Abstract 512: Anorectic and Thermogenic Effects of Chronic Vagal Nerve Stimulation in Mice

Abstract

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 by which chronic VNS causes weight loss are largely unknown due in part to the unavailability of implantable nerve stimulators for mice excluding the use of genetically engineered mouse models to investigate these mechanisms. Identification such mechanisms promises to identify novel approaches for weight loss. Here, we report the development of a miniaturized microprocessor-operated nerve stimulator for chronic use in conscious mice. Effectiveness of the stimulator was verified by the bradycardia induced at stimulation frequencies above 5 Hz (3V, 1mA, 1ms pulses). Next, we used the stimulator to test whether changes in metabolic rate, caloric intake and feeding efficiency (body weight gain per calories consumed) contribute to chronic VNS-induced weight loss. Male C57Bl/6 mice (16 weeks old, on 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 re-established 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 group (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) during the first week, but not thereafter. In conclusion, reduced food intake and lower feeding efficiency contribute to VNS-induced weight loss in mice. We speculate that an initial increase in metabolic rate (assessed by oxygen consumption) may be antagonized by compensatory mechanisms triggered by chronic VNS.