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  • Gut 11/2013;
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    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/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 neurons was determined by retrograde tracing and QRT-PCR. NPW 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 neurons. In fasted mice gastric mucosal NPW and nodose GPR7 mRNA was reduced compared to SLD. A HFD had no effect on gastric NPW mRNA, but down-regulated nodose GPR7 expression. NPW modulates gastric vagal afferent activity, but the effect is dynamic and related to feeding status. This article is protected by copyright. All rights reserved.
    Acta Physiologica 08/2013;
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    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.
    Peptides 06/2013;
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    ABSTRACT: Energy intake is strongly influenced by vagal afferent signals from the stomach, and is also modulated by leptin. Leptin may be secreted from gastric epithelial cells, so we aimed to determine the direct effect of leptin on gastric vagal afferents under different feeding conditions. Female C57BL/6 mice were fed standard laboratory diet, high fat diet or were food restricted. The expression of leptin receptor and its signal transduction molecules in vagal afferents was determined by retrograde tracing and reverse-transcription polymerase chain reaction (RT-PCR), and the relationship between leptin immunopositive cells and gastric vagal afferent endings determined by anterograde tracing and leptin immunohistochemistry. An in vitro preparation was used to determine the functional effects of leptin on gastric vagal afferents and the second messenger pathways involved. Leptin potentiated vagal mucosal afferent responses to tactile stimuli, and epithelial cells expressing leptin were found close to vagal mucosal endings. After fasting or diet-induced obesity, potentiation of mucosal afferents by leptin was lost and leptin receptor expression reduced in the cell bodies of gastric mucosal afferents. These effects in diet-induced obese mice were accompanied by a reduction in anatomical vagal innervation of the gastric mucosa. In striking contrast, after fasting or diet-induced obesity, leptin actually inhibited responses to distension in tension receptors. The inhibitory effect on gastric tension receptors was mediated through PI3K-dependent activation of BKCa channels. The excitatory effect of leptin on gastric mucosal vagal afferents was mediated by PLC-dependent activation of TRPC1 channels. These data suggest the effect of leptin on gastric vagal afferent excitability is dynamic and related to the feeding state. Paradoxically, in obesity, leptin may reduce responses to gastric distension following food intake.
    The Journal of Physiology 12/2012;
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    ABSTRACT: Significant relationships exist between areal bone mineral density (BMD) derived from dual energy X-ray absorptiometry (DXA) and bone strength. However, the predictive validity of BMD for osteoporotic vertebral fractures remains suboptimal. The diagnostic sensitivity of DXA in the lumbar spine may be improved by assessing BMD from lateral-projection scans, as these might better approximate the objective of measuring the trabecular-rich bone in the vertebral body, compared to the commonly-used posterior-anterior (PA) projections. Nowadays, X-ray micro-computed tomography (μCT) allows non-destructive three-dimensional structural characterization of entire bone segments at high resolution. In this study, human lumbar cadaver spines were examined ex situ by DXA in lateral and PA projections, as well as by μCT, with the aims (1) to investigate the ability of bone quantity measurements obtained by DXA in the lateral projection and in the PA projection, to predict variations in bone quantity measurements obtained by μCT, and (2) to assess their respective capabilities to predict whole vertebral body strength, determined experimentally. Human cadaver spines were scanned by DXA in PA projections and lateral projections. Bone mineral content (BMC) and BMD for L2 and L3 vertebrae were determined. The L2 and L3 vertebrae were then dissected and entirely scanned by μCT. Total bone volume (BV(tot)=cortical+trabecular), trabecular bone volume (BV), and trabecular bone volume fraction (BV/TV) were calculated over the entire vertebrae. The vertebral bodies were then mechanically tested to failure in compression, to determine ultimate load. The variables BV(tot), BV, and BV/TV measured by μCT were better predicted by BMC and BMD measured by lateral-projection DXA, with higher R(2) values and smaller standard errors of the estimate (R(2)=0.65-0.90, SEE=11%-18%), compared to PA-projection DXA (R(2)=0.33-0.53, SEE=22%-34%). The best predictors of ultimate load were BV(tot) and BV assessed by μCT (R(2)=0.88 and R(2)=0.81, respectively), and BMC and BMD from lateral-projection DXA (R(2)=0.82 and R(2)=0.70, respectively). Conversely, BMC and BMD from PA-projection DXA were lower predictors of ultimate load (R(2)=0.49 and R(2)=0.37, respectively). This ex vivo study highlights greater capabilities of lateral-projection DXA to predict variations in vertebral body bone quantity as measured by μCT, and to predict vertebral strength as assessed experimentally, compared to PA-projection DXA. This provides basis for further exploring the clinical application of lateral-projection DXA analysis.
    Bone 03/2012; 50(6):1416-25.
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    ABSTRACT: Visceral pain following infection or inflammation is a major clinical problem. Although we have knowledge of how peripheral endings of colonic afferents change in disease, their central projections have been overlooked. With neuroanatomical tracing and colorectal distension (CRD), we sought to identify colonic afferent central terminals (CACTs), the dorsal horn (DH) neurons activated by colonic stimuli in the thoracolumbar (T10-L1) DH, and determine how they are altered by postinflammatory chronic colonic mechanical hypersensitivity. Retrograde tracing from the colon identified CACTs in the DH, whereas immunohistochemistry for phosphorylated MAP kinase ERK 1/2 (pERK) identified DH neurons activated by CRD (80 mmHg). In healthy mice, CACTs were located primarily in DH laminae I (LI) and V (LV) and projected down middle and lateral DH collateral pathways. CRD evoked pERK immunoreactivity in DH neurons, the majority of which were located in LI and LV, the same regions as CACTs. In postinflammatory mice, CACTs were significantly increased in T12-L1 compared with healthy mice. Although CACTs remained abundant in LI, they were more widespread and were now present in deeper laminae. After CRD, significantly more DH neurons were pERK-IR postinflammation (T12-L1), with abundant expression in LI and deeper laminae. In both healthy and postinflammatory mice, many pERK neurons were in close apposition to CACTs, suggesting that colonic afferents can stimulate specific DH neurons in response to noxious CRD. Overall, we demonstrate that CACT density and the number of responsive DH neurons in the spinal cord increase postinflammation, which may facilitate aberrant central representation of colonic nociceptive signaling following chronic peripheral hypersensitivity.
    The Journal of Comparative Neurology 01/2012; 520(10):2241-55.
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    ABSTRACT: Intestinal luminal exposure to glucose initiates changes in food intake and gastrointestinal (GI) motor and secretory function. It does this by stimulating the release of GI hormones and 5-hydroxytryptamine (5-HT) from enteroendocrine and enterochromaffin cells (EC), respectively, which in turn activate intrinsic and extrinsic neuronal pathways. An article in this issue of the journal provides new insight into the mechanisms involved in luminal glucose sensing. Vincent et al. have used a novel in vivo technique to determine activation of gut epithelial cells and vagal afferent pathways in rats by staining for activated calcium-calmodulin kinase II (pCaMKII) along the pathway. In the mucosa, they found that intraluminal glucose activated EC cells and brush cells. At the next stage, pCaMKII was seen in neurons of the myenteric plexus and vagal afferent neurons in the nodose ganglia. In the central nervous system (CNS), activation was seen in second- and higher-order neurons in the dorsal vagal complex and hypothalamus. They found that 5-HT(3) receptors were involved in initiating neural signaling as activation of neurons, but not EC cells, was reduced by 5-HT(3) receptor antagonism. Selectively stimulating the sodium-glucose cotransporter (SGLT-3) had similar effects to glucose. This suggests that SGLT-3 behaves as a glucose sensor, mainly on EC cells, inducing the release of 5-HT, which activates 5-HT(3) receptors on vagal afferent endings nearby and in turn, their connections in the CNS. There is evidence elsewhere that other sensors and transmitter mechanisms are involved in this pathway, so the possibility exists of multiple redundant systems.
    Neurogastroenterology and Motility 07/2011; 23(7):591-4.
  • Gastroenterology 06/2011; 141(2):423-7.
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    ABSTRACT: High-resolution micro computed tomography has enabled measurement of bone architecture derived from 3D representations of cancellous bone. Twenty-eight vertebral bodies were obtained from four embalmed male cadavers. From 3D anaglyphs, trabecular rod thickness and length were measured and the trabecular rod Buckling index was calculated. From 3D voxel-based datasets, bone volume density, trabecular thickness, and trabecular separation were measured. Also, trabecular bone pattern factor, structural model index, connectivity density, and degree of anisotropy were calculated. Bone volume density alone explains 59% of the variability in trabecular rod Buckling index. The addition of connectivity density, trabecular separation, and structural model index, in a multiple regression statistical model, improves the explanatory power to 77%. The relationships between measures of cancellous bone architecture and a derived measure of trabecular rod strength were investigated. Morphological descriptors of cancellous bone provide a composite explanatory model of trabecular rod strength.
    Journal of osteoporosis. 01/2010; 2010:641578.
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    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.
    Gastroenterology 10/2009; 138(3):1091-101.e1-5.
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