the ASIC1 gene. Loss of ASIC1 increased mechanosensitivity in all colonic and gastroesophageal mechanoreceptor subtypes. In addition, ASIC1-/- mice showed almost double the gastric emptying time of wild-type mice. In contrast, loss of ASIC1 did not affect function in any of the 5 types of cutaneous mechanoreceptors, nor did it affect paw withdrawal responses or fecal output. ASIC1 influences visceral but not cutaneous mechanoreceptor function, suggesting that different mechanisms underlie mechanosensory function in gut and skin. The role of ASIC1 is highlighted by prolonging gastric emptying of a meal in ASIC1-/- animals.
Publisher: S. Karger AG
Date: 1996
DOI: 10.1159/000159125
Abstract: The Langendorff heart preparation was used to investigate the release of ATP from the guinea pig heart in response to increased coronary flow. The lucifer-in-luciferase firefly technique was used to determine levels of ATP in the perfusate. During periods of increased flow, ATP release was rapidly and significantly increased by at least tenfold the basal release. The pressure/flow ratio was reduced in increased-flow conditions suggesting that coronary vasodilatation had occurred. It is concluded that ATP release from the guinea pig heart is increased under raised-flow conditions. It is suggested that this ATP release induces coronary vasodilatation.
Publisher: Elsevier BV
Date: 09-2015
Publisher: American Physiological Society
Date: 02-2021
Abstract: This study provides first evidence that gastric vagal afferent signaling is attenuated during pregnancy and inversely associated with meal size. Growth hormone attenuated mechanosensitivity of gastric vagal afferents, adding support that increases in maternal growth hormone may mediate adaptations in gastric vagal afferent signaling during pregnancy. These findings have important implications for the peripheral control of food intake during pregnancy.
Publisher: Frontiers Media SA
Date: 2011
Publisher: Springer Berlin Heidelberg
Date: 2009
DOI: 10.1007/978-3-540-79090-7_7
Abstract: Oesophageal pain is one of the most common reasons for physician consultation and/or seeking medication. It is most often caused by acid reflux from the stomach, but can also result from contractions of the oesophageal muscle. Different forms of pain are evoked by oesophageal acid, including heartburn and non-cardiac chest pain, but the basic mechanisms and pathways by which these are generated remain to be elucidated. Both vagal and spinal afferent pathways are implicated by basic research. The sensitivity of afferent fibres within these pathways may become altered after acid-induced inflammation and damage, but the severity of symptoms in humans does not necessarily correlate with the degree of inflammation. Gastro-oesophageal reflux disease (GORD) is caused by transient relaxations of the lower oesophageal sphincter, which are triggered by activation of gastric vagal mechanoreceptors. Vagal afferents are therefore an emerging therapeutic target for GORD. Pain in the absence of excess acid reflux remains a major challenge for treatment.
Publisher: MDPI AG
Date: 25-12-2020
DOI: 10.3390/NU12010061
Abstract: High amylose wheat (HAW) has a higher resistant starch content and lower glycaemic index than standard amylose wheat (SAW), which may be associated with health benefits. This study aimed to determine the effects of replacing SAW with HAW on metabolic and reproductive parameters in male and female mice. Male and female C57BL/6 mice were randomly ided into groups (n = 8/group/sex) and fed either a SAW65 (65% SAW w/w control), HAW35 (35% HAW w/w), HAW50 (50% HAW w/w) or HAW65 (65% HAW w/w) diet for eight weeks. In male but not female, the HAW65 group had a lower abdominal circumference, relative total fat mass, relative gonadal fat mass and plasma leptin concentration compared to the HAW35 group. There were no differences in fasting blood glucose concentrations or plasma concentrations of cholesterol, triglycerides or non-esterified fatty acids between groups in either males or females. The HAW-fed males had a higher testicular weight and HAW-fed females spent less time in diestrus and a longer time in metestrus compared to the SAW-fed mice. Higher dietary intake of HAW appears to reduce abdominal fat deposition compared to the lower level of HAW in a sexually dimorphic manner. The impacts on reproductive parameters in the HAW-fed mice require further investigation.
Publisher: Society for Neuroscience
Date: 16-03-2016
DOI: 10.1523/JNEUROSCI.2710-15.2016
Abstract: Rats with high-fat diet (HFD)-induced obesity increase daytime eating, suggesting an alteration in circadian food intake mechanisms. Gastric vagal afferents (GVAs) respond to mechanical stimuli to initiate satiety. These signals are d ened in HFD mice and exhibit circadian variations inversely with food intake in lean mice. Furthermore, leptin shows circadian variation in its circulating level and is able to modulate GVA mechanosensitivity. However, whether leptin's ability to modulate GVAs occurs in a circadian manner is unknown. Therefore, we investigated whether changes in the circadian intake of food in HFD-induced obesity is associated with a disruption in GVA circadian rhythms. Eight-week-old male C57BL/6 mice were fed a standard laboratory diet (SLD) or a HFD for 12 weeks. A subgroup of SLD and HFD mice were housed in metabolic cages. After 12 weeks, ex vivo GVA recordings were taken at 3 h intervals starting at zeitgeber time 0 (ZT0) and stomach content was measured. After 12 weeks, HFD mice consumed more food during the light phase through larger and more frequent meals compared with SLD mice. SLD mice exhibited circadian fluctuation in stomach content, which peaked at ZT18 and reached a nadir at ZT9. At these time points, both tension and mucosal receptor mechanosensitivity were the lowest and highest, respectively. HFD mice exhibited little circadian variation in stomach content or GVA mechanosensitivity. Leptin potentiated mucosal receptor mechanosensitivity only in SLD mice and with reduced potency during the dark phase. In conclusion, loss of circadian variation in GVA signaling may underpin changes in eating behavior in HFD-induced obesity. SIGNIFICANCE STATEMENT Appropriate circadian control of food intake is vital for maintaining metabolic health. Diet-induced obesity is associated with strong circadian changes in food intake, but the contributing mechanisms have yet to be determined. Vagal afferents are involved in regulation of feeding behavior, particularly meal size, and have been shown to exhibit circadian fluctuation in mechanosensitivity, potentially allowing for time of day-specific levels of satiety signaling. Our study indicates that, in diet-induced obesity, these circadian fluctuations in gastric vagal afferent mechanosensitivity are lost. This was accompanied by increased light phase eating, particularly increased meal size. This is the first evidence that diet-induced disruption to vagal afferent signaling may cause a perturbation in circadian eating patterns.
Publisher: Wiley
Date: 10-1998
DOI: 10.1046/J.1365-2982.1998.00118.X
Abstract: Prolonged oesophageal acidification may impair lower oesophageal sphincter (LOS) function in reflux disease. The aim of this study was to investigate aspects of altered LOS innervation in a model of oesophagitis. Oesophagitis was induced by acid (HCl, 0.15 M) and pepsin (0.1% w/v) infusions in anaesthetized ferrets. LOS muscle strip responses to the following stimuli were measured in vitro from control and acid epsin-treated ferrets: electrical field stimulation (EFS 1-50 Hz), potassium chloride KCl 20 mM), substance P, [beta-Ala8]-neurokinin A 4-10, [Sar9, Met (O2)11]-substance P (all 10(-10) to 10(-6) M) and capsaicin (10(-8) to 10(-6) M). LOS relaxation occurred in response to all stimuli except [beta-Ala8]-neurokinin A 4-10, which evoked contraction. In muscle strips from acid epsin-treated animals there were no differences in litude or sensitivity of relaxation following EFS, KCl or substance P vs controls. However, the inhibitory response to capsaicin was increased four-fold (10(-8) M P < 0.05) and an increased sensitivity of the inhibitory response to [Sar9, Met (O2)11]-substance P occurred (pD2 = 8.64 +/- 0.12 acid epsin-treated vs 7.94 +/- 0.24 control, P < 0.05). We conclude that in acute oesophagitis, increased sensitivity of capsaicin-activated inhibitory pathways occurs in which activation of NK-1 receptors plays an integral role in the ferret LOS.
Publisher: Wiley
Date: 19-06-2014
Publisher: Society for Neuroscience
Date: 14-05-2018
DOI: 10.1523/JNEUROSCI.0052-18.2018
Abstract: Mechanosensitive gastric vagal afferents (GVAs) are involved in the regulation of food intake. GVAs exhibit diurnal rhythmicity in their response to food-related stimuli, allowing time of day-specific satiety signaling. This diurnal rhythmicity is ablated in high-fat-diet (HFD)-induced obesity. Time-restricted feeding (TRF) has a strong influence on peripheral clocks. This study aimed to determine whether diurnal patterns in GVA mechanosensitivity are entrained by TRF. Eight-week-old male C57BL/6 mice ( N = 256) were fed a standard laboratory diet (SLD) or HFD for 12 weeks. After 4 weeks of diet acclimatization, the mice were fed either ad libitum or only during the light phase [Zeitgeber time (ZT) 0–12] or dark phase (ZT12–24) for 8 weeks. A subgroup of mice from all conditions ( n = 8/condition) were placed in metabolic cages. After 12 weeks, ex vivo GVA recordings were taken at 3 h intervals starting at ZT0. HFD mice gained more weight than SLD mice. TRF did not affect weight gain in the SLD mice, but decreased weight gain in the HFD mice regardless of the TRF period. In SLD mice, diurnal rhythms in food intake were inversely associated with diurnal rhythmicity of GVA mechanosensitivity. These diurnal rhythms were entrained by the timing of food intake. In HFD mice, diurnal rhythms in food intake and diurnal rhythmicity of GVA mechanosensitivity were d ened. Loss of diurnal rhythmicity in HFD mice was abrogated by TRF. In conclusion, diurnal rhythmicity in GVA responses to food-related stimuli can be entrained by food intake. TRF prevents the loss of diurnal rhythmicity that occurs in HFD-induced obesity. SIGNIFICANCE STATEMENT Diurnal control of food intake is vital for maintaining metabolic health. Diet-induced obesity is associated with strong diurnal changes in food intake. Vagal afferents are involved in regulation of feeding behavior, particularly meal size, and exhibit diurnal fluctuations in mechanosensitivity. These diurnal fluctuations in vagal afferent mechanosensitivity are lost in diet-induced obesity. This study provides evidence that time-restricted feeding entrains diurnal rhythmicity in vagal afferent mechanosensitivity in lean and high-fat-diet (HFD)-induced obese mice and, more importantly, prevents the loss of rhythmicity in HFD-induced obesity. These data have important implications for the development of strategies to treat obesity.
Publisher: Wiley
Date: 31-12-2016
DOI: 10.1113/JP271669
Publisher: Elsevier BV
Date: 03-2017
DOI: 10.1016/J.PEPTIDES.2017.01.005
Abstract: Food intake is regulated by vagal afferent signals from the stomach. Nesfatin-1 is an anorexigenic peptide produced within the gastrointestinal tract and has well defined central effects. We aimed to determine if nesfatin-1 can modulate gastric vagal afferent signals in the periphery and further whether this is altered in different nutritional states. Female C57BL/6J mice were fed either a standard laboratory diet (SLD) or a high fat diet (HFD) for 12 weeks or fasted overnight. Plasma nucleobindin-2 (NUCB2 nesfatin-1 precursor)/nesfatin-1 levels were assayed, the expression of NUCB2 in the gastric mucosa and adipose tissue was assessed using real-time quantitative reverse-transcription polymerase chain reaction. An in vitro preparation was used to determine the effect of nesfatin-1 on gastric vagal afferent mechanosensitivity. HFD mice exhibited an increased body weight and adiposity. Plasma NUCB2/nesfatin-1 levels were unchanged between any of the groups of mice. NUCB2 mRNA was detected in the gastric mucosa and gonadal fat of SLD, HFD and fasted mice with no difference in mRNA abundance between groups in either tissue. In SLD and fasted mice nesfatin-1 potentiated mucosal receptor mechanosensitivity, an effect not observed in HFD mice. Tension receptor mechanosensitivity was unaffected by nesfatin-1 in SLD and fasted mice, but was inhibited in HFD mice. In conclusion, Nesfatin-1 modulates gastric vagal afferent mechanosensitivity in a nutritional state dependent manner.
Publisher: Elsevier BV
Date: 12-2021
DOI: 10.1016/J.PEPTIDES.2021.170673
Abstract: This study investigated the nutrient-mediated modulation of total ghrelin (TG) and acyl ghrelin (AG) secretion from the mouse gastric mucosa, and the role of long-chain fatty acid chemosensors, FFAR4 and CD36, in lipid-mediated modulation of TG and AG release. Ex-vivo experiments were conducted using mouse gastric mucosa to examine the effects of nutrients (D-glucose, L-phenylalanine, peptone (mixture of oligopeptides & single amino acids), D-mannitol, α-linolenic acid and fat emulsion (intralipid)) on TG and AG secretion. Additionally, inhibition of FFAR4 and CD36 on α-linolenic acid and intralipid-mediated regulation of TG and AG secretion was assessed. TG and AG secretion were unaffected by glucose and D-mannitol. Peptone stimulated the release of TG and AG. In contrast, L-phenylalanine reduced AG secretion only. Intralipid reduced TG secretion and stimulated AG secretion, and α-linolenic acid reduced AG release, without affecting TG mobilisation. Modulation of ghrelin secretion by lipids occurred in an FFAR4 and CD36-independent manner. Ghrelin secretion is modulated in a nutrient-specific manner by proteins and lipids, with TG and AG displaying independent responses to the same stimuli. In addition, FFAR4 and CD36 do not participate in modulation of TG and AG secretion by α-linolenic acid and intralipid.
Publisher: Wiley
Date: 06-1993
DOI: 10.1111/J.1476-5381.1993.TB13586.X
Abstract: 1. The Langendorff heart preparation was used to investigate the mechanism of action of the endothelium-dependent vasodilatation evoked by adenosine and its analogues in the guinea-pig coronary vasculature. 2. The relative order of potency of adenosine and its analogues in causing a reduction in perfusion pressure was D-5'-(N-ethylcarboxamide)adenosine (NECA) = 2-[p-(2-carboxyethyl)phenylethylamino]-5'-N- ethylcarboxamidoadenosine (CGS 21680)> R-N6-(2-phenylisopropyl)adenosine (R-PIA) = adenosine = 2-chloroadenosine (2-CA) > S-N6-(2-phenylisopropyl)adenosine (S-PIA) = N6-cyclopentyl-adenosine (CPA) thus suggesting the presence of A2-purinoceptors in this preparation. 3. 8-(p-Sulphophenyl)theophylline (8-PSPT 3 x 10(-5) M) significantly reduced both the maximum litude and area of the vasodilatation produced in response to adenosine (5 x 10(-10) -5 x 10(-8) mol) without having any effect on the response to the P2-purinoceptor agonist, 2-methylthioATP. The relaxation induced by adenosine (5 x 10(-12) -5 x 10(-8) mol) was unaffected by the selective A1-purinoceptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX 10(-8) M). This antagonist profile suggests that only A2-purinoceptors are present in the guinea-pig coronary vasculature. 4. The areas of the vasodilator response to adenosine (5 x 10(-10) -5 x 10(-7 mol), NECA (5 x 10(-12) -5 x 10(-7) mol) and CGS 21680 (5 x 10(-12) -5 x 10(-10) mol) were significantly reduced by NG-nitro-L-arginine methyl ester (L-NAME 3 x 10(-5) M). The litude of the responses to low concentrations of adenosine (5 x 10-10-5 x 10-9mol), NECA (5 x 1011 mol) and CGS 21680 (5 x 1011-5 x 10-9mol)were significantly reduced by L-NAME (3 x 10-5 M).5. L-Arginine (1.5 x 10-3 M) significantly reversed the inhibition, by L-NAME (3 x 10-5 M), of the relaxant response to adenosine (5 x 10-8 mol), NECA (5 x I0- mol) and CGS 21680 (5 x 10-11 mol).6. Indomethacin (10-6 M) did not inhibit the response to adenosine, except at low doses (5 x 10-11-5 x 10-10 mol).7. It is concluded that in the guinea-pig coronary vasculature, while a major part of the vasodilator action of adenosine is probably directly via A2-receptors on the smooth muscle, activation of a subpopulation of A2-purinoceptors on endothelial cells by adenosine and its analogues induces relaxation via production of nitric oxide prostanoids appear to play a minimal role in the relaxation induced by adenosine as in most other preparations.
Publisher: MDPI AG
Date: 14-08-2020
DOI: 10.3390/NU12082446
Abstract: Chronic isoleucine supplementation prevents diet-induced weight gain in rodents. Acute-isoleucine administration improves glucose tolerance in rodents and reduces postprandial glucose levels in humans. However, the effect of chronic-isoleucine supplementation on body weight and glucose tolerance in obesity is unknown. This study aimed to investigate the impact of chronic isoleucine on body weight gain and glucose tolerance in lean and high-fat-diet (HFD) induced-obese mice. Male C57BL/6-mice, fed a standard-laboratory-diet (SLD) or HFD for 12 weeks, were randomly allocated to: (1) Control: Drinking water (2) Acute: Drinking water with a gavage of isoleucine (300 mg/kg) prior to the oral-glucose-tolerance-test (OGTT) or gastric-emptying-breath-test (GEBT) (3) Chronic: Drinking water with 1.5% isoleucine, for a further six weeks. At 16 weeks, an OGTT and GEBT was performed and at 17 weeks metabolic monitoring. In SLD- and HFD-mice, there was no difference in body weight, fat mass, and plasma lipid profiles between isoleucine treatment groups. Acute-isoleucine did not improve glucose tolerance in SLD- or HFD-mice. Chronic-isoleucine impaired glucose tolerance in SLD-mice. There was no difference in gastric emptying between any groups. Chronic-isoleucine did not alter energy intake, energy expenditure, or respiratory quotient in SLD- or HFD-mice. In conclusion, chronic isoleucine supplementation may not be an effective treatment for obesity or glucose intolerance.
Publisher: American Physiological Society
Date: 12-2019
Abstract: Gastric vagal afferent (GVA) sensing of food-related mechanical stimuli is a crucial mechanism in the control of feeding behavior and gastric function. Stress is an important factor contributing to eating disorders and gastric diseases. Chronic stress has been shown to increase the mechanosensitivity of GVAs in mice and to reduce food intake and body weight. Whether the mechanosensitivity of GVAs is modulated by stress hormones is not known. This study aimed to determine the effect of stress hormones on GVA mechanosensitivity. The expression of stress hormone receptors in GVA cell bodies was determined in 8-wk-old male C57BL/6 mice using quantitative RT-PCR combined with laser capture microdissection. The mechanosensitivity of GVAs was determined in the absence and presence of stress hormones using an in vitro single-fiber recording preparation. NR3C1 and CRHR2 (mRNA isoforms of glucocorticoid receptor and CRF2 receptor, respectively) were expressed in GVA neurons. The glucocorticoid receptor agonist corticosterone had no effect on the mechanosensitivity of either tension or mucosal GVAs. Activation of CRF2 receptor by its specific analog, urocortin 3, significantly increased the mechanosensitivity of both tension and mucosal GVAs, an effect prevented by the CRF2 receptor antagonist astressin 2B. In conclusion, activation of CRF2 receptor increases the mechanosensitivity of GVAs. This may contribute to the stress- and CRF2 receptor-associated changes in feeding behavior and gastric function, possibly contributing to the hypersensitivity of GVAs in chronic stress conditions. NEW & NOTEWORTHY Gastric vagal afferents (GVAs) relay food-related signals to the central nervous system, where they are processed, eventually leading to modulation of food intake and gastric function. GVA signaling can be modulated by an array of hormones. Stress has been shown to induce GVA hypersensitivity. This study demonstrates that GVA neurons express subtypes of stress hormone receptors, specifically CRF2. Furthermore, activation of CRF2 receptor increases GVA mechanosensitivity, which could have implications for food intake and gastric function.
Publisher: Elsevier BV
Date: 09-2020
Publisher: MDPI AG
Date: 09-10-2021
Abstract: Colorectal cancer (CRC) is the fourth most common cause of cancer deaths worldwide. Although screening programs have reduced mortality rates, there is a need for research focused on finding the main factors that lead primary CRC to progress and metastasize. During tumor progression, malignant cells modify their habitat, corrupting or transforming cells of different origins and creating the tumor microenvironment (TME). Cells forming the TME like macrophages, neutrophils, and fibroblasts generate reactive oxygen species (ROS) that modify the cancer niche. The effects of ROS in cancer are very erse: they promote cellular proliferation, epithelial-to-mesenchymal transition (EMT), evasion of cell death programs, migration, and angiogenesis. Due to the multifaceted role of ROS in cancer cell survival and function, ROS-modulating agents such as antioxidants or pro-oxidants could have therapeutic potential in cancer prevention and/or as a complement to systemic treatments. In this review, we will examine the main ROS producer cells and their effects on cancer progression and metastasis. Furthermore, we will enumerate the latest clinical trials where pro-oxidants and antioxidants have therapeutic uses in CRC.
Publisher: Wiley
Date: 11-09-2019
DOI: 10.1111/NMO.13711
Abstract: Gastric vagal afferents (GVAs) respond to mechanical stimulation, initiating satiety. These afferents exhibit diurnal fluctuations in mechanosensitivity, facilitating food intake during the dark phase in rodents. In humans, desynchrony of diurnal rhythms (eg, shift work) is associated with a higher risk of obesity. To test the hypothesis that shift work disrupts satiety signaling, the effect of a rotating light cycles on diurnal rhythms in GVA mechanosensitivity in lean and high-fat diet (HDF)-induced obese mice was determined. Male C57BL/6 mice were fed standard laboratory diet (SLD) or HFD for 12 weeks. After 4 weeks, mice were randomly allocated to a normal light (NL 12 hour light: 12 hour dark lights on at zeitgeber time [ZT] 0) or rotating light (RL 3-day NL cycle, 4-day reversed light cycle [lights on: ZT12] repeated) cycle for 8 weeks. At week 12, eight mice from each group were housed in metabolic cages. After 12 weeks, ex vivo GVA recordings were taken at 3 hour intervals starting at ZT0. SLD-RL and HFD-RL gained more weight compared to SLD-NL and HFD-NL mice, respectively. Gonadal fat pad mass was higher in SLD-RL compared to SLD-NL mice. In SLD-NL mice, tension and mucosal receptor mechanosensitivity exhibited diurnal rhythms with a peak at ZT9. These rhythms were lost in SLD-RL, HFD-NL, and HFD-RL mice and associated with d ened diurnal rhythms in food intake. GVA diurnal rhythms are susceptible to disturbances in the light cycle and/or the obese state. This may underpin the observed changes in feeding behavior.
Publisher: Wiley
Date: 08-11-2006
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 31-07-2009
Abstract: Gastroesophageal reflux disease (GERD) affects >10% of the Western population. Conventionally, GERD is treated by reducing gastric acid secretion, which is effective in most patients but inadequate in a significant minority. We describe a new therapeutic approach for GERD, based on inhibition of transient lower esophageal sphincter relaxation (TLESR) with a proposed peripherally acting GABA(B) receptor agonist, (R)-(3-amino-2-fluoropropyl)phosphinic acid (AZD3355). AZD3355 potently stimulated recombinant human GABA(B) receptors and inhibited TLESR in dogs, with a biphasic dose-response curve. In mice, AZD3355 produced considerably less central side effects than the prototypical GABA(B) receptor agonist baclofen but evoked hypothermia at very high doses (blocked by a GABA(B) receptor antagonist and absent in GABA(B)-/- mice). AZD3355 and baclofen differed markedly in their distribution in rat brain AZD3355, but not baclofen, was concentrated in circumventricular organs as a result of active uptake (shown by avid intracellular sequestration) and related to binding of AZD3355 to native GABA transporters in rat cerebrocortical membranes. AZD3355 was also shown to be transported by all four recombinant human GABA transporters. AR-H061719 [(R/S)-(3-amino-2-fluoropropyl)phosphinic acid], (the racemate of AZD3355) inhibited the response of ferret mechanoreceptors to gastric distension, further supporting its peripheral site of action on TLESR. In summary, AZD3355 probably inhibits TLESR through stimulation of peripheral GABA(B) receptors and may offer a potential new approach to treatment of GERD.
Publisher: Wiley
Date: 11-1993
DOI: 10.1111/J.1476-5381.1993.TB13926.X
Abstract: 1. The effects of the pyrimidines, uridine 5'-triphosphate (UTP), thymidine 5'-triphosphate (TTP) and cytidine 5'-triphosphate (CTP), were examined in the guinea-pig coronary bed, by use of a Langendorff technique. Comparisons were made with the actions of the purines adenosine 5'-triphosphate (ATP), inosine 5'-triphosphate (ITP) and guanosine 5'-triphosphate (GTP). The effect of, the nitric oxide synthase inhibitor, L-NG-nitroarginine methyl ester (L-NAME) and, the prostaglandin synthesis inhibitor, indomethacin on the vasodilator response to these purines and pyrimidines was examined. The effects of these inhibitors were assessed on their ability to inhibit both the litude and the area of the vasodilator response. 2. The relative order of potency of the purines and pyrimidines studied was ATP > UTP > ITP >> GTP, TTP, CTP. 3. The maximum litude and area of the vasodilator response to the pyrimidines, UTP (5 x 10(-10)-5 x 10(-7) mol), TTP (5 x 10(-8)-5 x 10(-7) mol) and CTP (5 x 10(-7) mol), and purines, ITP (5 x 10(-9)-5 x 10(-7) mol) and GTP (5 x 10(-8)-5 x 10(-7) mol), were significantly reduced by L-NAME (3 x 10(-5) and 10(-4) M). 4. The inhibition of the response to ATP (5 x 10-8 mol), UTP (5 x 10-8 mol), ITP (5 x 10-8 mol), TTP(5 x 10-7 mol), CTP (5 x 10- mol) and GTP (5 x 10- mol) by L-NAME (3 x 10-5 M) was significantly reversed by L-arginine (1.5 x 10-3 M).5. L-NAME (3 x 10-5 and 10-4 M) only inhibited the litude of the vasodilator response to a low dose of ATP (5 x 10-mol), although the area of vasodilator response to ATP(5 x 10-11-5 x 10-7 mol) was significantly reduced by L-NAME (3 x 10-5 and 10-4 M).6. The maximum litude of the vasodilator response to ATP (5 x 10-10-5 x 10-7 mol) was significantly reduced by indomethacin (10-6 M), although the area of the vasodilator response to ATP was only significantly reduced at one intermediate dose (5 x 10-9 mol). Indomethacin (10-6 M) did not affect the maximum litude or area of the vasodilator responses to UTP (5 x 10-11-5 x 10-7 mol),ITP (5 x 10-10-5 x 10-7 mol), CTP (5 x 10-7 mol), TTP (5 x 10-8-5 x 10-7 mol) and GTP(5 x 10-8-5 x 10-7 mol).7. It is concluded that in the guinea-pig coronary vasculature, the vasodilatation evoked by the pyrimidines, UTP, TTP and CTP, was mediated in large part via nitric oxide, as were the vasodilatations evoked by the purines ITP and GTP. The vasodilatations evoked by ATP, however, appear to involve prostanoids in addition to the release of nitric oxide.
Publisher: Elsevier BV
Date: 2006
DOI: 10.1016/J.NEUROSCIENCE.2005.09.016
Abstract: GABA(B) receptors inhibit mechanosensitivity of visceral afferents. This is associated with reduced triggering of events that lead to gastro-esophageal reflux, with important therapeutic consequences. In other neuronal systems, GABA(B) receptor activation may be linked via G-proteins to reduced N-type Ca(2+) channel opening, increased inward rectifier K(+) channel opening, plus effects on a number of intracellular messengers. Here we aimed to determine the role of Ca(2+) and K(+) channels in the inhibition of vagal afferent mechanoreceptor function by the GABA(B) receptor agonist baclofen. The responses of three types of ferret gastro-esophageal vagal afferents (mucosal, tension and tension mucosal receptors) to graded mechanical stimuli were investigated in vitro. The effects of baclofen (200 microM) alone on these responses were quantified, and the effects of baclofen in the presence of the G-protein-coupled inward rectifier potassium channel blocker Rb(+) (4.7 mM) and/or the N-type calcium channel blocker omega-conotoxin GVIA (0.1 microM). Baclofen inhibition of mucosal receptor mechanosensitivity was abolished by both blockers. Its inhibitory effect on tension mucosal receptors was partly reduced by both. The inhibitory effect of baclofen on tension receptors was unaffected. The data indicate that the inhibitory action of GABA(B) receptors is mediated via different pathways in mucosal, tension and tension mucosal receptors via mechanisms involving both N-type Ca(2+) channels and inwardly rectifying K(+) channels and others.
Publisher: American Physiological Society
Date: 04-2002
Abstract: We used a novel in vitro mouse vagus-gastro-esophageal preparation to study the properties of peripheral vagal afferent endings. We found two types of mechanoreceptive fiber, mucosal receptors and tension receptors. These were distinguished by their sensitivity to mucosal stroking with von Frey hairs and circular tension applied via a claw-cantilever system. A comparison was made with gastro-esophageal afferents found in a similar preparation of ferret tissue. Responses of mouse tension receptors to circular tension were significantly greater than ferret tension and tension/mucosal receptors. Similarly the responses of mouse mucosal receptors to mucosal stroking were significantly greater than ferret mucosal and tension/mucosal receptors. Forty-seven percent of mouse mucosal receptors and 50% of tension receptors responded to one or more drugs or chemical stimuli applied to the receptive field. These included α,β-methylene ATP (10 −6 to 10 −3 M), 5-hydroxytryptamine (10 −6 to 10 −3 M), and hydrochloric acid (10 −2 to 10 −1 M). Drug responses were concentration dependent. One hundred percent of mucosal receptors and 61% of tension receptors tested responded to bile (1:8 to 1:1 dilution). A third type of fiber was recruited by bile. These fibers were mechanically insensitive and silent prior to bile exposure. In conclusion, we have shown three types of gastro-esophageal vagal afferent fibers in the mouse: mucosal mechanoreceptors, tension receptors, and specific chemoreceptors activated by bile.
Publisher: Wiley
Date: 28-08-2013
DOI: 10.1111/APHA.12154
Abstract: Neuropeptide W (NPW) is an endogenous ligand for the receptors GPR7 and GPR8 and is involved in central regulation of energy homeostasis. NPW in the periphery is found in gastric gastrin (G) cells. In the stomach, energy intake is influenced by vagal afferent signals, so we aimed to determine the effect of NPW on mechanosensitive gastric vagal afferents under different feeding conditions. Female C57BL/6 mice (N > 10 per group) were fed a standard laboratory diet (SLD), high-fat diet (HFD) or were food restricted. The relationship between NPW immunopositive cells and gastric vagal afferent endings was determined by anterograde tracing and NPW immunohistochemistry. An in vitro gastro-oesophageal preparation was used to determine the functional effects of NPW on gastric vagal afferents. Expression of NPW in the gastric mucosa and GPR7 in whole nodose ganglia was determined by quantitative RT-PCR (QRT-PCR). The expression of GPR7 in gastric vagal afferent neurones was determined by retrograde tracing and QRT-PCR. Neuropeptide W immunoreactive cells were found in close proximity to traced vagal afferents. NPW selectively inhibited responses of gastric vagal tension receptors to stretch in SLD but not HFD or fasted mice. In the nodose ganglia, GPR7 mRNA was specifically expressed in gastric vagal afferent neurones. In fasted mice gastric mucosal NPW and nodose GPR7, mRNA was reduced compared with SLD. A HFD had no effect on gastric NPW mRNA, but down-regulated nodose GPR7 expression. Neuropeptide W modulates gastric vagal afferent activity, but the effect is dynamic and related to feeding status.
Publisher: Elsevier BV
Date: 09-2014
Publisher: Wiley
Date: 12-01-2019
DOI: 10.1111/APHA.13243
Publisher: Wiley
Date: 23-12-2015
Publisher: Wiley
Date: 10-1992
DOI: 10.1111/J.1476-5381.1992.TB12790.X
Abstract: 1. The effects of L-NG-nitroarginine (L-NOARG) and L-NG-nitroarginine methyl ester (L-NAME) on vasodilatation induced by ATP, substance P, 5-hydroxytryptamine (5-HT), bradykinin and sodium nitroprusside (SNP) were examined in the guinea-pig coronary bed, by use of a Langendorff technique. The effects of these inhibitors of nitric oxide synthesis were assessed on their ability to inhibit both the litude and the area of the vasodilator response. 2. The vasodilator responses evoked by low doses of 5-HT (5 x 10(-10)-10(-8) mol) were almost abolished by L-NAME and L-NOARG (both at 10(-5), 3 x 10(-5) and 10(-4) M), although L-NOARG (3 x 10(-5) M) was significantly less potent than L-NAME (3 x 10(-5) M) as an inhibitor of vasodilator responses to 5-HT (5 x 10(-8) mol). 3. The vasodilator responses evoked by substance P (5 x 10(-12)-5 x 10(-9) mol) were reduced in the presence of L-NAME and L-NOARG (both at 10(-5) and 3 x 10(-5) M). The response to substance P was almost abolished by L-NAME and L-NOARG (both at 10(-4) M). 4. The litude of the vasodilator responses to ATP (5 x 10(-11) and 5 x 10(-9)-5 x 10(-7) mol) was little affected by either L-NAME or L-NOARG (both at 10(-5), 3 x 10(-5) and 10(-4) M).7. It is concluded that in the guinea-pig coronary vasculature, the vasodilatation evoked by substance P and low doses of 5-HT is mediated almost exclusively via nitric oxide, whereas the vasodilatations evoked by ATP and bradykinin appear to involve other mechanisms in addition to the release of nitric oxide. L-NAME was a more effective agent than L-NOARG in inhibiting the vasodilator actions of 5-HT and ATP in this preparation.
Publisher: Wiley
Date: 27-07-2021
DOI: 10.1111/APHA.13722
Publisher: Wiley
Date: 27-11-2019
DOI: 10.1113/JP278696
Publisher: Elsevier BV
Date: 05-2021
Publisher: BMJ
Date: 11-07-2015
Publisher: Wiley
Date: 21-06-2012
Publisher: Elsevier BV
Date: 1994
DOI: 10.1016/0014-2999(94)90413-8
Abstract: The effect of suramin, a P2 purinoceptor antagonist, on the vasodilator response to adenosine 5'-triphosphate (ATP), 2-methylthio-ATP (2-meSATP) and adenosine were examined in the Sprague-Dawley rat coronary vasculature using the Langendorff heart preparation. Relaxation induced by 2-meSATP was significantly inhibited by suramin. Only responses to low doses of adenosine and ATP were inhibited by suramin. 8-(p-Sulphophenyl)theophylline (8-PSPT) did not affect the relaxant response to ATP and 2-meSATP at a concentration that significantly inhibited the response to adenosine. It is concluded that 2-meSATP acts via P2Y purinoceptors while ATP appears to be acting largely through a different mechanism. It is not acting via a P1 purinoceptor because ATP was not inhibited by the P1 purinoceptor antagonist 8-PSPT.
Publisher: Wiley
Date: 29-12-2012
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 15-12-2020
Abstract: The physiology underlying "brain fog" in the absence of orthostatic stress in postural tachycardia syndrome (POTS) remains poorly understood. We evaluated cognitive and hemodynamic responses (cardiovascular and cerebral: heart rate, blood pressure, end‐tidal carbon dioxide, and cerebral blood flow velocity (CBFv) in the middle cerebral artery at baseline, after initial cognitive testing, and after (30‐minutes duration) prolonged cognitive stress test (PCST) whilst seated as well as after 5‐minute standing in consecutively enrolled participants with POTS (n=22) and healthy controls (n=18). Symptom severity was quantified with orthostatic hypotensive questionnaire at baseline and end of study. Subjects in POTS and control groups were frequency age‐ and sex‐matched (29±11 versus 28±13 years 86 versus 72% women, respectively both P ≥0.4). The CBFv decreased in both groups (condition, P =0.04) following PCST, but a greater reduction in CBFv was observed in the POTS versus control group (−7.8% versus −1.8% interaction, P =0.038). Notably, the reduced CBFv following PCST in the POTS group was similar to that seen during orthostatic stress (60.0±14.9 versus 60.4±14.8 cm/s). Further, PCST resulted in greater slowing in psychomotor speed (6.1% versus 1.4%, interaction, P =0.027) and a greater increase in symptom scores at study completion (interaction, P .001) in the patients with POTS, including increased difficulty with concentration. All other physiologic responses (blood pressure and end‐tidal carbon dioxide) did not differ between groups after PCST (all P .05). Reduced CBFv and cognitive dysfunction were evident in patients with POTS following prolonged cognitive stress even in the absence of orthostatic stress.
Publisher: Springer Science and Business Media LLC
Date: 29-02-2016
DOI: 10.1038/CDDISCOVERY.2016.9
Abstract: Gender-specific differences are commonly found in metabolic pathways and in response to nutritional manipulation. Previously, we identified a role for caspase-2 in age-related glucose homeostasis and lipid metabolism using male caspase-2 -deficient ( Casp2 −/− ) mice. Here we show that the resistance to age-induced glucose tolerance does not occur in female Casp2 −/− mice and it appears to be independent of insulin sensitivity in males. Using fasting (18 h) as a means to further investigate the role of caspase-2 in energy and lipid metabolism, we identified sex-specific differences in the fasting response and lipid mobilization. In aged (18–22 months) male Casp2 −/− mice, a significant decrease in fasting liver mass, but not total body weight, was observed while in females, total body weight, but not liver mass, was reduced when compared with wild-type (WT) animals. Fasting-induced lipolysis of adipose tissue was enhanced in male Casp2 −/− mice as indicated by a significant reduction in white adipocyte cell size, and increased serum-free fatty acids. In females, white adipocyte cell size was significantly smaller in both fed and fasted Casp2 −/− mice. No difference in fasting-induced hepatosteatosis was observed in the absence of caspase-2. Further analysis of white adipose tissue (WAT) indicated that female Casp2 −/− mice may have enhanced fatty acid recycling and metabolism with expression of genes involved in glyceroneogenesis and fatty acid oxidation increased. Loss of Casp2 also increased fasting-induced autophagy in both male and female liver and in female skeletal muscle. Our observations suggest that caspase-2 can regulate glucose homeostasis and lipid metabolism in a tissue and sex-specific manner.
Publisher: Elsevier BV
Date: 09-2022
DOI: 10.1016/J.NUT.2022.111662
Abstract: Intermittent fasting (IF) activates autophagy in cardiac muscle and pancreatic islets. We examined the effect of IF on markers of autophagy in liver and skeletal muscle in mice and in humans. Ten-wk-old C57 BL/6 J male mice were ad libitum (AL) fed a high-fat diet (HFD) or chow diet for 8 wk, before randomization to AL or IF (24-h fast, 3 non-consecutive days per week) for 8 wk (8-16 per group). Tissue was collected in the fed or 22-h fasted state. Fifty women (51 ± 2 y, 31.8 ± 4.3 kg/m Fasting increased hepatic LC3 I protein and Map1 lc3 b mRNA levels in IF mice fed chow or HFD. LAMP1 protein and Beclin1 mRNA levels in liver were also increased by fasting, but only in chow-fed mice. IF did not activate markers of autophagy in mouse muscle. In humans, a 24-h fast increased SQSTM1. BECLIN1, SQSTM1 and LAMP2 mRNA levels were decreased in IF70 after a 12-h overnight fast . Markers of autophagy in liver, but not in muscle, were elevated in response to IF in mice. In humans, autophagy markers in muscle were reduced, likely in response to weight loss.
Publisher: Elsevier BV
Date: 12-2009
Publisher: Wiley
Date: 18-02-2013
Publisher: Springer Science and Business Media LLC
Date: 22-06-2023
DOI: 10.1007/S00394-023-03191-Z
Abstract: To our knowledge, no studies have examined the association of diet quality and plant-based diets (PBD) with inflammatory-related mortality in obesity. Therefore, this study aimed to determine the joint associations of Healthy Eating Index-2015 (HEI-2015), plant-based dietary index (PDI), healthy PDI (hPDI), unhealthy PDI (uPDI), pro-vegetarian dietary index (PVD), and systemic inflammation with all-cause, cardiovascular disease (CVD), and cancer mortality risks by obesity status. Participants from NHANES were included in cross-sectional ( N = 27,915, cycle 1999–2010, 2015–2018) and longitudinal analysis ( N = 11,939, cycle 1999–2008). HEI-2015, PDI, hPDI, uPDI, and PVD were constructed based on the 24-h recall dietary interview. The grade of inflammation (low, moderate, and high) was determined based on C-reactive protein (CRP) values and multivariable ordinal logistic regression was used to determine the association. Cox proportional hazard models were used to determine the joint associations of diet and inflammation with mortality. In the fully adjusted model, HEI-2015 (OR T3vsT1 = 0.76, 95% CI 0.69–0.84 p -trend = 0.001), PDI (OR T3vsT1 = 0.83, 95% CI 0.75–0.91 p trend = 0.001), hPDI (OR T3vsT1 = 0.79, 95% CI 0.71–0.88 p trend = 0.001), and PVD (OR T3vsT1 = 0.85, 95% CI 0.75–0.97 p trend = 0.02) were associated with lower systemic inflammation. In contrast, uPDI was associated with higher systemic inflammation (OR T3vsT1 = 1.18, 95% CI 1.06–1.31 p-trend = 0.03). Severe inflammation was associated with a 25% increase in all-cause mortality (OR T3vsT1 = 1.25, 95% CI 1.03–1.53, p trend = 0.02). No association was found between PDI, hPDI, uPDI, and PVD with mortality. The joint association, between HEI-2015, levels of systemic inflammation, and all-cause, CVD and cancer mortality, was not significant. However, a greater reduction in mortality risk with an increase in HEI-2015 scores was observed in in iduals with low and moderate inflammation, especially those with obesity. Higher scores of HEI-2015 and increased intake of a healthy plant-based diet were associated with lower inflammation, while an unhealthy plant-based diet was associated with higher inflammation. A greater adherence to the 2015 dietary guidelines may reduce the risk of mortality associated with inflammation and may also benefit in iduals with obesity who had low and moderate inflammation.
Publisher: Wiley
Date: 03-2000
DOI: 10.1111/J.1469-7793.2000.00403.X
Abstract: 1. Using an in vitro single unit recording technique we studied the changes in mechanical and chemical sensitivity of vagal afferent fibres in acute oesophagitis, with particular attention to inflammatory products such as purines. 2. Histologically verified oesophagitis was induced by oesophageal perfusion of 1 mg ml-1 pepsin in 150 mM HCl in anaesthetized ferrets for 30 min on two consecutive days. Controls were infused with 154 mM NaCl. 3. The number of action potentials evoked in oesophageal mucosal afferents by mucosal stroking with calibrated von Frey hairs (10-1000 mg) was stimulus dependent. In oesophagitis responsiveness was reduced across the range of stimuli compared with controls. 4. Topical application of the P2X purinoceptor agonist alphabeta-methylene ATP had no direct excitatory effect on afferents. In oesophagitis, but not in controls, there was a significant increase in responses to stroking with von Frey hairs during superfusion with alphabeta-methylene ATP (1 microM). 5. Mucosal afferents responded directly to one or more chemical stimuli: 26 % (5/19 afferents) responded in controls, and 47 % (7/15 afferents) in oesophagitis. There were no differences in responsiveness to bradykinin (1 microM), prostaglandin E2 (100 microM), 5-hydroxytryptamine (100 microM), capsaicin (1 mM) or hydrochloric acid (150 mM) between control and oesophagitis groups. 6. We conclude that a sensitizing effect of a P2X purinoceptor agonist on mechanosensory function is induced in oesophagitis. This effect is offset by a decrease in basal mechanosensitivity.
Publisher: Elsevier BV
Date: 02-2005
DOI: 10.1053/J.GASTRO.2004.11.062
Abstract: Inhibitory G-protein-coupled receptors have demonstrated potential in treatment of gastroesophageal reflux disease (GERD) through actions on vagal afferent signaling. Metabotropic glutamate receptors (mGluR) belong to this receptor family and have great pharmacologic and molecular ersity, with 8 subtypes. We investigated mGluR in the vagal system of humans and other species. Expression of mGluR1-8 in human, dog, ferret, and rodent nodose ganglia was investigated by reverse-transcription polymerase chain reaction. mGluR1-8 immunohistochemistry was performed in combination with retrograde tracing of vagal afferents from ferret proximal stomach to nodose ganglia. Transport of mGluR peripherally was investigated by vagal ligation, followed by immunohistochemistry. Glutamate receptor pharmacology of ferret and rodent gastroesophageal vagal afferents was investigated by testing single fiber responses to graded mechanical stimuli during drug application to their peripheral endings. Messenger RNA for several mGluR was detected in the nodose ganglia of all species. Retrograde tracing indicated that ferret gastric vagal afferents express mGluR protein. Accumulation of immunoreactivity proximal to a ligature showed that mGluR were transported peripherally in the vagus nerves. Glutamate (1-30 mumol/L with kynurenate 0.1 mmol/L) concentration dependently inhibited vagal afferent mechanosensitivity. This was mimicked by selective group II and III mGluR agonists but not by a group I agonist. Conversely, a group III mGluR antagonist increased mechanosensitivity to intense stimuli. Both exogenous and endogenous glutamate inhibits mechanosensitivity of vagal afferents. Group II (mGluR2 and 3) and group III mGluR (mGluR4, 6, 7, 8) are novel targets for inhibition of vagal signaling with therapeutic potential in, for ex le, GERD.
Publisher: Wiley
Date: 14-07-2020
DOI: 10.1111/NMO.13944
Publisher: Wiley
Date: 26-06-2019
DOI: 10.1111/NMO.13669
Abstract: Stress exposure is known to trigger and exacerbate functional dyspepsia (FD) symptoms. Increased gastric sensitivity to food-related stimuli is widely observed in FD patients and is associated with stress and psychological disorders. The mechanisms underlying the hypersensitivity are not clear. Gastric vagal afferents (GVAs) play an important role in sensing meal-related mechanical stimulation to modulate gastrointestinal function and food intake. This study aimed to determine whether GVAs display hypersensitivity after chronic stress, and whether its interaction with leptin was altered by stress. Eight-week-old male C57BL/6 mice were exposed to unpredictable chronic mild stress or no stress (control) for 8 weeks. The metabolic rate, gastric emptying rate, and anxiety- and depression-like behaviors were determined. GVA mechanosensitivity, and its modulation by leptin, was determined using an in vitro single fiber recording technique. QRT-PCR was used to establish the levels of leptin and leptin receptor mRNA in the stomach and nodose ganglion, respectively. The stressed mice had lower body weight and food intake, and increased anxiety-like behavior compared to the control mice. The mechanosensitivity of mucosal and tension-sensitive GVAs was higher in the stressed mice. Leptin potentiated mucosal GVA mechanosensitivity in control but not stressed mice. The expression of leptin mRNA in the gastric mucosa was lower in the stressed mice. In conclusion, chronic stress enhances GVA mechanosensitivity, which may contribute to the gastric hypersensitivity in FD. In addition, the modulatory effect of leptin on GVA signaling is lost after chronic stress exposure.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2007
DOI: 10.1016/J.PAIN.2007.03.019
Abstract: The Deg/ENaC family of ion channels, including ASIC1, 2 and 3, are candidate mechanotransducers in visceral and somatic sensory neurons, although each channel may play a different role in different sensory pathways. Here we determined which distinct populations of visceral sensory neurons are sensitive to the non-selective Deg/ENaC blocker benzamil, and which ASIC channels are targets for benzamil by studying its actions in knockout mice. Single afferent fiber recordings were made in vitro from mouse high threshold colonic thoracolumbar splanchnic afferents and low threshold gastroesophageal vagal afferents. mRNA expression of ASIC subtypes was compared between colonic and gastroesophageal afferents by quantitative RT-PCR of transcripts following laser capture microdissection of retrogradely labeled cell bodies. Mechanosensitivity of colonic afferents was potently reduced by benzamil (10(-6)-3 x 10(-4)M), whereas gastroesophageal afferents were marginally inhibited. Inhibition of colonic afferent mechanosensitivity by benzamil was markedly diminished in ASIC2-/- and ASIC3-/- mice, but unchanged in ASIC1a-/-. Therefore ASIC2 and 3 are targets for benzamil to inhibit colonic afferent mechanosensitivity. Conversely, gastroesophageal afferents are less sensitive to benzamil, and its action depends less on ASIC expression. mRNA for ASIC3 showed higher and ASIC1a showed lower relative expression in colonic afferents from thoracolumbar dorsal root ganglia than in gastric afferents from nodose (vagal) ganglia. These data indicate that ASICs on colonic afferents present distinct pharmacological targets for visceral pain.
Publisher: Wiley
Date: 25-10-2016
DOI: 10.1111/NMO.12973
Publisher: Elsevier BV
Date: 11-2015
Publisher: Wiley
Date: 03-2005
Publisher: American Physiological Society
Date: 05-2007
Abstract: Ghrelin is a peptide released from gastric endocrine cells that has an orexigenic effect via a vagal pathway. Here we determine the effect of ghrelin on mechanosensitivity of upper-intestinal vagal afferent fibers in ferret and mouse. The responses of gastroesophageal vagal afferents to graded mechanical stimulation were determined in vitro before and during application of ghrelin to their peripheral endings. Three types of vagal afferent were tested: tension receptors responding to circumferential tension, mucosal receptors responding only to mucosal stroking, and tension/mucosal (TM) receptors in ferret esophagus that responded to both stimuli. In the mouse, ghrelin did not significantly affect the response of mucosal receptors to mucosal stroking with calibrated von Frey hairs. However, it significantly reduced responses of tension receptors to circumferential tension ( P 0.005 two-way ANOVA) by up to 40%. This inhibition was reversed by the ghrelin receptor antagonist [d-Lys-3]-growth hormone-releasing peptide (GHRP)-6. In the ferret, ghrelin significantly reduced the response of mucosal and TM receptors to mucosal stroking with calibrated von Frey hairs. Surprisingly, ghrelin did not significantly alter the response to circumferential tension in either tension or TM receptors. RT-PCR analysis indicated that both ghrelin and its receptor are expressed in vagal afferent cell bodies in mouse nodose ganglia. In conclusion, ghrelin selectively inhibits subpopulations of mechanically sensitive gastroesophageal vagal afferents there is also potential for ghrelin release from vagal afferents. However, the subpopulation of afferents inhibited differs between species. These data have broad implications for ghrelin's role in food intake regulation and reflex control of gastrointestinal function.
Publisher: American Physiological Society
Date: 02-2007
Abstract: Metabotropic glutamate receptors (mGluR) are classified into group I, II, and III mGluR. Group I (mGluR1, mGluR5) are excitatory, whereas group II and III are inhibitory. mGluR5 antagonism potently reduces triggering of transient lower esophageal sphincter relaxations and gastroesophageal reflux. Transient lower esophageal sphincter relaxations are mediated via a vagal pathway and initiated by distension of the proximal stomach. Here, we determined the site of action of mGluR5 in gastric vagal pathways by investigating peripheral responses of ferret gastroesophageal vagal afferents to graded mechanical stimuli in vitro and central responses of nucleus tractus solitarius (NTS) neurons with gastric input in vivo in the presence or absence of the mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP). mGluR5 were also identified immunohistochemically in the nodose ganglia and NTS after extrinsic vagal inputs had been traced from the proximal stomach. Gastroesophageal vagal afferents were classified as mucosal, tension, or tension-mucosal (TM) receptors. MPEP (1–10 μM) inhibited responses to circumferential tension of tension and TM receptors. Responses to mucosal stroking of mucosal and TM receptors were unaffected. MPEP (0.001–10 nmol icv) had no major effect on the majority of NTS neurons excited by gastric distension or on NTS neurons inhibited by distension. mGluR5 labeling was abundant in gastric vagal afferent neurons and sparse in fibers within NTS vagal subnuclei. We conclude that mGluR5 play a prominent role at gastroesophageal vagal afferent endings but a minor role in central gastric vagal pathways. Peripheral mGluR5 may prove a suitable target for reducing mechanosensory input from the periphery, for therapeutic benefit.
Publisher: Elsevier BV
Date: 12-2015
DOI: 10.1016/J.PHYSBEH.2015.06.016
Abstract: Food intake is regulated by vagal afferent signals from the stomach. Adiponectin, secreted primarily from adipocytes, also has a role in regulating food intake. However, the involvement of vagal afferents in this effect remains to be established. We aimed to determine if adiponectin can modulate gastric vagal afferent (GVA) satiety signals and further whether this is altered in high fat diet (HFD)-induced obesity. Female C57BL/6J mice were fed either a standard laboratory diet (SLD) or a HFD for 12weeks. Plasma adiponectin levels were assayed, and the expression of adiponectin in the gastric mucosa was assessed using real-time quantitative reverse-transcription polymerase chain reaction (qRT-PCR). The location of adiponectin protein within the gastric mucosa was determined by immunohistochemistry. To evaluate the direct effect of adiponectin on vagal afferent endings we determined adiponectin receptor expression in whole nodose ganglia (NDG) and also specifically in GVA neurons using retrograde tracing and qRT-PCR. An in vitro preparation was used to determine the effect of adiponectin on GVA response to mechanical stimulation. HFD mice exhibited an increased body weight and adiposity and showed delayed gastric emptying relative to SLD mice. Plasma adiponectin levels were not significantly different in HFD compared to SLD mice. Adiponectin mRNA was detected in the gastric mucosa of both SLD and HFD mice and presence of protein was confirmed immunohistochemically by the detection of adiponectin immunoreactive cells in the mucosal layer of the stomach. Adiponectin receptor 1 (ADIPOR1) and 2 (ADIPOR2) mRNA was present in both the SLD and HFD whole NDG and also specifically traced gastric mucosal and muscular neurons. There was a reduction in ADIPOR1 mRNA in the mucosal afferents of the HFD mice relative to the SLD mice. In HFD mice adiponectin potentiated gastric mucosal afferent responses to mucosal stroking, an effect not observed in SLD mice. Adiponectin reduced the responses of tension receptors to circular stretch to a similar extent in both SLD and HFD mice. In conclusion, adiponectin modulates GVA satiety signals. This modulatory effect is altered in HFD-induced obesity. It remains to be conclusively determined whether this modulation is involved in the regulation of food intake and what the whole animal phenotypic consequence is.
Publisher: Elsevier BV
Date: 02-2000
DOI: 10.1016/S0306-4522(99)00547-3
Abstract: Capsaicin is an important tool for investigation of thin afferent fibres, but its acute effects on subtypes of vagal afferent endings are unknown. In the gastrointestinal tract, these subtypes are: muscle endings (thought to be purely tension sensitive), mucosal endings (sensitive to stroking and chemical stimuli) and endings in the oesophagus with both properties. Acute capsaicin sensitivity was investigated in ferrets using in vivo and in vitro methods. Single-fibre activity was recorded from 63 vagal afferents: 12 Adelta-fibres, 15 C-fibres and 36 unclassified fibres with endings in the oesophagus (n=42), stomach (n=19) and duodenum (n=2). Responses to capsaicin occurred independently of motility changes and were therefore due to direct activation of the receptor ending. In the oesophagus in vivo, two of 10 tension receptors and one of one mucosal receptor responded to intraluminal application of 3.25 mM capsaicin. In the stomach and duodenum, five of 14 tension receptors and two of four mucosal receptors responded to close-systemic (32-164 nmol) capsaicin. In an in vitro gastro-oesophageal preparation, three of five tension, four of 21 mucosal and two of eight tension/mucosal receptors responded to topical application of 1mM capsaicin. Occurrence of responses was therefore unrelated to location of endings and isolation of tissue. Responsiveness was also unrelated to conduction velocity. Capsaicin caused desensitization of responses to further capsaicin application in 37% of afferents. It additionally caused cross-desensitization to mechanical stimuli, which was also seen in afferents that did not respond directly to capsaicin. In conclusion, capsaicin acutely activates all subtypes of gut vagal afferents in vivo and in vitro, although responsiveness is restricted to 30% of fibres and follows no specific pattern. Acute desensitization may be induced with or without a response.
Publisher: Wiley
Date: 15-07-2011
Publisher: MDPI AG
Date: 27-05-2019
DOI: 10.3390/NU11051183
Abstract: We aimed to examine the association between chili intake and cognitive function in Chinese adults. This is a longitudinal study of 4852 adults (age 63.4 ± 7.7) attending the China Health and Nutrition Survey during 1991 and 2006. Cognitive function was assessed in 1997, 2000, 2004 and 2006. In total, 3302 completed cognitive screening tests in at least two surveys. Chili intake was assessed by a 3-day food record during home visits in each survey between 1991 and 2006. Multivariable mixed linear regression and logistic regression were used. Chili intake was inversely related to cognitive function. In fully adjusted models, including sociodemographic and lifestyle factors, compared with non-consumers, those whose cumulative average chili intake above 50 g/day had the regression coefficients (and 95% CI) for global cognitive function of −1.13 (−1.71–0.54). Compared with non-consumers, those with chili consumption above 50 g/day had the odds ratio (and 95% CI) of 2.12(1.63–2.77), 1.56(1.23–1.97) for self-reported poor memory and self-reported memory decline, respectively. The positive association between chili intake and cognitive decline was stronger among those with low BMI than those with high BMI. The longitudinal data indicate that higher chili intake is positively associated with cognitive decline in Chinese adults in both genders.
Publisher: American Physiological Society
Date: 10-2019
DOI: 10.1152/AJPENDO.00102.2019
Abstract: Endocannabinoids (ECs) mediate effects via cannabinoid receptor types 1 and 2 (CB1 and 2) and transient receptor potential channel-vanilloid subfamily member 1 (TRPV1) channels. In high-fat diet (HFD)-induced obese mice overactivity of the EC system and inhibition of CB1 increase skeletal muscle glucose uptake. We explored the role of TRPV1. Male TRPV1 +/+ (WT) and TRPV1 −/− (KO)-mice were fed (20 wk) a standard laboratory diet (SLD) or HFD. An intraperitoneal glucose tolerance test was performed. RT-PCR was performed to measure mRNA of genes involved in glucose/lipid metabolism and the EC system in soleus (SOL) and extensor digitorum longus (EDL) muscles. Cultured L6 cells were used to measure glucose uptake in skeletal muscle. HFD mice weighed more and had higher insulin levels than SLD mice, with no genotype differences. Basal and peak glucose were higher in HFD mice irrespective of genotype, but glucose cleared faster in HFD WT vs. HFD KO-mice. 2-Arachidonoylglycerol augmented insulin-induced glucose uptake in skeletal L6-cells, an effect blocked by the TRPV1 antagonist SB-366791. In EDL, fatty acid amide hydrolase (FAAH) mRNA was increased in KO vs. WT mice, irrespective of diet. Pyruvate dehydrogenase kinase isozyme 4 (PDK4) and mitochondrial uncoupling protein 3 (UCP3) were elevated and FA desaturase 2 (FADS2) mRNA lower in HFD mice, irrespective of genotype. CB1 and stearoyl-CoA desaturase 1 (SCD1) were lower in HFD WT mice only. In SOL, PDK4, UCP3, hormone-sensitive lipase (LIPE), fatty acid translocase (CD36), and carnitine palmitoyl transferase 2 (CPT2) were elevated and SCD1, FAAH, FADS2, and Troponin 1 (TNNC1) mRNA lower in HFD mice, irrespective of genotype. In conclusion, TRPV1 regulates glucose disposal in HFD mice. We propose that TRPV1 plays a role in coordinating glucose metabolism in EDL under conditions of metabolic stress.
Publisher: Elsevier BV
Date: 12-2014
DOI: 10.1016/J.PEPTIDES.2014.09.003
Abstract: Neuropeptide W (NPW) is secreted from gastrin (G) cells in the stomach in response to food intake. The mechanisms underlying food intake-induced regulation of gastric NPW is largely unknown. We hypothesized that specific macronutrients were responsible for food-induced NPW secretion. We evaluated the acute effects of fat, carbohydrate and protein on plasma NPW concentrations in humans and mice. The effect of different nutrients on expression of NPW in the antral stomach was also determined in mice. Primary cell cultures of mouse gastric antral mucosal cells were used to investigate the signaling pathway of NPW expression. Plasma NPW concentrations did not change after nutrient ingestion in either humans or mice. NPW mRNA expression and the number of NPW positive cells in the mouse antrum were increased in mice gavage fed with protein or glucose, but not lipid. In primary antral mucosal cell culture, NPW mRNA expression was stimulated by l-phenylalanine, but not glucose. Calcium-sensing receptor (CaSR) positive cells were largely co-localized with NPW in mouse gastric antral mucosal cells, and NPW mRNA expression was inhibited by a selective antagonist of CaSR NPS2143. However, the l-phenylalanine-induced increase in NPW expression was not affected by NPS2143. In conclusion, these studies indicated an inconsistency between plasma and gastric NPW expression in response to nutrient ingestion, suggesting food induced gastric NPW expression may play a more important role locally. Moreover, glucose and especially protein are potent regulators of gastric NPW, via distinct mechanisms.
Publisher: Wiley
Date: 05-1997
Publisher: Wiley
Date: 08-10-0014
DOI: 10.1002/OBY.23224
Abstract: A sufficient and balanced maternal diet is critical to meet the nutritional demands of the developing fetus and to facilitate deposition of fat reserves for lactation. Multiple adaptations occur to meet these energy requirements, including reductions in energy expenditure and increases in maternal food intake. The central nervous system plays a vital role in the regulation of food intake and energy homeostasis and responds to multiple metabolic and nutrient cues, including those arising from the gastrointestinal tract. This review describes the nutrient requirements of pregnancy and the impact of over‐ and undernutrition on the risk of pregnancy complications and adult disease in progeny. The central and peripheral regulation of food intake is then discussed, with particular emphasis on the adaptations that occur during pregnancy and the mechanisms that drive these changes, including the possible role of the pregnancy‐associated hormones progesterone, estrogen, prolactin, and growth hormone. We identify the need for deeper mechanistic understanding of maternal adaptations, in particular, changes in gut–brain axis satiety signaling. Improved understanding of food intake regulation during pregnancy will provide a basis to inform strategies that prevent maternal under‐ or overnutrition, improve fetal health, and reduce the long‐term health and economic burden for mothers and offspring.
Publisher: Elsevier BV
Date: 05-2010
Publisher: Wiley
Date: 30-08-2007
Publisher: American Physiological Society
Date: 04-2008
Abstract: Despite universal use of opioids in the clinic to inhibit pain, there is relatively little known of their peripheral actions on sensory nerve endings, where in fact they may be better targeted with more widespread applications. Here we show differential effects of μ-, κ-, and δ-opioids on mechanosensitive ferret esophageal vagal afferent endings investigated in vitro. The effects of selective agonists [d-Ala 2 ,N-Me-Phe 4 ,Gly-ol 5 ]-enkephalin (DAMGO), 2-(3, 4-dichlorophenyl)- N-methyl- N-[(1S)-1phenyl-2-(1-pyrrolidinyl) ethyl] acetamide hydrochlorine (ICI 199441), and (+)-4-[(αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]- N, N-diethylbenzamide (SNC-80), respectively, on mechanosensory stimulus-response functions were quantified. DAMGO (10 −7 to 10 −5 M) reduced the responses of tension receptors to circumferential tension (1–5 g) by up to 50%, and the responses of mucosal receptors to mucosal stroking (10–1,000 mg von Frey hair) by %. DAMGO effects were reversed by naloxone (10 −5 M). Tension/mucosal (TM) receptor responses to tension and stroking were unaffected by DAMGO. ICI 199441 (10 −6 to 10 −5 M) potently inhibited all responses except TM receptor responses to tension, and SNC-80 (10 −5 to 10 −3 M) had no effect other than a minor inhibition of mucosal receptor responses to intense stimuli at 10 −3 M. We conclude that μ- and κ-opioids have potent and selective peripheral effects on esophageal vagal afferents that may have applications in treatment of disorders of visceral sensation.
Publisher: Elsevier BV
Date: 08-2013
DOI: 10.1016/J.PEPTIDES.2013.06.004
Abstract: Leptin, ghrelin and neuropeptide W (NPW) modulate vagal afferent activity, which may underlie their appetite regulatory actions. High fat diet (HFD)-induced obesity induces changes in the plasma levels of these peptides and alters the expression of receptors on vagal afferents. We investigated homologous and heterologous receptor regulation by leptin, ghrelin and NPW. Mice were fed (12 weeks) a standard laboratory diet (SLD) or HFD. Nodose ganglia were cultured overnight in the presence or absence of each peptide. Leptin (LepR), ghrelin (GHS-R), NPW (GPR7) and cholecystokinin type-1 (CCK1R) receptor mRNA, and the plasma leptin, ghrelin and NPW levels were measured. SLD: leptin reduced LepR, GPR7, increased GHS-R and CCK1R mRNA ghrelin increased LepR, GPR7, CCK1R, and decreased GHS-R. HFD: leptin decreased GHS-R and GPR7, ghrelin increased GHS-R and GPR7. NPW decreased all receptors except GPR7 which increased with HFD. Plasma leptin was higher and NPW lower in HFD. Thus, HFD-induced obesity disrupts inter-regulation of appetite regulatory receptors in vagal afferents.
Publisher: MDPI AG
Date: 02-05-2021
DOI: 10.3390/NU13051536
Abstract: Evidence on the association between various dietary constructs and obesity risk is limited. This study aims to investigate the longitudinal relationship between different diet indices and dietary patterns with the risk of obesity. Non-obese participants (n = 787) in the North West Adelaide Health Study were followed from 2010 to 2015. The dietary inflammatory index (DII®), plant-based dietary index (PDI) and factor-derived dietary pattern scores were computed based on food frequency questionnaire data. We found the incidence of obesity was 7.62% at the 5-year follow up. In the adjusted model, results from multivariable log-binomial logistic regression showed that a prudent dietary pattern (RRQ5 vs. Q1 = 0.38 95% CI: 0.15–0.96), healthy PDI (RR = 0.31 95% CI: 0.12–0.77) and overall PDI (RR = 0.56 95% CI: 0.23–1.33) were inversely associated with obesity risk. Conversely, the DII (RR = 1.59 95% CI: 0.72–3.50), a Western dietary pattern (RR = 2.16 95% CI: 0.76–6.08) and unhealthy PDI (RR = 1.94 95% CI: 0.81–4.66) were associated with increased risk of obesity. Based on the cubic spline analysis, the association between an unhealthy PDI or diet quality with the risk of obesity was non-linear. In conclusion, an anti-inflammatory diet, healthy diet or consumption of healthy plant-based foods were all associated with a lower risk of developing obesity.
Publisher: Wiley
Date: 23-01-2019
DOI: 10.1113/JP277195
Publisher: Springer Science and Business Media LLC
Date: 30-07-2013
DOI: 10.1038/IJO.2013.138
Abstract: Gastric vagal afferents convey satiety signals in response to mechanical stimuli. The sensitivity of these afferents is decreased in diet-induced obesity. Leptin, secreted from gastric epithelial cells, potentiates the response of vagal afferents to mechanical stimuli in lean mice, but has an inhibitory effect in high-fat diet (HFD)-induced obese mice. We sought to determine whether changes in vagal afferent function and response to leptin in obesity were reversible by returning obese mice consuming a HFD to standard laboratory chow diet (SLD). Eight-week-old female C57BL/6 mice were either fed a SLD (N=20) or HFD (N=20) for 24 weeks. A third group was fed a HFD for 12 weeks and then a SLD for a further 12 weeks (RFD, N=18). An in vitro gastro-oesophageal vagal afferent preparation was used to determine the mechanosensitivity of gastric vagal afferents and the modulatory effect of leptin (0.1-10 nM) was examined. Retrograde tracing and quantitative RT-PCR were used to determine the expression of leptin receptor (LepR) messenger RNA (mRNA) in whole nodose and specific cell bodies traced from the stomach. After 24 weeks, both the HFD and RFD mice had increased body weight, gonadal fat mass, plasma leptin, plasma insulin and daily energy consumption compared with the SLD mice. The HFD and RFD mice had reduced tension receptor mechanosensitivity and leptin further inhibited responses to tension in HFD, RFD but not SLD mice. Mucosal receptors from both the SLD and RFD mice were potentiated by leptin, an effect not seen in HFD mice. LepR expression was unchanged in the whole nodose, but was reduced in the mucosal afferents of the HFD and RFD mice. Disruption of gastric vagal afferent function by HFD-induced obesity is only partially reversible by dietary change, which provides a potential mechanism preventing maintenance of weight loss.
Publisher: Elsevier BV
Date: 03-2010
DOI: 10.1053/J.GASTRO.2009.08.053
Abstract: During gastroesophageal reflux, transient lower esophageal sphincter relaxation and crural diaphragm (CD) inhibition occur concomitantly. Modifying vagus nerve control of transient lower esophageal sphincter relaxation is a major focus of development of therapeutics for gastroesophageal reflux disease, but neural mechanisms that coordinate the CD are poorly understood. Nerve tracing and immunolabeling were used to assess innervation of the diaphragm and lower esophageal sphincter in ferrets. Mechanosensory responses of vagal afferents in the CD and electromyography responses of the CD were recorded in novel in vitro preparations and in vivo. Retrograde tracing revealed a unique population of vagal CD sensory neurons in nodose ganglia and CD motor neurons in brainstem vagal nuclei. Anterograde tracing revealed specialized vagal endings in the CD and phrenoesophageal ligament-sites of vagal afferent mechanosensitivity recorded in vitro. Spontaneous electromyography activity persisted in the CD following bilateral phrenicotomy in vivo, while vagus nerve stimulation evoked electromyography responses in the CD in vitro and in vivo. We conclude that vagal sensory and motor neurons functionally innervate the CD and phrenoesophageal ligament. CD vagal afferents show mechanosensitivity to distortion of the gastroesophageal junction, while vagal motor neurons innervate both CD and distal esophagus and may represent a common substrate for motor control of the reflux barrier.
Publisher: MDPI AG
Date: 19-08-2020
DOI: 10.3390/NU12092493
Abstract: The stomach is the primary source of the orexigenic and adiposity-promoting hormone, ghrelin. There is emerging evidence on the nutrient-mediated modulation of gastric ghrelin secretion. However, limited information is available on gastric nutrient-sensing mechanisms in high-fat diet (HFD)-induced obesity. This study investigated the impact of HFD-induced obesity on the expression of nutrient chemosensors in mouse stomach, particularly ghrelin cells. Male C57BL/6 mice were fed either a standard laboratory diet (SLD) or HFD for 12 weeks. The expression of ghrelin, enzymes involved in ghrelin production (PC1/3, GOAT) and nutrient chemosensors (CD36, FFAR2& , GPR93, CaSR, mGluR4 and T1R3) was determined by quantitative RT-PCR in the mouse corpus and antrum. Immunohistochemistry assessed the protein expression of CaSR and ghrelin in the corpus and antrum. Antral mRNA levels of CaSR and PC1/3 were increased in HFD compared to SLD mice, while mRNA levels of all other nutrient chemosensors examined remained unchanged. CaSR immunolabelling was observed in the gastric antrum only. Nearly 80% of antral ghrelin cells expressed CaSR, with a similar cell density and co-expression in SLD and HFD mice. In conclusion, HFD-induced obesity increased CaSR mRNA expression in mouse antrum. However, the high antral co-expression of CaSR and ghrelin was unaltered in HFD compared to SLD mice.
Publisher: MDPI AG
Date: 02-2023
DOI: 10.3390/BIOM13020276
Abstract: Nausea and vomiting are common gastrointestinal side effects of oxaliplatin chemotherapy used for the treatment of colorectal cancer. However, the mechanism underlying oxaliplatin-induced nausea and vomiting is unknown. The stomach is involved in the emetic reflex but no study investigated the effects of oxaliplatin treatment on the stomach. In this study, the in vivo effects of oxaliplatin treatment on eating behaviour, stomach content, intrinsic gastric neuronal population, extrinsic innervation to the stomach, levels of mucosal serotonin (5-hydroxytryptamine, 5-HT), and parasympathetic vagal efferent nerve activity were analysed. Chronic systemic oxaliplatin treatment in mice resulted in pica, indicated by increased kaolin consumption and a reduction in body weight. Oxaliplatin treatment significantly increased the stomach weight and content. The total number of myenteric and nitric oxide synthase-immunoreactive neurons as well as the density of sympathetic, parasympathetic, and sensory fibres in the stomach were decreased significantly with oxaliplatin treatment. Oxaliplatin treatment significantly increased the levels in mucosal 5-HT and the number of enterochromaffin-like cells. Chronic oxaliplatin treatment also caused a significant increase in the vagal efferent nerve activity. The findings of this study indicate that oxaliplatin exposure has adverse effects on multiple components of gastric innervation, which could be responsible for pica and gastric dysmotility.
Publisher: Elsevier BV
Date: 06-2008
Publisher: Society for Neuroscience
Date: 03-06-2009
DOI: 10.1523/JNEUROSCI.6099-08.2009
Abstract: Nitric oxide (NO) plays important roles in CNS and smooth muscle function. Here we reveal an additional function in peripheral sensory transmission. We hypothesized that endogenous NO modulates the function of gastrointestinal vagal afferent endings. The nonselective NO synthase (NOS) inhibitor N G -nitro- l -arginine methyl ester hydrochloride increased responses to tactile mechanical stimuli of mucosal afferent endings in two species, in some cases severalfold. This was mimicked by a neuronal NOS inhibitor but not an endothelial NOS inhibitor. NOS inhibitors did not affect the responsiveness of smooth muscle afferent endings, suggesting that the endogenous source of NO is exclusively accessible to mucosal receptors. The role of the NO-soluble guanylyl cyclase (sGC)–cGMP pathway was confirmed using the sGC inhibitor 1 H -[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one and the cGMP phosphodiesterase 5′ inhibitor sildenafil. The first enhanced and the second inhibited mechanosensory function. Exogenous NO, from the donor S -nitroso- N -acetylpenicillamine, significantly reduced mechanosensitivity of both types of ending. Up to one-third of stomach-projecting afferent neurons in the nodose ganglia expressed neuronal NOS (nNOS). However, anterograde-traced vagal endings were nNOS negative, indicating NOS is not transported peripherally and there are alternative sources of NO for afferent modulation. A subpopulation of enteroendocrine cells in the gut mucosa were nNOS positive, which were found anatomically in close apposition with mucosal vagal afferent endings. These results indicate an inhibitory neuromodulatory role of epithelial NO, which targets a select population of vagal afferents. This interaction is likely to play a role in generation of symptoms and behaviors from the upper gastrointestinal system.
Publisher: Wiley
Date: 10-12-2021
DOI: 10.1111/APHA.13588
Publisher: Wiley
Date: 11-1998
DOI: 10.1111/J.1469-7793.1998.907BD.X
Abstract: 1. A novel preparation of the oesophagus with attached vagus nerve from the ferret maintained in vitro was used to study the properties of single vagal afferent nerve fibres with identified receptive fields. 2. Recordings were made from three types of gastro-oesophageal vagal afferent fibres that were classified on the basis of their sensitivity to mechanical stimulation. There were those responding to mucosal stroking (mucosal receptors), to circular tension (tension receptors) and those responding to mucosal stroking and circular tension, which we have termed tension/mucosal (TM) receptors. 3. The conduction velocities for mucosal, TM and tension receptor fibres were 6.38 +/- 1.22 m s-1 (n = 22), 6.20 +/- 1.49 m s-1 (n = 13) and 5.33 +/- 0.86 m s-1 (n = 22), respectively. 4. Receptive fields of afferents showed random topographical distribution by fibre type and conduction velocity. They were found mainly distal but also occasionally proximal to the point of vagal dissection. 5. Twenty-eight per cent of mucosal, 63% of TM and 43% of tension receptors responded to one or more drugs or chemical stimuli applied to the receptive field. 6. In conclusion, this experimental preparation provides evidence for the existence of three types of oesophageal vagal afferent fibre, namely mucosal, tension and the newly identified tension/mucosal receptors.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-1994
DOI: 10.1097/00005344-199405000-00010
Abstract: The Langendorff heart preparation was used to investigate the mechanism of action of vasodilatation evoked by ATP and its analogues in guinea pig coronary vasculature. The relative order of potency of ATP and its analogues in causing a reduction in perfusion pressure was 2-methylthioATP (2-meSATP) > ATP > beta, gamma-methyleneATP (beta,gamma-meATP) > or = alpha,beta-methyleneATP (alpha,beta-meATP), thus establishing the presence of P2y-purinoceptors in this preparation. L-NG-nitroarginine methyl ester (L-NAME, 3 x 10(-5) M) significantly attenuated both the area under the flow-time curve and the maximum decrease in perfusion pressure of the vasodilatation produced in response to 2-meSATP (5 x 10(-12)-5 x 10(-9) mol). However, for ATP (5 x 10(-7)-5 x 10(-10) mol), L-NAME 3 x 10(-5) M significantly attenuated the area under the flow-time curve of the response but did not reduce the maximum decrease in perfusion pressure except at one low dose (5 x 10(-10) mol). L-Arginine 1.5 x 10(-3) M significantly reversed inhibition of the area under the flow-time curve of the response to 2-meSATP 5 x 10(-10) mol and ATP 5 x 10(-8) mol by L-NAME 3 x 10(-5) M. The maximum decrease in perfusion pressure of the response to ATP 5 x 10(-10)-5 x 10(-7) mol was significantly attenuated in the presence of indomethacin 10(-6) M.(ABSTRACT TRUNCATED AT 250 WORDS)
Publisher: Elsevier BV
Date: 08-1996
DOI: 10.1016/0301-2115(96)02466-9
Abstract: To investigate local vascular control in the isolated perfused premenopausal human ovary by measuring flow-induced release of vasoactive substances. Release of adenosine 5' triphosphate (ATP), substance P (SP), endothelin (ET), and vasopressin (AVP) from the ovarian vascular endothelium was estimated in perfusate under basal conditions and during two periods of increased flow. Vascular resistance ATP, SP, ET and AVP release. The mean ratio (pressure/flow during increased flow):(pressure/flow at basal flow) was 1.27 +/- 0.04 for the first, and 1.15 +/- 0.05 for the second period of increased flow (n = 10), indicating significant vasoconstriction (P < 0.01 and 0.05, respectively), present to a greater extent during the first period of increased flow compared to the second (P < 0.05). ATP release was seen in response to increased flow (n = 8, P < 0.05). From 12 ovarian bed preparations, five released ET and SP and three of these released AVP. Four of the five perfused ovaries that released peptides contained either a developing follicle or a corpus luteum while all those that showed no peptide release were inactive. ATP release may play a role in the local control of the human premenopausal ovarian vasculature independent of ovulatory status. Peptides may also contribute to local vascular control in the ovary and their release from predominantly active ovaries suggests a relationship between ovulation and vascular endothelial function.
Publisher: Wiley
Date: 11-10-2021
DOI: 10.1113/JP282291
Publisher: Wiley
Date: 05-2020
DOI: 10.1113/JP279449
Publisher: Elsevier BV
Date: 09-2020
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Start Date: 2012
End Date: 2014
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2009
End Date: 2011
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2013
End Date: 2013
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2013
End Date: 2015
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2014
End Date: 2016
Funder: Australian Research Council
View Funded ActivityStart Date: 2015
End Date: 2015
Funder: Australian Research Council
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