Transcutaneous auricular vagus nerve stimulation augments postprandial inhibition of ghrelin

Vagus nerve stimulation (VNS) facilitates weight loss in animals and patients treated with VNS for depression or epilepsy. Likewise, chronic transcutaneous auricular VNS (taVNS) reduces weight gain and improves glucose tolerance in Zucker diabetic fatty rats. If these metabolic effects of taVNS observed in rats translate to humans is unknown. Therefore, the hypothesis of this study was that acute application of taVNS affects glucotropic and orexigenic hormones which could potentially facilitate weight loss and improve glucose tolerance if taVNS were applied chronically. In two single-blinded randomized cross-over protocols, blood glucose levels, plasma concentrations of insulin, C-peptide, glucagon, leptin, and ghrelin, together with heart rate variability and baroreceptor-heart rate reflex sensitivity were determined before and after taVNS (left ear, 10 Hz, 300 µs, 2.0–2.5 mA, 30 min) or sham-taVNS (electrode attached to ear with the stimulator turned off). In a first protocol, subjects (n = 16) were fasted throughout the protocol and in a second protocol, subjects (n = 10) received a high-calorie beverage (220 kCal) after the first blood sample, just before initiation of taVNS or sham-taVNS. No significant effects of taVNS on heart rate variability and baroreceptor-heart rate reflex sensitivity and only minor effects on glucotropic hormones were observed. However, in the second protocol taVNS significantly lowered postprandial plasma ghrelin levels (taVNS: −115.5 ± 28.3 pg/ml vs. sham-taVNS: −51.2 ± 30.6 pg/ml, p < 0.05). This finding provides a rationale for follow-up studies testing the hypothesis that chronic application of taVNS may reduce food intake through inhibition of ghrelin and, therefore, may indirectly improve glucose tolerance through weight loss.

1 INTRODUCTION

Recently, highly innovative approaches to control metabolism through neuromodulation, including optogenetic techniques (Fontaine et al., 2021) and focused ultrasound stimulation (Huerta et al., 2021) have been developed. More traditionally, electrical modulation of neurometabolic circuits has been investigated as a potential tool for the treatment of metabolic diseases, including obesity and diabetes (Masi et al., 2018). However, most of these neuromodulatory approaches are invasive (Cigaina, 2004; Vijgen et al., 2013), not available in humans yet (Fontaine et al., 2021; Malbert et al., 2017), or only available in few specialized centers (Huerta et al., 2021). Thus, it is not surprising that cost-effective and noninvasive alternatives have been explored. Among those, transcutaneous auricular vagus nerve stimulation (taVNS) has been investigated most thoroughly (Farmer et al., 2020), but other noninvasive approaches, such as percutaneous electrical stimulation of dermatome T6 have also been tested for the treatment of obesity (Giner-Bernal et al., 2020). Regarding taVNS, human cadaver studies demonstrated that the vagus nerve sends afferent sensory nerve fibers to the concha and cymba conchae of the ear (Peuker & Filler, 2002), where the auricular branch of the vagus nerve can be stimulated by taVNS (Butt et al., 2020; Peuker & Filler, 2002). Thus, taVNS selectively stimulates afferent vagal nerve fibers, which is in line with functional MRI studies that demonstrated that taVNS activates the classical vagal centers in the central nervous system, including the nucleus of the solitary tract (Yakunina et al., 2017).

Our previous studies have demonstrated that cervical VNS inhibits insulin secretion and results in marked elevations in blood glucose levels in non-diabetic rats even without food intake (Meyers et al., 2016; Stauss et al., 2018). This hyperglycemic response to cervical VNS started almost instantaneously and peak blood glucose levels were observed within less than 30 min (Figure 1 in Meyers et al. (2016)). Depending on the stimulation parameters, cervical VNS may also raise blood glucose levels in non-diabetic humans (Liu et al., 2020; Stauss et al., 2019). We also demonstrated that this hyperglycemic effect of cervical VNS is mediated through afferent vagal nerve fibers projecting to the central nervous system (Meyers et al., 2016). These findings led to the hypothesis that even in the absence of food intake, acute application of taVNS, through activation of afferent vagal nerve fibers, inhibits pancreatic insulin secretion and raises blood glucose levels, potentially through hepatic glucose release. The first protocol of this study (Figure 1) was designed to test this hypothesis by studying the acute effects of taVNS on blood glucose levels and glucotropic hormones, including glucagon, insulin, and C-peptide in generally healthy volunteers.

This significant postprandial decrease in plasma ghrelin levels with taVNS following a carbohydrate-rich beverage is consistent with anorexic effects of vagal nerve stimulation reported in animal (Chapleau et al., 2016; Stauss et al., 2014; Yu et al., 2021) and human (Bodenlos et al., 2014; Pardo et al., 2007) studies.

As to the lack of effect on HRV in this study, the authors offer this

It is possible that the autonomic effects of taVNS only become apparent with repeated chronic applications. For example, in previous studies we applied taVNS on three consecutive days (Dalgleish et al., 2021; Kania et al., 2021). As in the current study, no significant effects of taVNS on heart rate variability were observed on the first study day of these prior studies. However, when pooling the data from all three study days, a significant increase in RMSSD was observed following taVNS, suggesting that repeated chronic applications of taVNS increases parasympathetic modulation of cardiac function.