Vagal mechanisms as neuromodulatory targets for the treatment of metabolic disease

Abstract

With few effective treatments available, the global rise of metabolic diseases, including obesity, type 2 diabetes mellitus, and cardiovascular disease, seems unstoppable. Likely caused by an obesogenic environment interacting with genetic susceptibility, the pathophysiology of obesity and metabolic diseases is highly complex and involves crosstalk between many organs and systems, including the brain. The vagus nerve is in a key position to bidirectionally link several peripheral metabolic organs with the brain and is increasingly targeted for neuromodulation therapy to treat metabolic disease. Here, we review the basics of vagal functional anatomy and its implications for vagal neuromodulation therapies. We find that most existing vagal neuromodulation techniques either ignore or misinterpret the rich functional specificity of both vagal efferents and afferents as demonstrated by a large body of literature. This lack of specificity of manipulating vagal fibers is likely the reason for the relatively poor beneficial long-term effects of such therapies. For these therapies to become more effective, rigorous validation of all physiological endpoints and optimization of stimulation parameters as well as electrode placements will be necessary. However, given the large number of function-specific fibers in any vagal branch, genetically guided neuromodulation techniques are more likely to succeed.

Keywords: anti-inflammatory pathways; diabetes; electrical stimulation; genetically guided; gut-brain communication; neuromodulation; obesity; vagotomy.

Figure 1

Overview of autonomic nervous system innervation of organs and tissues important for metabolic regulation. For vagal innervation, the line thickness roughly reflects the number of afferent and efferent axons in the respective branches, as mainly observed in rats. There are not sufficient data available for similar analyses in the sympathetic and dorsal root systems. AMB, nucleus ambiguous; DMV, dorsal motor nucleus of the vagus; DRG, dorsal root ganglia; NTS, nucleus tractus solitarius.

Figure 2

Major vagal nerve branches and central projections from the nucleus tractus solitarius (NTS) in the rat, based on anterograde and retrograde tracing experiments. Note that the arrows only indicate the innervated organs and tissues and do not distinguish afferents and efferents. Also note that the spleen is not innervated by the vagus. amb, nucleus ambiguous; AP, area postrema; BST, bed nucleus of the stria terminalis; CeA, central nucleus amygdala; DM, dorsal nucleus hypothalamus; dmnX, dorsal motor nucleus of the vagus; LHA, lateral hypothalamic area; PAG, periaqueductal gray; PBN, parabrachial nucleus; PVN, paraventricular nucleus hypothalamus; RVL, rostral ventrolateral medulla; SN, substantia nigra; agd, gastroduodenal artery; ags, left gastric artery; ahc, hepatic artery proper; al, splenic artery; ams, superior mesenteric artery. (Figure modified after Ref. 16.)

Figure 3

Overview of the central representation of functional vagal efferent outflow, based on experiments combining retrograde tracing, electrical stimulation, and specific vagal branch cuts in rats. Note the organotopic longitudinal columnar organization within the dorsal motor nucleus of the vagus, as indicated by solid, dashed, and punctuated lines, respectively. ap, area postrema; dmv, dorsal motor nucleus vagus; na, nucleus ambiguous; n. XII, hypoglossal nucleus; NTS, nucleus tractus solitarius.

Figure 4

Intrapancreatic ganglion in the head of the human pancreas stained with hematoxylin/eosin. Postmortem processed tissue from a body donated to the Institute of Anatomy and Cell Biology, University of Erlangen.

Figure 5

Vascular perfusion with intact neural supply to disconnect a given organ from the systemic circulation as the gold standard for identification of vagal functional anatomy. Electrical stimulation of the vagal trunks (or chemical stimulation in the brain) can release humoral substances upstream (e.g., the pancreas and gut) and, if the organ was not vascularly disconnected, can thus be potentially responsible for the observed functional effects in the observed organ (e.g., the liver), particularly when the responses are slow, such as biochemical changes.

Figure 6

Role of the vagal and sympathetic systems in reciprocal immune‐to‐brain communication and neuroimmunomodulation. Besides their role as afferents to the central nervous system, peptidergic dorsal root ganglia (DRG) neurons can influence immune cells via their so‐called local effector function. DMV, dorsal motor nucleus vagus; PVN, paraventricular nucleus hypothalamus; ME/ARC, median eminence/arcuate nucleus; SC/IML, spinal cord/intermediolateral column; A, adrenaline; NA, noradrenaline; αAR, alpha‐adrenergic receptor; βAR, beta‐adrenergic receptor; ACTH, adrenocorticotrophic hormone; CRH, corticotrophin‐releasing hormone; α7‐nAChR, alpha‐7 nicotinic acetylcholine receptor; ENK, encephalin; CGRP, calcitonin gene‐related peptide; NPY, neuropeptide Y; SP, substance P; GR, glucocorticoid receptor.