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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 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

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  1. 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

  2. Obesity • 1/3 obese • 2/3 obese or overweight • 400,000 deaths • 147 billion cost Prevalence is still increasing

  3. Electrical Stimulation for Obesity ? We Eat We Exercise What can this do for us?

  4. 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

  5. Aims To study the feasibility of VNS at low frequency for treating obesity and possible mechanisms of action in a rodent model of obesity

  6. 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

  7. * * * * * Sham-VNS vs. VNS p<0.001 VNS reduced food intake VNS3 (40Hz, continuous,0.2ms , 6mA),

  8. Experimental Procedure 4 wk VNS/sham VNS Autonomic function measure (HRV) Gastric emptying/volume tests GLP-1, PYY and ghrelin Pancreaticpolypeptide

  9. p<0.001 * * * * * Sham-VNS vs. VNS p<0.001 VNS reduced food intake in DIO rats (4 weeks )

  10. * * * * 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

  11. P<0.001 VNS delayed gastric emptying 40% decrease

  12. p=0.004 VNS increased gastric volume Substantial decrease Sham-VNS VNS

  13. VNS increased plasma PP

  14. 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

  15. Ghrelin: reduced in obesity but not altered by VNS

  16. GLP-1: increased with VNS

  17. PYY: increased with VNS

  18. 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

  19. 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

  20. 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.

  21. 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.

  22. 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.

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