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Effects and Mechanisms of Vagal Nerve Stimulation on Food Intake and Body Weight in Rats. Fei Dai 1 , Yong Lei 1 and J D Z Chen 1, 2 1 Veterans Research and Education Foundation, VA Medical Center, Oklahoma city, OK

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effects and mechanisms of vagal nerve stimulation on food intake and body weight in rats

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, OK

2Division of Gastroenterology, University of Texas Medical Branch, Galveston, TX

obesity
Obesity
  • 1/3 obese
  • 2/3 obese or overweight
  • 400,000 deaths
  • 147 billion cost

Prevalence is still increasing

electrical stimulation for obesity

Electrical Stimulation for Obesity

?

We Eat

We Exercise

What can this do for us?

vagal nerve stimulation for obesity
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
slide5
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
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

slide7

*

*

*

*

* Sham-VNS vs. VNS p<0.001

VNS reduced food intake

VNS3 (40Hz, continuous,0.2ms , 6mA),

experimental procedure
Experimental Procedure

4 wk VNS/sham VNS

Autonomic function measure (HRV)

Gastric emptying/volume tests

GLP-1, PYY and ghrelin

Pancreaticpolypeptide

vns decreased weight i n dio rats

*

*

*

*

Total 4 weeks

Sham-VNS vs. VNS p<0.001

* Sham-VNS vs. VNS p<0.001

VNS decreased weight in DIO rats

25% reduction in weight with VNS of 4 wks

vns increased gastric volume

p=0.004

VNS increased gastric volume

Substantial decrease

Sham-VNS

VNS

vns normalized autonomic function

P=0.462

P<0.001

P=0.003

P=0.024

P=0.032

P=0.246

P=0.425

P=0.003

P=0.005

VNS “normalized” autonomic function

VNS inhibited sympathetic activity and

increased vagal activity

conclusions
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
VNS in obese rats

Experiment 2: Effects of optimal VNS parameter on food intake and body weight in DIO 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

experimental protocols
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 protocols1
Experimental protocols

Experiment 4: Effects of VNS on solid gastric emptying and gastric volumes in DIO rats

♦ 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.

experimental protocols2
Experimental protocols

Experiment 5: Effects of VNS on gut hormones in DIO rats

♦ 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.