Chronic electrical vagal nerve stimulation (VNS) has emerged as a new tool to treat human diseases including obesity. Indeed, chronic VNS has been shown to cause weight loss in humans and in experimental animal models. However, the mechanisms for VNS-induced weight loss are largely unknown. We hypothesized that an increase in metabolic rate together with reduced caloric intake and reduced feeding efficiency (body weight gain per calories consumed) contribute to chronic VNS-induced weight loss or reduced weight gain. To test this hypothesis, we developed a miniaturized microprocessor-operated nerve stimulator for chronic use in conscious mice. Effectiveness of the stimulator was verified by bradycardia at stimulation frequencies above 5 Hz (3V, 1mA, 1ms pulses). Male C57Bl/6 mice (16 weeks old, standard mouse chow diet) were instrumented with nerve stimulators (3V, 1mA, 1ms pulses at 5 Hz) on the right cervical vagal nerve and body weight, food intake and metabolic rate (indirect calorimetry) were determined at baseline and weekly thereafter. After the initial post-surgical weight loss, sham animals (n=9, stimulators off) regained pre-surgical body weight within 16 days (100.0±2.7%). In contrast, mice with chronic VNS (n=12) never reestablished pre-surgical body weight (94.5±0.9% on day 16, P<0.05 vs. sham). Caloric intake was significantly reduced in mice with chronic VNS compared to sham animals (74.7±2.4 vs. 84.6±4.2 kcal/week, P<0.05). Likewise, mice with chronic VNS showed significantly reduced feeding efficiency compared to sham mice (2.6±2.0 vs. 10.6±2.4 mg body weight gain per kcal consumed). Oxygen consumption tended to be elevated (2734±152 vs. 2490±124 mL/kg/h, P=0.23) during the first week, but not thereafter. In conclusion reduced food intake and lower feeding efficiency contribute to reduced weight gain in mice with chronic VNS. We speculate that an initial increase in metabolic rate (assessed by oxygen consumption) may be antagonized by compensatory mechanisms in response to chronic VNS.
GPR40 full agonism exerts feeding suppression and weight loss through afferent vagal nerve