16 results on '"Isaacs NJ"'
Search Results
2. A Gut-Intrinsic Melanocortin Signaling Complex Augments L-Cell Secretion in Humans.
- Author
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Sun EW, Iepsen EW, Pezos N, Lumsden AL, Martin AM, Schober G, Isaacs NJ, Rayner CK, Nguyen NQ, de Fontgalland D, Rabbitt P, Hollington P, Wattchow DA, Hansen T, Holm JC, Liou AP, Jackson VM, Torekov SS, Young RL, and Keating DJ
- Subjects
- Autocrine Communication, Blood Glucose metabolism, Case-Control Studies, Enteroendocrine Cells drug effects, Glucose administration & dosage, Glucose Tolerance Test, Humans, Intestinal Mucosa drug effects, Loss of Function Mutation, Paracrine Communication, Pro-Opiomelanocortin genetics, Receptor, Melanocortin, Type 4 agonists, Receptor, Melanocortin, Type 4 genetics, Secretory Pathway, Signal Transduction, Time Factors, alpha-MSH pharmacology, Enteroendocrine Cells metabolism, Glucagon-Like Peptide 1 metabolism, Intestinal Mucosa metabolism, Peptide YY metabolism, Pro-Opiomelanocortin metabolism, Receptor, Melanocortin, Type 4 metabolism, alpha-MSH metabolism
- Abstract
Objective: Hypothalamic melanocortin 4 receptors (MC4R) are a key regulator of energy homeostasis. Brain-penetrant MC4R agonists have failed, as concentrations required to suppress food intake also increase blood pressure. However, peripherally located MC4R may also mediate metabolic benefits of MC4R activation. Mc4r transcript is enriched in mouse enteroendocrine L cells and peripheral administration of the endogenous MC4R agonist, α-melanocyte stimulating hormone (α-MSH), triggers the release of the anorectic hormones Glucagon-like peptide-1 (GLP-1) and peptide tyrosine tyrosine (PYY) in mice. This study aimed to determine whether pathways linking MC4R and L-cell secretion exist in humans., Design: GLP-1 and PYY levels were assessed in body mass index-matched individuals with or without loss-of-function MC4R mutations following an oral glucose tolerance test. Immunohistochemistry was performed on human intestinal sections to characterize the mucosal MC4R system. Static incubations with MC4R agonists were carried out on human intestinal epithelia, GLP-1 and PYY contents of secretion supernatants were assayed., Results: Fasting PYY levels and oral glucose-induced GLP-1 secretion were reduced in humans carrying a total loss-of-function MC4R mutation. MC4R was localized to L cells and regulates GLP-1 and PYY secretion from ex vivo human intestine. α-MSH immunoreactivity in the human intestinal epithelia was predominantly localized to L cells. Glucose-sensitive mucosal pro-opiomelanocortin cells provide a local source of α-MSH that is essential for glucose-induced GLP-1 secretion in small intestine., Conclusion: Our findings describe a previously unidentified signaling nexus in the human gastrointestinal tract involving α-MSH release and MC4R activation on L cells in an autocrine and paracrine fashion. Outcomes from this study have direct implications for targeting mucosal MC4R to treat human metabolic disorders., (Crown Copyright © 2021. Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
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3. Sugar Responses of Human Enterochromaffin Cells Depend on Gut Region, Sex, and Body Mass.
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Lumsden AL, Martin AM, Sun EW, Schober G, Isaacs NJ, Pezos N, Wattchow DA, de Fontgalland D, Rabbitt P, Hollington P, Sposato L, Due SL, Rayner CK, Nguyen NQ, Liou AP, Jackson VM, Young RL, and Keating DJ
- Subjects
- Cells, Cultured, Dose-Response Relationship, Drug, Female, Humans, Male, Sex Factors, Body Weight, Carbohydrates pharmacology, Enterochromaffin Cells drug effects, Gastrointestinal Tract cytology
- Abstract
Gut-derived serotonin (5-HT) is released from enterochromaffin (EC) cells in response to nutrient cues, and acts to slow gastric emptying and modulate gastric motility. Rodent studies also evidence a role for gut-derived 5-HT in the control of hepatic glucose production, lipolysis and thermogenesis, and in mediating diet-induced obesity. EC cell number and 5-HT content is increased in the small intestine of obese rodents and human, however, it is unknown whether EC cells respond directly to glucose in humans, and whether their capacity to release 5-HT is perturbed in obesity. We therefore investigated 5-HT release from human duodenal and colonic EC cells in response to glucose, sucrose, fructose and α-glucoside (αMG) in relation to body mass index (BMI). EC cells released 5-HT only in response to 100 and 300 mM glucose (duodenum) and 300 mM glucose (colon), independently of osmolarity. Duodenal, but not colonic, EC cells also released 5-HT in response to sucrose and αMG, but did not respond to fructose. 5-HT content was similar in all EC cells in males, and colonic EC cells in females, but 3 to 4-fold higher in duodenal EC cells from overweight females ( p < 0.05 compared to lean, obese). Glucose-evoked 5-HT release was 3-fold higher in the duodenum of overweight females ( p < 0.05, compared to obese), but absent here in overweight males. Our data demonstrate that primary human EC cells respond directly to dietary glucose cues, with regional differences in selectivity for other sugars. Augmented glucose-evoked 5-HT release from duodenal EC is a feature of overweight females, and may be an early determinant of obesity.
- Published
- 2019
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4. Augmented capacity for peripheral serotonin release in human obesity.
- Author
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Young RL, Lumsden AL, Martin AM, Schober G, Pezos N, Thazhath SS, Isaacs NJ, Cvijanovic N, Sun EWL, Wu T, Rayner CK, Nguyen NQ, Fontgalland D, Rabbitt P, Hollington P, Sposato L, Due SL, Wattchow DA, Liou AP, Jackson VM, and Keating DJ
- Subjects
- Adult, Blood Glucose metabolism, Cells, Cultured, Colon metabolism, Endoscopy, Gastrointestinal, Female, Humans, Male, Middle Aged, Obesity metabolism, Peripheral Nervous System metabolism, Real-Time Polymerase Chain Reaction, Signal Transduction, Colon cytology, Enterochromaffin Cells metabolism, Obesity physiopathology, Peripheral Nervous System physiology, Serotonin metabolism
- Abstract
Background/objectives: Evidence from animal studies highlights an important role for serotonin (5-HT), derived from gut enterochromaffin (EC) cells, in regulating hepatic glucose production, lipolysis and thermogenesis, and promoting obesity and dysglycemia. Evidence in humans is limited, although elevated plasma 5-HT concentrations are linked to obesity., Subjects/methods: We assessed (i) plasma 5-HT concentrations before and during intraduodenal glucose infusion (4 kcal/min for 30 min) in non-diabetic obese (BMI 44 ± 4 kg/m
2 , N = 14) and control (BMI 24 ± 1 kg/m2 , N = 10) subjects, (ii) functional activation of duodenal EC cells (immunodetection of phospho-extracellular related-kinase, pERK) in response to glucose, and in separate subjects, (iii) expression of tryptophan hydroxylase-1 (TPH1) in duodenum and colon (N = 39), and (iv) 5-HT content in primary EC cells from these regions (N = 85)., Results: Plasma 5-HT was twofold higher in obese than control responders prior to (P = 0.025), and during (iAUC, P = 0.009), intraduodenal glucose infusion, and related positively to BMI (R2 = 0.334, P = 0.003) and HbA1c (R2 = 0.508, P = 0.009). The density of EC cells in the duodenum was twofold higher at baseline in obese subjects than controls (P = 0.023), with twofold more EC cells activated by glucose infusion in the obese (EC cells co-expressing 5-HT and pERK, P = 0.001), while the 5-HT content of EC cells in duodenum and colon was similar; TPH1 expression was 1.4-fold higher in the duodenum of obese subjects (P = 0.044), and related positively to BMI (R2 = 0.310, P = 0.031)., Conclusions: Human obesity is characterized by an increased capacity to produce and release 5-HT from the proximal small intestine, which is strongly linked to higher body mass, and glycemic control. Gut-derived 5-HT is likely to be an important driver of pathogenesis in human obesity and dysglycemia.- Published
- 2018
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5. Duodenal fatty acid sensor and transporter expression following acute fat exposure in healthy lean humans.
- Author
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Cvijanovic N, Isaacs NJ, Rayner CK, Feinle-Bisset C, Young RL, and Little TJ
- Subjects
- Adult, Appetite, Blood Glucose metabolism, Body Mass Index, Cholecystokinin blood, Cholecystokinin metabolism, Diet, Duodenum metabolism, Emulsions administration & dosage, Enteroendocrine Cells metabolism, Fatty Acids, Unsaturated administration & dosage, Female, Gastrointestinal Hormones blood, Gastrointestinal Hormones metabolism, Glucagon-Like Peptide 1 blood, Glucagon-Like Peptide 1 metabolism, Humans, Insulin blood, Male, Non-Randomized Controlled Trials as Topic, Phospholipids administration & dosage, Receptors, G-Protein-Coupled genetics, Receptors, G-Protein-Coupled metabolism, Soybean Oil administration & dosage, Surveys and Questionnaires, Thinness diet therapy, Diet, High-Fat adverse effects, Duodenum drug effects, Fatty Acids administration & dosage, Thinness blood
- Abstract
Background & Aims: Free fatty acids (FFAs) and their derivatives are detected by G-protein coupled receptors (GPRs) on enteroendocrine cells, with specific transporters on enterocytes. It is unknown whether acute fat exposure affects FFA sensors/transporters, and whether this relates to hormone secretion and habitual fat intake., Methods: We studied 20 healthy participants (10M, 10F; BMI: 22 ± 1 kg/m
2 ; age: 28 ± 2 years), after an overnight fast, on 2 separate days. On the first day, duodenal biopsies were collected endoscopically before, and after, a 30-min intraduodenal (ID) infusion of 10% Intralipid® , and relative transcript expression of FFA receptor 1 (FFAR1), FFA receptor 4 (FFAR4), GPR119 and the FFA transporter, cluster of differentiation-36 (CD36) was quantified from biopsies. On the second day, ID Intralipid® was infused for 120-min, and plasma concentrations of cholecystokinin (CCK) and glucagon-like peptide-1 (GLP-1) evaluated. Habitual dietary intake was assessed using food frequency questionnaires (FFQs)., Results: ID Intralipid® increased expression of GPR119, but not FFAR1, FFAR4 and CD36, and stimulated CCK and GLP-1 secretion. Habitual polyunsaturated fatty acid (PUFA) consumption was negatively associated with basal GPR119 expression., Conclusions: GPR119 is an early transcriptional responder to duodenal lipid in lean humans, although this response appeared reduced in individuals with high PUFA intake. These observations may have implications for downstream regulation of gut hormone secretion and appetite. This study was registered as a clinical trial with the Australia and New Zealand Clinical Trial Registry (Trial number: ACTRN12612000376842)., (Copyright © 2016 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)- Published
- 2017
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6. Lipid stimulation of fatty acid sensors in the human duodenum: relationship with gastrointestinal hormones, BMI and diet.
- Author
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Cvijanovic N, Isaacs NJ, Rayner CK, Feinle-Bisset C, Young RL, and Little TJ
- Subjects
- Adult, Appetite Regulation drug effects, CD36 Antigens metabolism, Energy Intake, Female, Humans, Lipids administration & dosage, Male, Obesity metabolism, Obesity physiopathology, Overweight metabolism, Overweight physiopathology, RNA, Messenger genetics, RNA, Messenger metabolism, Receptors, G-Protein-Coupled metabolism, Satiety Response drug effects, Thinness metabolism, Thinness physiopathology, Appetite Regulation physiology, Body Mass Index, Diet, Duodenum drug effects, Duodenum metabolism, Enteral Nutrition, Hormones metabolism, Lipids pharmacology, Satiety Response physiology
- Abstract
Background and Aims: The small intestinal free fatty acid (FFA) sensors, FFA receptor 1 (FFAR1), FFAR4, G-protein receptor 119 (GPR119) and cluster of differentiation-36 (CD36), mediate the fat-induced release of gastrointestinal (GI) hormones. We investigated whether expression of duodenal FFA sensors in humans was (i) altered by intraduodenal (ID) lipid infusion, (ii) disordered in overweight or obese individuals, (iii) related to lipid-induced GI hormone secretion or (iv) affected by habitual dietary patterns., Methods: Endoscopic duodenal biopsies were collected from 20 lean (body mass index (BMI): 22±1 kg m
-2 ), 18 overweight (BMI: 27±1 kg m- 2 ) and 19 obese (BMI: 35±1 kg m- 2 ) participants at baseline, and following a 30 min ID Intralipid infusion (2 kcal min-1 ); FFA sensor expression was quantified by reverse transcription-PCR. On a separate day, participants underwent ID Intralipid infusion (2 kcal min- 1 ) for 120 min, to assess GI hormone responses. Habitual diet was evaluated using food frequency questionnaires., Results: Baseline FFAR1 and FFAR4 expression were lower, and CD36 was higher, in obese participants compared with lean participants. ID lipid increased GPR119 and FFAR1 expression equally across study groups, but did not alter FFAR4 or CD36 expression. Increased FFAR1 expression correlated positively with glucose-dependent insulinotropic polypeptide (GIP) secretion (r=0.3, P<0.05), whereas there was no relationship between habitual diet with the expression of FFA sensors., Conclusions: Obesity is associated with altered duodenal expression of FFAR1, FFAR4 and CD36, suggesting altered capacity for the sensing, absorption and metabolism, of dietary lipids. GPR119 and FFAR1 are early transcriptional responders to the presence of ID lipid, whereas FFAR1 may be an important trigger for lipid-induced GIP release in humans.- Published
- 2017
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7. Characterization of duodenal expression and localization of fatty acid-sensing receptors in humans: relationships with body mass index.
- Author
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Little TJ, Isaacs NJ, Young RL, Ott R, Nguyen NQ, Rayner CK, Horowitz M, and Feinle-Bisset C
- Subjects
- Adult, Biopsy, CD36 Antigens genetics, CD36 Antigens metabolism, Case-Control Studies, Duodenum metabolism, Energy Intake, Enteroendocrine Cells chemistry, Enteroendocrine Cells metabolism, Feeding Behavior, Female, Habits, Humans, Immunohistochemistry, Intestinal Mucosa metabolism, Male, Middle Aged, Obesity diagnosis, Obesity genetics, Overweight diagnosis, Overweight genetics, RNA, Messenger analysis, Receptors, G-Protein-Coupled genetics, Receptors, G-Protein-Coupled metabolism, Reverse Transcriptase Polymerase Chain Reaction, Body Mass Index, CD36 Antigens analysis, Duodenum chemistry, Fatty Acids metabolism, Intestinal Mucosa chemistry, Obesity metabolism, Overweight metabolism, Receptors, G-Protein-Coupled analysis
- Abstract
Fatty acids (FAs) stimulate the secretion of gastrointestinal hormones, including cholecystokinin (CCK) and glucagon like peptide-1 (GLP-1), which suppress energy intake. In obesity, gastrointestinal responses to FAs are attenuated. Recent studies have identified a key role for the FA-sensing receptors cluster of differentiation (CD)36, G protein-coupled receptor (GPR)40, GPR120, and GPR119 in mediating gastrointestinal hormone secretion. This study aimed to determine the expression and localization of these receptors in the duodenum of humans and to examine relationships with obesity. Duodenal mucosal biopsies were collected from nine lean [body mass index (BMI): 22 ± 1 kg/m2], six overweight (BMI: 28 ± 1 kg/m2), and seven obese (BMI: 49 ± 5 kg/m2) participants. Absolute levels of receptor transcripts were quantified using RT-PCR, while immunohistochemistry was used for localization. Transcripts were expressed in the duodenum of lean, overweight, and obese individuals with abundance of CD36>>GPR40>GPR120>GPR119. Expression levels of GPR120 (r = 0.46, P = 0.03) and CD36 (r = 0.69, P = 0.0004) were directly correlated with BMI. There was an inverse correlation between expression of GPR119 with BMI (r2 = 0.26, P = 0.016). Immunolabeling studies localized CD36 to the brush border membrane of the duodenal mucosa and GPR40, GPR120, and GPR119 to enteroendocrine cells. The number of cells immunolabeled with CCK (r = -0.54, P = 0.03) and GLP-1 (r = -0.49, P = 0.045) was inversely correlated with BMI, such that duodenal CCK and GLP-1 cell density decreased with increasing BMI. In conclusion, CD36, GPR40, GPR120, and GPR119 are expressed in the human duodenum. Transcript levels of duodenal FA receptors and enteroendocrine cell density are altered with increasing BMI, suggesting that these changes may underlie decreased gastrointestinal hormone responses to fat and impaired energy intake regulation in obesity., (Copyright © 2014 the American Physiological Society.)
- Published
- 2014
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8. Sensory neuro-immune interactions differ between irritable bowel syndrome subtypes.
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Hughes PA, Harrington AM, Castro J, Liebregts T, Adam B, Grasby DJ, Isaacs NJ, Maldeniya L, Martin CM, Persson J, Andrews JM, Holtmann G, Blackshaw LA, and Brierley SM
- Subjects
- Adult, Animals, Case-Control Studies, Cells, Cultured, Colon immunology, Colon innervation, Constipation etiology, Constipation immunology, Culture Media, Conditioned pharmacology, Cytokines biosynthesis, Diarrhea etiology, Diarrhea immunology, Female, Ganglia, Spinal immunology, Humans, Irritable Bowel Syndrome complications, Irritable Bowel Syndrome physiopathology, Leukocytes, Mononuclear metabolism, Male, Mice, Middle Aged, Neuroimmunomodulation immunology, Neurons, Afferent drug effects, Neurons, Afferent physiology, Pain etiology, Pain immunology, Receptors, Cytokine metabolism, beta-Endorphin metabolism, Irritable Bowel Syndrome immunology, Neuroimmunomodulation physiology
- Abstract
Objective: The gut is a major site of contact between immune and sensory systems and evidence suggests that patients with irritable bowel syndrome (IBS) have immune dysfunction. Here we show how this dysfunction differs between major IBS subgroups and how immunocytes communicate with sensory nerves., Design: Peripheral blood mononuclear cell supernatants from 20 diarrhoea predominant IBS (D-IBS) patients, 15 constipation predominant IBS (C-IBS) patients and 36 healthy subjects were applied to mouse colonic sensory nerves and effects on mechanosensitivity assessed. Cytokine/chemokine concentration in the supernatants was assessed by proteomic analysis and correlated with abdominal symptoms, and expression of cytokine receptors evaluated in colonic dorsal root ganglia neurons. We then determined the effects of specific cytokines on colonic afferents., Results: D-IBS supernatants caused mechanical hypersensitivity of mouse colonic afferent endings, which was reduced by infliximab. C-IBS supernatants did not, but occasionally elevated basal discharge. Supernatants of healthy subjects inhibited afferent mechanosensitivity via an opioidergic mechanism. Several cytokines were elevated in IBS supernatants, and levels correlated with pain frequency and intensity in patients. Visceral afferents expressed receptors for four cytokines: IL-1β, IL-6, IL-10 and TNF-α. TNF-α most effectively caused mechanical hypersensitivity which was blocked by a transient receptor potential channel TRPA1 antagonist. IL-1β elevated basal firing, and this was lost after tetrodotoxin blockade of sodium channels., Conclusions: Distinct patterns of immune dysfunction and interaction with sensory pathways occur in different patient groups and through different intracellular pathways. Our results indicate IBS patient subgroups would benefit from selective targeting of the immune system.
- Published
- 2013
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9. Modulation of murine gastric vagal afferent mechanosensitivity by neuropeptide W.
- Author
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Li H, Kentish SJ, Kritas S, Young RL, Isaacs NJ, O'Donnell TA, Blackshaw LA, Wittert GA, and Page AJ
- Subjects
- Animals, Eating physiology, Female, Immunohistochemistry, Mice, Mice, Inbred C57BL, Real-Time Polymerase Chain Reaction, Receptors, G-Protein-Coupled metabolism, Receptors, Neuropeptide metabolism, Reverse Transcriptase Polymerase Chain Reaction, Stomach innervation, Stress, Mechanical, Afferent Pathways metabolism, Gastric Mucosa metabolism, Neuropeptides metabolism, Vagus Nerve metabolism
- Abstract
Aim: 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., Methods: 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., Results: 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., Conclusion: Neuropeptide W modulates gastric vagal afferent activity, but the effect is dynamic and related to feeding status., (© 2013 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.)
- Published
- 2013
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10. Identifying spinal sensory pathways activated by noxious esophageal acid.
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Harrington AM, Brierley SM, Isaacs NJ, Young RL, and Blackshaw LA
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- Animals, Esophagus drug effects, Female, Gastric Acid, Immunohistochemistry, Mice, Mice, Inbred C57BL, Mice, Knockout, Pain, Spinal Cord cytology, Afferent Pathways cytology, Afferent Pathways metabolism, Esophagus innervation, Esophagus metabolism, Pepsin A toxicity, TRPV Cation Channels metabolism
- Abstract
Background: The transient receptor potential vanilloid 1 (TRPV1) channel is critical for spinal afferent signaling of burning pain throughout the body. Such pain frequently originates from the esophagus, following acid reflux. The contribution of TRPV1 to spinal nociceptor signaling from the esophagus remains unclear. We aimed to identify the spinal afferent pathways that convey nociceptive signaling from the esophagus, specifically those sensitive to acid, and the extent to which TRPV1 contributes., Methods: Acid/pepsin (150 mM HCl/1 mg mL(-1) pepsin) or saline/pepsin was perfused into the esophageal lumen of anesthetized wild-type and TRPV1 null mice over 20 min, followed by atraumatic perfuse fixation and removal of the cervical and thoracic spinal cord and dorsal root ganglia (DRG). To identify neurons responsive to esophageal perfusate, immunolabeling for neuronal activation marker phosphorylated extracellular receptor-regulated kinase (pERK) was used. Labeling for calcitonin gene-related peptide (CGRP) and isolectin B4 (IB4) was then used to characterize responsive neurons., Key Results: Esophageal acid/pepsin perfusion significantly increased the number of pERK-immunoreactive (IR) neurons in the DRG and the cervical and thoracic spinal cord dorsal horn (DH) relative to saline/pepsin (DRG P < 0.01; cervical DH P < 0.05 and thoracic DH P < 0.005). The number of pERK-IR neurons following acid perfusion was significantly attenuated in TRPV1 -/- mice (DH P < 0.05 and DRG P < 0.05)., Conclusions & Inferences: This study has identified populations of spinal afferent DRG neurons and DH neurons involved in signaling of noxious acid from the esophagus. There is a major contribution of TRPV1 to signaling within these pathways., (© 2013 John Wiley & Sons Ltd.)
- Published
- 2013
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11. Disordered control of intestinal sweet taste receptor expression and glucose absorption in type 2 diabetes.
- Author
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Young RL, Chia B, Isaacs NJ, Ma J, Khoo J, Wu T, Horowitz M, and Rayner CK
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- 3-O-Methylglucose metabolism, Blood Glucose metabolism, Cross-Over Studies, Diabetes Mellitus, Type 2 metabolism, Epithelial Cells metabolism, Fasting, Female, Glucose Clamp Technique, Humans, Hyperglycemia metabolism, Intestinal Absorption, Intestines pathology, Male, C-Peptide metabolism, Diabetes Mellitus, Type 2 physiopathology, Glycated Hemoglobin metabolism, Hyperglycemia physiopathology, Intestinal Mucosa metabolism, Receptors, G-Protein-Coupled metabolism
- Abstract
We previously established that the intestinal sweet taste receptors (STRs), T1R2 and T1R3, were expressed in distinct epithelial cells in the human proximal intestine and that their transcript levels varied with glycemic status in patients with type 2 diabetes. Here we determined whether STR expression was 1) acutely regulated by changes in luminal and systemic glucose levels, 2) disordered in type 2 diabetes, and 3) linked to glucose absorption. Fourteen healthy subjects and 13 patients with type 2 diabetes were studied twice, at euglycemia (5.2 ± 0.2 mmol/L) or hyperglycemia (12.3 ± 0.2 mmol/L). Endoscopic biopsy specimens were collected from the duodenum at baseline and after a 30-min intraduodenal glucose infusion of 30 g/150 mL water plus 3 g 3-O-methylglucose (3-OMG). STR transcripts were quantified by RT-PCR, and plasma was assayed for 3-OMG concentration. Intestinal STR transcript levels at baseline were unaffected by acute variations in glycemia in healthy subjects and in type 2 diabetic patients. T1R2 transcript levels increased after luminal glucose infusion in both groups during euglycemia (+5.8 × 10(4) and +5.8 × 10(4) copies, respectively) but decreased in healthy subjects during hyperglycemia (-1.4 × 10(4) copies). T1R2 levels increased significantly in type 2 diabetic patients under the same conditions (+6.9 × 10(5) copies). Plasma 3-OMG concentrations were significantly higher in type 2 diabetic patients than in healthy control subjects during acute hyperglycemia. Intestinal T1R2 expression is reciprocally regulated by luminal glucose in health according to glycemic status but is disordered in type 2 diabetes during acute hyperglycemia. This defect may enhance glucose absorption in type 2 diabetic patients and exacerbate postprandial hyperglycemia.
- Published
- 2013
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12. Gastric vagal afferent modulation by leptin is influenced by food intake status.
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Kentish SJ, O'Donnell TA, Isaacs NJ, Young RL, Li H, Harrington AM, Brierley SM, Wittert GA, Blackshaw LA, and Page AJ
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- Animals, Diet, High-Fat, Female, Gastric Mucosa innervation, Gastric Mucosa physiology, Mice, Mice, Inbred C57BL, Muscle, Smooth physiology, Nodose Ganglion physiology, Obesity physiopathology, Receptors, Leptin metabolism, Vagus Nerve physiology, Eating physiology, Gastric Mucosa drug effects, Leptin pharmacology, Vagus Nerve drug effects
- 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 (Lep-R) and its signal transduction molecules in vagal afferents was determined by retrograde tracing and reverse-transcription polymerase chain reaction, 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 Lep-R 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 phosphatidylinositol 3-kinase-dependent activation of large-conductance calcium-activated potassium channels. The excitatory effect of leptin on gastric mucosal vagal afferents was mediated by phospholipase C-dependent activation of canonical transient receptor potential 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.
- Published
- 2013
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13. Diet-induced adaptation of vagal afferent function.
- Author
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Kentish S, Li H, Philp LK, O'Donnell TA, Isaacs NJ, Young RL, Wittert GA, Blackshaw LA, and Page AJ
- Subjects
- Adaptation, Physiological genetics, Adaptation, Physiological physiology, Afferent Pathways metabolism, Animals, Eating genetics, Eating physiology, Energy Intake, Female, Gastric Mucosa metabolism, Ghrelin metabolism, Mechanotransduction, Cellular, Mice, Mice, Inbred C57BL, Nerve Endings metabolism, Nerve Endings physiology, Neurons, Afferent metabolism, Nodose Ganglion metabolism, Nodose Ganglion physiology, RNA, Messenger genetics, Receptors, Ghrelin genetics, Receptors, Ghrelin metabolism, Vagus Nerve metabolism, Afferent Pathways physiology, Diet, High-Fat, Gastric Mucosa innervation, Neurons, Afferent physiology, Vagus Nerve physiology
- Abstract
Afferent signals from the stomach play an important role in inhibition of food intake during a meal. The gastric hormone ghrelin can influence gastric satiety signalling by altering the sensitivity of gastric vagal afferents. Changes in diet, including food restriction and high fat diet (HFD) alter satiety signalling. We hypothesised that the function of gastric vagal afferent endings are affected by both a period of food restriction and a high fat diet, and that the inhibitory effect of ghrelin on vagal afferents is influenced by the different feeding conditions. We found that both fasting and HFD reduced the responses of gastric vagal tension receptors to distension, but not responses of mucosal receptors to mucosal contact. We traced vagal afferents anterogradely to their terminals in the mucosa where we found they were in close apposition to ghrelin-containing cells. Ghrelin receptor mRNA was expressed in vagal afferent cell bodies of the nodose ganglia, and increased in response to caloric restriction, but decreased in HFD mice. In control mice, ghrelin decreased the sensitivity of tension but not mucosal receptors. After caloric restriction or high fat diet, ghrelin inhibited mucosal receptors, and the inhibition of mechanosensitive tension receptors was enhanced. Therefore, both caloric restriction and HFD decrease mechanosensory vagal afferent signals, and augment the inhibitory effect of ghrelin on vagal afferents, but different mechanisms mediate the short- and longer-term changes.
- Published
- 2012
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14. SMALL-DOSE EMULSION TREATMENT OF RAGWEED POLLINOSIS. A DOUBLE-BLIND STUDY CONTINUED FOR THREE SEASONS.
- Author
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DWORETZKY M and ISAACS NJ
- Subjects
- Adolescent, Humans, Allergens, Ambrosia, Biomedical Research, Double-Blind Method, Drug Therapy, Emulsions, Geriatrics, Placebos, Pollen, Rhinitis, Allergic, Seasonal, Seasons, Statistics as Topic
- Published
- 1964
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15. Evaluation of the steroid treatment of asthma since 1950.
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BALDWIN HS, DWORETZKY M, and ISAACS NJ
- Subjects
- Adrenal Cortex Hormones therapy, Asthma therapy
- Published
- 1961
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16. Urticaria and pruritus: uncommon manifestations of hyperthyroidism.
- Author
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Isaacs NJ and Ertel NH
- Subjects
- Adult, Aged, Catecholamines metabolism, Child, Female, Humans, Hyperthyroidism drug therapy, Iodine Isotopes therapeutic use, Methimazole therapeutic use, Middle Aged, Pruritus drug therapy, Pruritus etiology, Thyroid Function Tests, Urticaria drug therapy, Hyperthyroidism complications, Urticaria etiology
- Published
- 1971
- Full Text
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