Background: Cervical vagus nerve stimulation (VNS) is an emerging bioelectronic treatment for brain, metabolic, cardiovascular and immune disorders. Its desired and off-target effects are mediated by different nerve fiber populations and knowledge of their engagement could guide calibration and monitoring of VNS therapies. Objective: Stimulus-evoked compound action potentials (eCAPs) directly provide fiber engagement information but are currently not feasible in humans. A method to estimate fiber engagement through common, noninvasive physiological readouts could be used in place of eCAP measurements. Methods: In anesthetized rats, we recorded eCAPs while registering acute physiological response markers to VNS: cervical electromyography (EMG), changes in heart rate (DHR) and breathing interval (DBI). Quantitative models were established to capture the relationship between A-, Band C-fiber type activation and those markers, and to quantitatively estimate fiber activation from physiological markers and stimulation parameters. Results: In bivariate analyses, we found that EMG correlates with A-fiber, DHR with B-fiber and DBI with C-fiber activation, in agreement with known physiological functions of the vagus. We compiled multivariate models for quantitative estimation of fiber engagement from these markers and stimulation parameters. Finally, we compiled frequency gain models that allow estimation of fiber engagement at a wide range of VNS frequencies. Our models, after calibration in humans, could provide noninvasive estimation of fiber engagement in current and future therapeutic applications of VNS.

High-protein diets (HPDs) recently have been used to obtain body weight and fat mass loss and expand muscle mass. Several studies have documented that HPDs reduce appetite and food intake. Our goal was to determine the long-term effects of an HPD on body weight, energy intake and expenditure, and metabolic hormones. Male C57BL/6 mice (8 wk old) were fed either an HPD (60% of energy as protein) or a control diet (CD; 20% of energy as protein) for 12 wk. Body composition and food intakes were determined, and plasma hormone concentrations were measured in mice after being fed and after overnight feed deprivation at several time points. HPD mice had significantly lower body weight (in means ± SEMs; 25.73 ± 1.49 compared with 32.5 ± 1.31 g; = 0.003) and fat mass (9.55% ± 1.24% compared with 15.78% ± 2.07%; = 0.05) during the first 6 wk compared with CD mice, and higher lean mass throughout the study starting at week 2 (85.45% ± 2.25% compared with 75.29% ± 1.90%; = 0.0001). Energy intake, total energy expenditure, and respiratory quotient were significantly lower in HPD compared with CD mice as shown by cumulative energy intake and eating rate. Water vapor was significantly higher in HPD mice during both dark and light phases. In HPD mice, concentrations of leptin [feed-deprived: 41.31 ± 11.60 compared with 3041 ± 683 pg/mL ( = 0.0004); postprandial: 112.5 ± 102.0 compared with 8273 ± 1415 pg/mL ( < 0.0001)] and glucagon-like peptide 1 (GLP-1) [feed-deprived: 5.664 ± 1.44 compared with 21.31 ± 1.26 pg/mL ( = <0.0001); postprandial: 6.54 ± 2.13 compared with 50.62 ± 11.93 pg/mL ( = 0.0037)] were significantly lower, whereas postprandial glucagon concentrations were higher than in CD-fed mice. In male mice, the 12-wk HPD resulted in short-term body weight and fat mass loss, but throughout the study preserved body lean mass and significantly reduced energy intake and expenditure as well as leptin and GLP-1 concentrations while elevating postprandial glucagon concentrations. This study suggests that long-term use of HPDs may be an effective strategy to decrease energy intake and expenditure and to maintain body lean mass.

Vasoactive Intestinal Peptide binds with high affinity to VPAC1R and VPAC2R, thus regulating key physiologic functions. Previously, we documented in VIP−/− mice a leaner body phenotype and altered metabolic hormones. Past reports described in VPAC2−/− mice impaired circadian rhythm, reduced food intake, and altered metabolism. To better define the effects of VPAC1R on body phenotype, energy/glucose homeostasis, and metabolism, we conducted a 12-week study in a VPAC1R null model. Our results reveal that VPAC1−/− mice experienced significant metabolic alterations during the dark cycle with greater numbers of feeding bouts (p = 0.009), lower Total Energy Expenditure (p = 0.025), VO2 (p = 0.029), and VCO2 (p = 0.016); as well as during the light cycle with lower Total Energy Expenditure (p = 0.04), VO2 (p = 0.044), and VCO2 (p = 0.029). Furthermore, VPAC1−/− mice had significantly higher levels of GLP-1 and PYY during fasting, and higher levels of GLP-1, glucagon leptin and PYY during postprandial conditions. In addition, VPAC1−/− mice had lower levels of glucose at 60′ and 120′, as assessed by insulin tolerance test. In conclusion, this study supports a key role for VPAC1R in the regulation of body glucose/energy homeostasis and metabolism.