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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 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 • 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
* * * * * 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 Pancreaticpolypeptide
p<0.001 * * * * * Sham-VNS vs. VNS p<0.001 VNS reduced food intake in DIO rats (4 weeks )
* * * * 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
P<0.001 VNS delayed gastric emptying 40% decrease
p=0.004 VNS increased gastric volume Substantial decrease Sham-VNS VNS
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 • 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 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 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 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 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.