Abstract 20340: Defect of Ca 2+ -activated Cl - Channel in Intestinal Nodose Neurons Contributes to Impaired Satiety Signal in High-Fat Diet Induced Obesity

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Runping Wang ◽  
Yongjun Lu ◽  
Michael Z Cicha ◽  
Kamal Rahmouni ◽  
Mark W Chapleau ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Vagal Afferents ◽  
High Fat ◽  
Altered Expression ◽  
Cck Receptors ◽  
Whole Cell Patch Clamp ◽  
Nodose Ganglia ◽  
Maximum Current ◽  
Vagal Afferent ◽  
High Level

High fat diet inhibits the cholecystokinin (CCK) induced satiety signal in vagal afferents, which may contribute to the associated increased food intake. We hypothesized that a defect of Ca 2+ -activated chloride channel (CaCC) in high fat (HFD) fed mice leads to the reduction of CCK responses in intestinal vagal afferent nodose neurons. By using the whole cell patch-clamp in cultured nodose ganglia neurons isolated from C57BL/6 mice, we found that CCK (10nM) induced large inward chloride (Cl - ) currents (36.0±11pA/pF) that were eliminated with the fast Ca 2+ chelator BAPTA (1.0±0.5pA/pF, n=7), and reduced significantly by the CaCC channel inhibitor niflumic acid (100 μM, 13.6±2.0pA/pF, p<0.05, n=8). The response to CCK in DiI-labeled proximal intestinal nodose neurons from obese mice fed a 60% HFD for 10 weeks was reduced significantly (6.1±2.9pA/pF, n=7, p<0.01) relative to control lean mice (24.8±4.9pA/pF, n=7). The underlying molecular mechanism of the reduced CCK response in mice fed a HFD did not involve altered expression of CCK receptors in nodose neurons. We found that the relative mRNA (qPCR) of CCK receptor B was not significantly changed (1.01±0.13 in control vs. 1.18±0.31 in HFD nodose ganglia, n=4, p>0.05) and the mRNA of CCK receptor A was even increased from 1.06±0.37 in control to 1.54±0.41 in HFD ganglia (n=4, p<0.05). In contrast, the CaCC channel mRNA (Ano I) was decreased to 0.61±0.09 relative to 1.01±0.20 (n=4, p<0.001), and Ano II mRNA was decreased to 0.31±0.07 relative to 1.02±0.22 (n=4, p<0.001) in nodose ganglia from HFD fed vs. control lean mice. Since the maximum current induced by a saturation level of ligand reflects the level of protein expressed on the cytoplasmic membrane, we tested the CaCC current induced by a high level of intracellular Ca 2+ (20μM). We found that the maximum current was smaller in DiI labeled intestinal nodose neurons from HFD fed mice (13.7±2.9 pA/pF vs. 26.9±3.6 pA/pF in control mice, n=10, p<0.05). Our results indicate that CCK-activated currents recorded from intestinal vagal afferent nodose neurons are reduced in mice fed a HFD, and are associated with reduced expression of a CCK-activated Ca 2+ -dependent Cl - channel. This mechanism may contribute significantly to HFD-induced suppression of the satiety reflex.

scholarly journals Diet-induced obesity leads to the development of leptin resistance in vagal afferent neurons

2011 ◽  
Vol 301 (1) ◽  
pp. E187-E195 ◽  
Author(s):  
Guillaume de Lartigue ◽  
Claire Barbier de la Serre ◽  
Elvis Espero ◽  
Jennifer Lee ◽  
Helen E. Raybould
Keyword(s):  
High Fat Diet ◽  
Leptin Resistance ◽  
Afferent Neurons ◽  
High Fat ◽  
Leptin Signaling ◽  
Protein Levels ◽  
Diet Induced Obesity ◽  
Nodose Ganglia ◽  
Vagal Afferent

Ingestion of high-fat, high-calorie diets is associated with hyperphagia, increased body fat, and obesity. The mechanisms responsible are currently unclear; however, altered leptin signaling may be an important factor. Vagal afferent neurons (VAN) integrate signals from the gut in response to ingestion of nutrients and express leptin receptors. Therefore, we tested the hypothesis that leptin resistance occurs in VAN in response to a high-fat diet. Sprague-Dawley rats, which exhibit a bimodal distribution of body weight gain, were used after ingestion of a high-fat diet for 8 wk. Body weight, food intake, and plasma leptin levels were measured. Leptin signaling was determined by immunohistochemical localization of phosphorylated STAT3 (pSTAT3) in cultured VAN and by quantifaction of pSTAT3 protein levels by Western blot analysis in nodose ganglia and arcuate nucleus in vivo. To determine the mechanism of leptin resistance in nodose ganglia, cultured VAN were stimulated with leptin alone or with lipopolysaccharide (LPS) and SOCS-3 expression measured. SOCS-3 protein levels in VAN were measured by Western blot following leptin administration in vivo. Leptin resulted in appearance of pSTAT3 in VAN of low-fat-fed rats and rats resistant to diet-induced obesity but not diet-induced obese (DIO) rats. However, leptin signaling was normal in arcuate neurons. SOCS-3 expression was increased in VAN of DIO rats. In cultured VAN, LPS increased SOCS-3 expression and inhibited leptin-induced pSTAT3 in vivo. We conclude that VAN of diet-induced obese rats become leptin resistant; LPS and SOCS-3 may play a role in the development of leptin resistance.

High-fat diet is associated with blunted splanchnic sympathoinhibitory responses to gastric leptin and cholecystokinin: implications for circulatory control

2011 ◽  
Vol 300 (3) ◽  
pp. H961-H967 ◽  
Author(s):  
Jackie M. Y. How ◽  
Barbara C. Fam ◽  
Anthony J. M. Verberne ◽  
Daniela M. Sartor
Keyword(s):  
Arterial Pressure ◽  
High Fat Diet ◽  
Cardiovascular Effects ◽  
Vagal Afferents ◽  
Sprague Dawley ◽  
High Fat ◽  
Lower Plasma ◽  
Lower Tertile ◽  
Circulatory Control ◽  
Plasma Leptin

Gastric leptin and cholecystokinin (CCK) act on vagal afferents to induce cardiovascular effects and reflex inhibition of splanchnic sympathetic nerve discharge (SSND) and may act cooperatively in these responses. We sought to determine whether these effects are altered in animals that developed obesity in response to a medium high-fat diet (MHFD). Male Sprague-Dawley rats were placed on a low-fat diet (LFD; n = 8) or a MHFD ( n = 24) for 13 wk, after which the animals were anesthetized and artificially ventilated. Arterial pressure was monitored and blood was collected for the determination of plasma leptin and CCK. SSND responses to leptin (15 μg/kg) and CCK (2 μg/kg) administered close to the coeliac artery were evaluated. Collectively, MHFD animals had significantly higher plasma leptin but lower plasma CCK levels than LFD rats ( P < 0.05), and this corresponded to attenuated or reversed SSND responses to CCK (LFD, −21 ± 2%; and MHFD, −12 ± 2%; P < 0.05) and leptin (LFD, −6 ± 2%; and MHFD, 4 ± 1%; P < 0.001). Alternatively, animals on the MHFD were stratified into obesity-prone (OP; n = 8) or obesity-resistant (OR; n = 8) groups according to their weight gain falling within the upper or lower tertile, respectively. OP rats had significantly higher resting arterial pressure, adiposity, and plasma leptin but lower plasma CCK compared with LFD rats ( P < 0.05). The SSND responses to CCK or leptin were not significantly different between OP and OR animals. These results demonstrate that a high-fat diet is associated with blunted splanchnic sympathoinhibitory responses to gastric leptin and CCK and may impact on sympathetic vasomotor mechanisms involved in circulatory control.

High fat diet induced changes in gastric vagal afferent response to adiponectin

2015 ◽  
Vol 152 ◽  
pp. 354-362 ◽  
Author(s):  
Stephen J. Kentish ◽  
Kyle Ratcliff ◽  
Hui Li ◽  
Gary A. Wittert ◽  
Amanda J. Page
Keyword(s):  
High Fat Diet ◽  
High Fat ◽  
Vagal Afferent ◽  
Induced Changes ◽  
Afferent Response

Abstract 199: Hydrogen Peroxide Mediates the pH Conditioned Chloride Conductance in Nodose Ganglia Neurons

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Runping Wang ◽  
Yongjun Lu ◽  
Carol A Whiteis ◽  
Christopher J Benson ◽  
Mark W Chapleau ◽  
...  
Keyword(s):  
Conditioned Response ◽  
Vagal Afferents ◽  
Induced Responses ◽  
Oxygen Species ◽  
Patch Clamp Technique ◽  
Whole Cell Patch Clamp ◽  
Nodose Ganglia ◽  
Rate Of Increase ◽  
Induced Currents ◽  
Superoxide Scavenger

pH sensitivity has been rarely studied in vagal afferents of nodose ganglia (NG) neurons. Using whole-cell patch-clamp technique in isolated NG neurons, we recently identified a pH-conditioned Cl - current (pH-I) that was evoked following 2 or 3 brief (10s) exposures to low extracellular pH (7.0-6.0) in 16 of 22 (70%) cells (FASEB J, 2012). The current is large (904.3±159.9pA) and prolonged, lasting 10∼15 minutes, and causes significant depolarization (Δ35.2±4.4mV). In the present study, we tested the hypothesis that reactive oxygen species (ROS) mediates this pH-conditioned Cl - conductance. We found that the rate of increase in fluorescence [(F-F 0 )/F 0 ] of NG neurons loaded with dihydroethidine (ROS dye) rose dramatically following the brief exposures to pH 6.0 from a control of 0.04±0.01 to 0.12±0.02 units/min over 10∼15 minutes (n=31 neurons, p<0.01). Moreover superfusion of neurons with H 2 O 2 induced currents that mimicked the pH conditioned currents. Because of similarities between the pH-conditioned Cl - conductance and the previously described “swell-activated” Cl - current induced with hypoosmotic solutions, we superfused the NG neurons with the H 2 O 2 scavenger PEG-catalase (1000 units/ml). PEG-catalase blocked significantly (p<0.01) the “swell” response to 210 mOsm from 23.3±6.3pA/pF to 0.57±0.39 pA/pF (n=4) as well as the pH-conditioned response from 25.7±6.5pA/pF (n=6) to 6.9±1.4 pA/pF (n=12). The superoxide scavenger PEG-SOD did not affect the current. These results indicate that both pH-conditioned and swell-induced responses are mediated by H 2 O 2 . Opening of these outward Cl - conductances that cause sustained depolarization of vagal afferents may induce a beneficial reflex sympathoinhibition during myocardial ischemia/acidosis or initiate a gastro-intestinal post-prandial satiety reflex.

The Thiamine Requirement of Pigs as Related to the Fat Content of the Diet

1944 ◽  
Vol 27 (3) ◽  
pp. 253-262
Author(s):  
N. R. Ellis ◽  
L. L. Madsen
Keyword(s):  
Body Temperature ◽  
High Fat Diet ◽  
General Health ◽  
Maximum Rate ◽  
Good Health ◽  
High Fat ◽  
Low Fat ◽  
Young Pigs ◽  
Medium Level ◽  
High Level

Summary The thiamine requirements of young pigs have been studied on three diets containing approximately 2, 11, and 28% of fat. As indicated by failure in appetite and cessation of growth, the animals on the low level of fat showed evidence of thiamine depletion on the average in 25 days, those on the medium level in 28 days, and on the high level in 33 days. Lack of thiamine resulted in marked weakening of the heart, decrease in body temperature, emaciation, and other changes. When thiamine was fed to pigs depleted of their stores of this substance, the response in appetite, growth, and general health was usually prompt and striking. Intermediate levels of thiamine produced the greatest response in the pigs fed the high-fat diet, followed in order by those on the intermediate and the low-fat. It was found that the level of thiamine required to produce a maximum rate of growth and otherwise maintain the pigs in good health fell within the range of 125 to 141 μg. per 100 gm. of carbohydrate and protein. These levels of thiamine, however, were insufficient to promote the storage of normal amounts in the meat tissue such as is found in commercial pork cuts.

scholarly journals High fat diet attenuates glucose-dependent facilitation of 5-HT3-mediated responses in rat gastric vagal afferents

2015 ◽  
Vol 594 (1) ◽  
pp. 99-114 ◽  
Author(s):  
Amanda E. Troy ◽  
Sarah S. Simmonds ◽  
Sean D. Stocker ◽  
Kirsteen N. Browning
Keyword(s):  
High Fat Diet ◽  
Vagal Afferents ◽  
High Fat

Relationships between gastric motility and gastric vagal afferent responses to CCK and GRP in rats differ

1997 ◽  
Vol 272 (6) ◽  
pp. R1726-R1733 ◽  
Author(s):  
G. J. Schwartz ◽  
T. H. Moran ◽  
W. O. White ◽  
E. E. Ladenheim
Keyword(s):  
Gastric Motility ◽  
Direct Action ◽  
Muscle Tension ◽  
Vagal Afferents ◽  
Gut Peptides ◽  
Cck Receptors ◽  
Gastric Pressure ◽  
Vagal Afferent ◽  
Motor Effects ◽  
The Relationship

The brain-gut peptides cholecystokinin (CCK) and the mammalian bombesin-like peptide gastrin-releasing peptide (GRP) suppress food intake. Vagotomy blocks CCK- but not bombesin (BN)-induced feeding suppression, demonstrating differential vagal contributions. We examined the relationship between the ability of CCK and the active fragment of GRP, GRP-(18-27), to stimulate gastric vagal afferent activity and their ability to elicit changes in gastric motility. We also examined ligated cervical vagal segments and revealed specific 125I-CCK vagal binding without evidence of radiolabeled BN binding sites. Both close arterial and intraperitoneal CCK and GRP-(18-27) produced dose-dependent increases in activity in gastric vagal mechanoreceptive afferents. CCK dose dependently decreased gastric pressure without altering antral wall tension, whereas GRP-(18-27) dose dependently increased both gastric pressure and peak antral wall muscle tension. These results suggest that GRP-(18-27) activates gastric vagal afferents secondary to its stimulation of gastric motor effects. CCK activates this same population of vagal afferents independent of changes in gastric tension, suggesting a direct action of CCK at functional vagal CCK receptors.

Exercise training prevents the development of cardiac dysfunction in the low-dose streptozotocin diabetic rats fed a high-fat diet

2013 ◽  
Vol 91 (1) ◽  
pp. 80-89 ◽  
Author(s):  
Riley A. Epp ◽  
Shanel E. Susser ◽  
Marc P. Morissette ◽  
D. Scott Kehler ◽  
Davinder S. Jassal ◽  
...  
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Exercise Training ◽  
Protein Content ◽  
Cardiac Dysfunction ◽  
High Fat Diet ◽  
Low Dose ◽  
Diabetic Rats ◽  
Left Ventricular ◽  
High Fat ◽  
Altered Expression

This study tested the hypothesis that exercise training would prevent the development of diabetes-induced cardiac dysfunction and altered expression of sarcoplasmic reticulum Ca2 +-transport proteins in the low-dose streptozotocin-induced diabetic rats fed a high-fat diet (HFD+STZ). Male Sprague–Dawley rats (4 weeks old; 125–150 g) were made diabetic using a high-fat diet (40% fat, w/w) and a low-dose of streptozotocin (35 mg·(kg body mass)–1) by intravenous injection. Diabetic animals were divided among a sedentary group (Sed+HFD+STZ) or an exercise-trained group (Ex+HFD+STZ) that accumulated 3554 ± 338 m·day–1 of voluntary wheel running (mean ± SE). Sedentary animals fed a low-fat diet served as the control (Sed+LFD). Oral glucose tolerance was impaired in the sedentary diabetic group (1179 ± 29; area under the curve (a.u.c.)) compared with that in the sedentary control animals (1447 ± 42 a.u.c.). Although left ventricular systolic function was unchanged by diabetes, impaired E/A ratios (i.e., diastolic function) and rates of pressure decay (–dP/dt) indicated the presence of diastolic dysfunction. Diabetes also reduced SERCA2a protein content and maximal SERCA2a activity (Vmax) by 21% and 32%, respectively. In contrast, the change in each parameter was attenuated by exercise training. Based on these data, it appears that exercise training prevented the development of diabetic cardiomyopathy and the dysregulation of sarcoplasmic reticulum protein content in an inducible animal model of type 2 diabetes.

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