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
Obesity 1/3 obese
2/3 obese or overweight 400,000 deaths 147 billion cost
Prevalence is still increasing
Electrical Stimulation for Obesity
We Eat We Exercise
What can this do for
us?
?
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
Aims
To study the feasibility of VNS at low frequency for treating obesity and possible mechanisms of action in a rodent model of obesity
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
0
10
20
30
40
50
60
VNS1 VNS2 VNS3 VNS4
Red
uctio
n of
food
inta
ke%
0
5
10
15
20
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),
Experimental Procedure
4 wk VNS/sham VNS
Autonomic function measure (HRV)
Gastric emptying/volume tests
GLP-1, PYY and ghrelin Pancreatic polypeptide
VNS reduced food intake in DIO rats (4 weeks )
0
5
10
15
20
25
1st Week 2nd Week 3rd Week 4th Week
Food
inta
ke(g
)
Sham-VNSVNS
**
**
* Sham-VNS vs. VNS p<0.001
0
5
10
15
20
25
Total 4 weeks
Food
inta
ke(g
)
Sham-VNSVNS
p<0.001
25% reduction in weight with VNS of 4 wks
- 6
- 5
-4
-3
-2
-1
0
1
2
3
4
1st Week 2nd Week 3rd Week 4th Week
Bod
y W
eigh
t Cha
nge%
Sham- VNSVNS
* Sham-VNS vs. VNS p<0.001
** *
*
- 20
- 15
- 10
- 5
0
5
10
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
VNS delayed gastric emptying
40% decrease
0
10
20
30
40
50
60
70
80
90
Gas
tric
Empt
ying
%
Sham-VNSVNS
P<0.001
VNS increased gastric volume
Substantial decrease
012345678
Gastric Volumes
Sham-VNSVNS
p=0.004
VNS Sham-VNS
VNS increased plasma PP
0
10
20
30
40
50
60
70
80
90
100
Control Sham-VNS VNS
Plas
ma
PP c
once
ntra
tion
(pg/
ml)
P = 0.002
P = 0.824
P = 0.008
VNS “normalized” autonomic function VNS inhibited sympathetic activity and increased vagal activity
0
0. 5
1
1. 5
2
2. 5
3
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
Ghrelin: reduced in obesity but not altered by VNS
0
100
200
300
400
500
600
700
800
900
1000
Control Sham-VNS VNS
Plas
ma
ghre
line
conc
entra
tion
(pg/
ml)
P = 0.009
P = 0.745
P = 0.047
GLP-1: increased with VNS
0
10
20
30
40
50
60
70
80
90
Control Sham-VNS VNS
Plas
ma
GLP-
1 co
ncen
tratio
n(pg
/ml)
P = 0.008P = 0.012
P = 0.979
PYY: increased with VNS
0
10
20
30
40
50
60
70
80
90
Control Sham-VNS VNS
Plas
ma
PYY
conc
entra
tion
(pg/
ml)
P = 0.004
P = 0.956
P = 0.008
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
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
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.
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
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
