Effects and Mechanisms of Vagal Nerve Stimulation on Food Intake and Body Weight in Rats
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Effects and Mechanisms of Vagal Nerve Stimulation on Food Intake and Body Weight in Rats
Fei Dai1, Yong Lei1 and J D Z Chen1, 2
1Veterans Research and Education Foundation, VA Medical Center, Oklahoma city, OK2Division of Gastroenterology, University of Texas Medical Branch, Galveston, TX
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Obesity 1/3 obese
2/3 obese or overweight 400,000 deaths 147 billion cost
Prevalence is still increasing
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Electrical Stimulation for Obesity
We Eat We Exercise
What can this do for
us?
?
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Vagal nerve stimulation for obesity
VNS of 5000Hz to block vagal activity
Significant weight loss in open label studies
Controlled clinical trial did not reach endpoint
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Aims
To study the feasibility of VNS at low frequency for treating obesity and possible mechanisms of action in a rodent model of obesity
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Searching for effective VNS• Normal rats (N-10) • Food intake test with VNS during eating • Different parameters test
VNS1 (40Hz, 2s-on and 3s-off, 0.2ms, 6mA), VNS2 (40Hz, 2s-on and 3s-off, 0.6ms, 6mA), VNS3 (40Hz, continuous, 0.2ms , 6mA), VNS4 (40Hz, continuous, 0.6ms , 6mA
10 days/each parameter set
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VNS1 VNS2 VNS3 VNS4
Red
uctio
n of
food
inta
ke%
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25
VNS1 VNS2 VNS3 VNS4
Food
intake
(g)
Sham-VNSVNS* ***
* Sham-VNS vs. VNS p<0.001
VNS reduced food intake
VNS3 (40Hz, continuous, 0.2ms , 6mA),
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Experimental Procedure
4 wk VNS/sham VNS
Autonomic function measure (HRV)
Gastric emptying/volume tests
GLP-1, PYY and ghrelin Pancreatic polypeptide
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VNS reduced food intake in DIO rats (4 weeks )
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1st Week 2nd Week 3rd Week 4th Week
Food
inta
ke(g
)
Sham-VNSVNS
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* Sham-VNS vs. VNS p<0.001
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Total 4 weeks
Food
inta
ke(g
)
Sham-VNSVNS
p<0.001
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25% reduction in weight with VNS of 4 wks
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- 5
-4
-3
-2
-1
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1st Week 2nd Week 3rd Week 4th Week
Bod
y W
eigh
t Cha
nge%
Sham- VNSVNS
* Sham-VNS vs. VNS p<0.001
** *
*
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- 15
- 10
- 5
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15
Bod
y W
eigh
t Cha
nge%
Sham-VNSVNS
Total 4 weeks
Sham-VNS vs. VNS p<0.001
VNS decreased weight in DIO rats
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VNS delayed gastric emptying
40% decrease
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Gas
tric
Empt
ying
%
Sham-VNSVNS
P<0.001
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VNS increased gastric volume
Substantial decrease
012345678
Gastric Volumes
Sham-VNSVNS
p=0.004
VNS Sham-VNS
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VNS increased plasma PP
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Control Sham-VNS VNS
Plas
ma
PP c
once
ntra
tion
(pg/
ml)
P = 0.002
P = 0.824
P = 0.008
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VNS “normalized” autonomic function VNS inhibited sympathetic activity and increased vagal activity
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LF HF LF/HF
Control DIODIO after VNS
P=0.246
P=0.005P=0.003
P=0.425
P<0.001
P=0.462
P=0.024
P=0.003
P=0.032
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Ghrelin: reduced in obesity but not altered by VNS
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Control Sham-VNS VNS
Plas
ma
ghre
line
conc
entra
tion
(pg/
ml)
P = 0.009
P = 0.745
P = 0.047
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GLP-1: increased with VNS
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Control Sham-VNS VNS
Plas
ma
GLP-
1 co
ncen
tratio
n(pg
/ml)
P = 0.008P = 0.012
P = 0.979
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PYY: increased with VNS
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Control Sham-VNS VNS
Plas
ma
PYY
conc
entra
tion
(pg/
ml)
P = 0.004
P = 0.956
P = 0.008
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Conclusions * VNS at a low frequency of 40Hz
reduces food intake and body weight in DIO rats
* Possible mechanisms of action * Aterations in autonomic functions* Inhibited motility* Increase in GLP-1 and PYY
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VNS in obese rats
16 rats randomly divided into two groups: ♦ 8 rats with VNS3 (40Hz, continuous, 0.2ms,
6mA) ♦ 8 rats with sham-VNS for 4 week
Experiment 2: Effects of optimal VNS parameter on food intake and body weight in DIO rats
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Experimental protocols
Experiment 3: Effects of VNS on heart rate variability (HRV) in DIO rats
* A special amplifier was used to record the electrocardiogram (ECG) via three cutaneous electrodes. * The ECG was recorded for 30 min at baseline and 30 min after VNS3/sham-VNS in the fasting state and postprandial state. * The sympathovagal activity was assessed using spectral analysis of the HRV signal.
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Experimental protocols
♦ The rats were fasted for a period of 24 hours and given 1.5g high fat food.
♦ During the 90-min postprandial period, 8 DIO rats were applied with VNS3 , 8 rats applied with sham-VNS.
♦ Ninety minutes after the feeding, the gastric volumes were measured and the content of the stomach were removed for the assessment of gastric emptying.
Experiment 4: Effects of VNS on solid gastric emptying and gastric volumes in DIO rats
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Experimental protocols
♦ After being fasted for 12 h, 8 SD rats were received sham-VNS, 8 DIO rats were applied with VNS3 , 8 DIO rats applied with sham-VNS for 2 hours; during 2 h without food in the restrainers.
♦ After stimulation, blood sample was collected from the tail vein. Plasma Ghrelin, GLP-1, PYY and PP were measured on duplicate samples using commercially available kits.
Experiment 5: Effects of VNS on gut hormones in DIO rats