Gastric Vagal Afferent Mechanosensitivity Research Articles

Pregnancy-related plasticity of gastric vagal afferent signals in mice.

Gastric vagal afferents (GVAs) sense food-related mechanical stimuli and signal to the central nervous system, to integrate control of meal termination. Pregnancy is characterized by increased maternal food intake, which is essential for normal fetal growth and to maximize progeny survival and health. However, it is unknown whether GVA function is altered during pregnancy to promote food intake. This study aimed to determine the mechanosensitivity of GVAs and food intake during early, mid-, and late stages of pregnancy in mice. Pregnant mice consumed more food compared with nonpregnant mice, notably in the light phase during mid- and late pregnancy. The increased food intake was predominantly due to light-phase increases in meal size across all stages of pregnancy. The sensitivity of GVA tension receptors to gastric distension was significantly attenuated in mid- and late pregnancy, whereas the sensitivity of GVA mucosal receptors to mucosal stroking was unchanged during pregnancy. To determine whether pregnancy-associated hormonal changes drive these adaptations, the effects of estradiol, progesterone, prolactin, and growth hormone on GVA tension receptor mechanosensitivity were determined in nonpregnant female mice. The sensitivity of GVA tension receptors to gastric distension was augmented by estradiol, attenuated by growth hormone, and unaffected by progesterone or prolactin. Together, the data indicate that the sensitivity of GVA tension receptors to tension is reduced during pregnancy, which may attenuate the perception of gastric fullness and explain increased food intake. Further, these adaptations may be driven by increases in maternal circulating growth hormone levels during pregnancy.NEW & NOTEWORTHY 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.

Relieving tension: effects of cannabinoids on vagal afferent sensitivity.

Endocannabinoids are produced within the gastrointestinal (GI) tract and modulate energy homeostasis and food intake, at least in part, via vagally-dependent actions. The recent paper by Christie etal., [Christie, etal. J Physiol, 2019] demonstrate, for the first time, that cannabinoids exert biphasic effects on the mechanosensitivity of tension-sensitive gastric vagal afferents. At higher concentrations, anandamide increased vagal afferent sensitivity in a CB1 and TRPV1 receptor dependent manner. At lower concentrations, however, anandamide decreased afferent mechanosensitivity; while this was also dependent upon CB1 and TRPV1 receptors, it also appeared dependent upon signaling via the potent orexigenic neurohormone, ghrelin. These results provide further evidence to support the remarkable degree of neuroplasticity within vagal afferent signaling, and suggest that untangling the complex interactions of cannabinoid effects on food intake and energy homeostasis will require careful physiological and pharmacological investigations. This article is protected by copyright. All rights reserved.

Activation of CRF2 receptor increases gastric vagal afferent mechanosensitivity.

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.

Biphasic effects of methanandamide on murine gastric vagal afferent mechanosensitivity.

The fine control of food intake is important for the maintenance of a healthy metabolic state. Gastric vagal afferents (GVAs) are involved in the peripheral regulation of food intake via signalling the degree of distension of the stomach which ultimately leads to feelings of fullness and satiety. This study provides evidence that endocannabinoids such as anandamide are capable of regulating GVA sensitivity in a concentration-dependent biphasic manner. This biphasic effect is dependent upon interactions between the CB1, TRPV1 and GHSR receptors. These data have important implications for the peripheral control of food intake. Gastric vagal afferents (GVAs) signal to the hindbrain resulting in satiety. Endocannabinoids are endogenous ligands of cannabinoid 1 receptor (CB1) and transient receptor potential vanilloid-1 (TRPV1) channels. The endocannabinoid anandamide (AEA) is expressed in the stomach, and its receptor CB1 is expressed in ghrelin-positive gastric mucosal cells. Further, TRPV1, CB1 and growth hormone secretagogue receptor (ghrelin receptor, GHSR) are expressed in subpopulations of GVA neurons. This study aimed to determine the interaction between TRPV1, CB1, GHSR and endocannabinoids in the modulation of GVA signalling. An in vitro electrophysiology preparation was used to assess GVA mechanosensitivity in male C57BL/6 mice. Effects of methanandamide (mAEA; 1-100nm), on GVA responses to stretch were determined in the absence and presence of antagonists of CB1, TRPV1, GHSR, protein kinase-A (PKA), protein kinase-C (PKC) and G-protein subunits Gαi/o , or Gαq . Low doses (1-10nm) of mAEA reduced GVA responses to 3g stretch, whereas high doses (30-100nm) increased the response. The inhibitory and excitatory effects of mAEA (1-100nm) were reduced/lost in the presence of a CB1 and TRPV1 antagonist. PKA, Gαi/o or GHSR antagonists prevented the inhibitory effect of mAEA on GVA mechanosensitivity. Conversely, in the presence of a PKC or Gαq antagonist the excitatory effect of mAEA was reduced or lost, respectively. Activation of CB1, by mAEA, can activate or inhibit TRPV1 to increase or decrease GVA responses to stretch, depending on the pathway activated. These interactions could play an important role in the fine control of food intake.

Stress-induced modulation of vagal afferents.

Vagally dependent gastric functions, including motility, tone, compliance, and emptying rate, play an important role in the regulation of food intake and satiation. Vagal afferent fibers relay sensory information from the stomach, including meal-related information, centrally and initiate co-ordinated autonomic efferent responses that regulate upper gastrointestinal responses. The purpose of this mini-review is to highlight several recent studies which have uncovered the remarkable degree of neuroplasticity within gastric mechanosensitive vagal afferents and the recent study by Li et al, in this issue of Neurogastroenterology and Motility, who show that the mechanosensitivity of gastric vagal afferents is dysregulated in a murine model of chronic stress. The authors demonstrate that both gastric mucosal and tension afferents are hypersensitive following chronic stress, and responses to mucosal stroking and muscle stretch are enhanced significantly. As gastric distension and volumetric signaling is important in satiety signaling and meal termination, this may provide a mechanistic basis for the gastric hypersensitivity associated with stress-associated clinical problems such as functional dyspepsia.

NADPH oxidase modulates leptin effects on gastric vagal afferent mechanosensitivity

NADPH oxidase modulates leptin effects on gastric vagal afferent mechanosensitivity

Apelin modulates murine gastric vagal afferent mechanosensitivity.

Gastric vagal afferents play an important role in the peripheral control of food intake. Apelin, a central appetite regulating hormone, is also abundantly released from the stomach. Whether apelin modulates gastric vagal afferent signalling is unknown. We aimed to determine whether apelin modulates gastric vagal afferent signalling under different states of nutrition. Female C57BL/6 mice were fed either a standard laboratory diet (SLD) or a high fat diet (HFD) for 12 weeks. An in vitro gastric vagal afferent preparation was used to determine the effect of apelin on gastric vagal afferent mechanosensitivity in SLD mice, fed ad libitum or fasted overnight, and HFD mice. To determine the signalling pathway of apelin via gastric vagal afferents, we determined the expression of apelin receptor (APJ receptor) in the gastric mucosa, the whole nodose ganglion and in gastric vagal afferent neurons innervating the stomach using retrograde tracing and real-time quantitative reverse-transcription polymerase chain reaction (qRT-PCR). The location of apelin and APJ receptor within the gastric mucosa was determined by immunohistochemistry. Expression of apelin and APJ receptor mRNA in gastric mucosa was determined using qRT-PCR. Apelin inhibited the response of gastric mucosal vagal afferents to mucosal stroking in fasted SLD mice, but not in mice fed ad libitum a SLD or HFD. Apelin inhibited the response of gastric tension sensitive afferents to circular stretch in SLD mice fed ad libitum or fasted, an effect not observed in HFD mice. APJ receptor mRNA was detected in the gastric mucosa and whole nodose ganglion, but not specifically in gastric vagal afferents neurons. In the gastric mucosa, APJ receptor immunoreactive cells were co-localised or closely associated with apelin containing cells and co-localised with serotonin, gastrin, histamine and gastric intrinsic factor containing cells. In conclusion, apelin modulates gastric vagal afferent signalling in a nutritional status dependent manner. Further, apelin modulates gastric vagal afferents through an indirect pathway, possibly through the release of hormones/peptides from the gastric mucosa.

Time-Restricted Feeding Prevents Ablation of Diurnal Rhythms in Gastric Vagal Afferent Mechanosensitivity Observed in High-Fat Diet-Induced Obese Mice.

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 dampened. 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.

Nesfatin-1 modulates murine gastric vagal afferent mechanosensitivity in a nutritional state dependent manner

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.

High-Fat Diet-Induced Obesity Ablates Gastric Vagal Afferent Circadian Rhythms.

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.

TRPV1 Channels and Gastric Vagal Afferent Signalling in Lean and High Fat Diet Induced Obese Mice.

AimWithin the gastrointestinal tract vagal afferents play a role in control of food intake and satiety signalling. Activation of mechanosensitive gastric vagal afferents induces satiety. However, gastric vagal afferent responses to mechanical stretch are reduced in high fat diet mice. Transient receptor potential vanilloid 1 channels (TRPV1) are expressed in vagal afferents and knockout of TRPV1 reduces gastro-oesophageal vagal afferent responses to stretch. We aimed to determine the role of TRPV1 on gastric vagal afferent mechanosensitivity and food intake in lean and HFD-induced obese mice.MethodsTRPV1+/+ and -/- mice were fed either a standard laboratory diet or high fat diet for 20wks. Gastric emptying of a solid meal and gastric vagal afferent mechanosensitivity was determined.ResultsGastric emptying was delayed in high fat diet mice but there was no difference between TRPV1+/+ and -/- mice on either diet. TRPV1 mRNA expression in whole nodose ganglia of TRPV1+/+ mice was similar in both dietary groups. The TRPV1 agonist N-oleoyldopamine potentiated the response of tension receptors in standard laboratory diet but not high fat diet mice. Food intake was greater in the standard laboratory diet TRPV1-/- compared to TRPV1+/+ mice. This was associated with reduced response of tension receptors to stretch in standard laboratory diet TRPV1-/- mice. Tension receptor responses to stretch were decreased in high fat diet compared to standard laboratory diet TRPV1+/+ mice; an effect not observed in TRPV1-/- mice. Disruption of TRPV1 had no effect on the response of mucosal receptors to mucosal stroking in mice on either diet.ConclusionTRPV1 channels selectively modulate gastric vagal afferent tension receptor mechanosensitivity and may mediate the reduction in gastric vagal afferent mechanosensitivity in high fat diet-induced obesity.

Neuropeptide W modulation of gastric vagal afferent mechanosensitivity: Impact of age and sex

AimGastric vagal afferents are activated in response to mechanical stimulation, an effect attenuated by neuropeptide W (NPW) in 20-week-old female mice. In this study we aimed to determine whether there were age and sex dependent effects of NPW on gastric vagal afferent mechanosensitivity. MethodsAn in vitro gastro-oesophageal preparation was used to determine the effect of NPW on gastric vagal afferent mechanosensitivity from 8 and 20-week-old male and female C57BL/6 mice. Retrograde tracing and laser capture microdissection were used to selectively collect gastric vagal afferent cell bodies. Expression of NPW in the gastric mucosa and its receptor, GPR7, in gastric vagal afferent cell bodies was determined using quantitative RT-PCR. ResultsNPW inhibited gastric tension sensitive vagal afferents from 20-week-old male and female mice, but not 8-week-old mice. In contrast, NPW inhibited the mechanosensitivity of gastric mucosal vagal afferents in 8-week-old male and female mice, but not 20-week-old mice. NPW mRNA expression in the gastric mucosa was higher in 20-week-old male mice compared to 8-week-old male mice. GPR7 mRNA expression in vagal afferent neurons innervating the gastric muscular layers was higher in 20-week-old mice compared to 8-week-old mice in both sexes. ConclusionThe inhibitory effect of NPW on gastric tension sensitive and mucosal vagal afferents is age but not sex-dependent. These findings suggest that the physiological role of NPW varies depending on the age of the mice.

Vagal plasticity the key to obesity.

Vagal plasticity the key to obesity.

Circadian Variation in Gastric Vagal Afferent Mechanosensitivity

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.

Effects of bariatric surgery on sympathetic activity and cardiac risk in non-diabetic severely obese patients

diet-induced obesity disrupts circadian variation of gastric vagal afferent activity is unknown. Therefore, we fed 8 week old female C57BL/6 mice either a standard laboratory diet (SLD; 7% energy from fat, N = 12) or high fat diet (HFD; 60% energy from fat, N = 12) for 12 weeks. At which time mice were sacrificed at 6 h intervals starting at 18:00. Stomach contents were measured and single fibre recordings from gastric vagal tension and mucosal receptors were obtained at each time point, in the absence and presence of leptin (1 nM) [5]. In SLD mice, at 00:00 as compared to 12:00, stomach contents were 168% greater (p < 0.01), response of tension receptors to tension (3 g) was reduced by 59% (p < 0.01) and that of mucosal receptors to stroking (50mg) was reduced by 62% (p < 0.001). Leptin potentiation of mucosal receptor responses to stroking (50mg), were 70% less at 00:00 than 12:00 (p < 0.05). In HFD mice circadian variation in stomach contents, vagal afferent mechanosensitivity, and leptin inhibition of tension receptors, was minimal. In conclusion, HFD induced obesity suppresses circadian variations in gastric vagal afferent mechanosensitivity, responsiveness of tension receptors to leptin and alters food intake patterns.

Modulation of murine gastric vagal afferent mechanosensitivity by neuropeptide W

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.

Altered gastric vagal mechanosensitivity in diet-induced obesity persists on return to normal chow and is accompanied by increased food intake

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.

Circadian variations in gastric vagal afferent mechanosensitivity and satiety signalling

Circadian variations in gastric vagal afferent mechanosensitivity and satiety signalling