The vagus nerve, also known as Cranial Nerve 10, is a complex and extensive nerve that plays a vital role in the communication between the brain and various organs in the body. Recent research has highlighted the vagus nerve's involvement in the development of obesity and its potential as a therapeutic target for weight loss interventions. This article explores the intricate connection between the vagus nerve and weight management, examining the mechanisms involved, the impact of vagal nerve stimulation and blockade, and future directions for pharmacotherapy.
Understanding the Vagus Nerve
The vagus nerve is one of 12 pairs of cranial nerves, characterized by its complex structure and diverse functions. The vagus nerve has been implicated in mediating an extensive range of physiological functions. It is a mixed nerve, comprising three fiber types:
- Highly myelinated, low activation, large-diameter A-fibers (further broken down into α to δ subgroups)
- Lightly myelinated, intermediate-diameter B-fibers
- Unmyelinated, small-diameter, high activation threshold C-fibers
These fibers facilitate bidirectional communication between the brain and peripheral organs. The majority of the fibers are vagal afferent fibers that carry sensory information from visceral organs to the brain (predominantly Aδ- and C-fibers); the remainder are vagal efferent fibers that convey motor information to control peripheral organ function. Afferent fibers vastly outnumber efferent fibers within the vagus nerve.
Anatomical Overview
As the vagus nerve leaves the skull, the superior (jugular) and inferior (nodose) ganglia contain the afferent cell bodies. Neural tracing studies demonstrated that branches leaving the cervical vagus in the thorax innervate the skin, acoustic meatus, pharynx, larynx, trachea, bronchi, lung, aortic arch, heart, and esophagus. Both the ventral and dorsal gastric branches innervate the stomach and proximal duodenum; the dorsal accessory celiac branch has weak innervation to the liver but predominantly joins the ventral celiac branch innervating the distal duodenum, jejunum, ileum, cecum, and colon. The common hepatic branch exclusively derives from the ventral trunk. As its name suggests, this branch supplies the hepatic triads, bile duct, and portal vein in the liver, but also branches off to innervate lower parts of the stomach, pyloric sphincter, pancreas, and proximal duodenum.
The Vagus Nerve's Role in Metabolism and Obesity
The vagus nerve innervating the gut plays an important role in controlling metabolism. It communicates peripheral information about the volume and type of nutrients between the gut and the brain. Depending on the nutritional status, vagal afferent neurons express two different neurochemical phenotypes that can inhibit or stimulate food intake. Chronic ingestion of calorie-rich diets reduces sensitivity of vagal afferent neurons to peripheral signals and their constitutive expression of orexigenic receptors and neuropeptides. This disruption of vagal afferent signalling is sufficient to drive hyperphagia and obesity.
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Vagal Afferent Neurons and Nutritional Status
Vagal afferent neurons play a critical role in sensing and relaying information about the volume and type of nutrients present in the gut. These neurons express chemoreceptors on their terminals in the gut that sense these hormones and mechanoreceptors that sense distension. This sensory information is then transmitted to the nucleus tractus solitarii (NTS) in the hindbrain, which plays a crucial role in regulating meal size and duration. NTS neurons are activated and reduce meal size and duration, signal to higher order neurons in the forebrain to regulate reward or energy homeostasis, and/or signal to the vagal efferent neurons in the dorsal motor nucleus (DMN) in the hindbrain.
The vagal afferent neurons exhibit plasticity, adapting their neurochemical phenotypes based on nutritional status. In the presence of food, enteroendocrine cells release anorectic hormones that inhibit food intake. In the absence of food, different enteroendocrine cells of the gut release orexigenic hormones that stimulate food intake.
Impact of Calorie-Rich Diets
Chronic consumption of calorie-rich diets can disrupt the normal functioning of vagal afferent neurons. This can lead to reduced sensitivity to peripheral signals, such as hormones released by the gut in response to food intake. Furthermore, calorie-rich diets can alter the expression of orexigenic receptors and neuropeptides in vagal afferent neurons, further contributing to hyperphagia (excessive eating) and the development of obesity.
Modulation of the Vagus Nerve for Weight Loss
Neuromodulation of the vagus nerve represents a promising avenue for the treatment of obesity. Vagal nerve stimulation prevents weight gain in response to a high-fat diet. While the mechanisms are still being investigated, studies have shown that both vagal nerve stimulation and vagal blockade can lead to weight loss.
Vagal Nerve Stimulation (VNS)
Vagal nerve stimulation (VNS) involves the use of electrical impulses to stimulate the vagus nerve. In small clinical studies, in patients with depression or epilepsy, vagal nerve stimulation has been demonstrated to promote weight loss. An electrode from the device courses subcutaneously and attaches to the trunk of the left vagus nerve about half way between the clavicle and the mastoid. The device is programmed to deliver preset stimuli using an external, magnetic, programming wand.
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Fourteen patients were treated over 2 years with cervical vagus nerve stimulation (VNS) for adjunctive therapy of severe, treatment-resistant depression. The weight loss was proportional to the initial BMI, that is, the more severe the obesity, the greater the weight loss. Weight loss did not correlate with changes in mood symptoms.
Vagal Blockade
Vagal blockade, which inhibits the vagus nerve, results in significant weight loss. Vagal blockade is proposed to inhibit aberrant orexigenic signals arising in obesity as a putative mechanism of vagal blockade-induced weight loss.
The Gut-Brain Connection and Appetite Regulation
The intricate communication between the gut and the brain, mediated by the vagus nerve, plays a pivotal role in regulating appetite and food intake. The vagus nerve acts as a conduit for signals related to satiation, the feeling of fullness that leads to the termination of a meal, as well as appetition, the motivation to seek and consume food.
Satiation Signals
Vagal afferent terminals within the gastrointestinal tract are equipped with mechanosensitive and chemosensitive receptors that respond to distension and nutrient type/quantity, respectively. In the presence of food, enteroendocrine cells release anorectic hormones that activate vagal afferent terminals, sending satiating signals to the NTS in the hindbrain. Decerebrated rats, in which hindbrain-forebrain communication is abolished, are capable of terminating a meal, suggesting that the caudal hindbrain is sufficient to suppress food intake and gastric emptying rates.
One well-known example is cholecystokinin (CCK), released from enteroendocrine I cells in response to proteins or fat. CCK activates CCKA receptors on vagal afferent terminals, promoting satiation and slowing motility.
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Appetition Signals
While earlier research focused mainly on mechanisms for signaling satiation, there is now much appreciation for signaling of appetition and food reward from the gut to the brain. The term “appetition” was coined by Sclafani and his colleagues based on the observation that the interaction of certain nutrients with the intestinal mucosa elicits more appetite, rather than less, as in satiation. Animals learn to associate taste and flavor of ingested foods with its postingestive consequences. This learning mechanism has two important consequences. First, the increased intake of the flavored solution when paired with intragastric glucose or lipids as compared with intragastric water indicates that intragastric nutrients act as positive reinforcers that can activate the brain reward system. Second, this mechanism is fundamental for subsequent food choice and survival, as it allows acceptance of beneficial foods or rejection of harmful foods before any large amount is sampled and ingested.
Advanced Vagal Manipulations and Future Directions
Recent advances in genetics-based identification of molecularly distinct neurons have tremendously enriched our tool kit to study functional anatomy of the peripheral nervous system.
Genetic and Molecular Approaches
The advent of advanced techniques, such as single-cell RNA sequencing (scRNA-Seq), has enabled researchers to create comprehensive atlases of molecularly distinct clusters of neurons within the vagal ganglia. This has allowed for a more detailed understanding of the organization of vagal afferent innervation of abdominal organs.
Optogenetic Silencing
Optogenetic silencing of a specific population of enteroendocrine cells (EECs) that make synaptic contacts with vagal afferent neurons in the proximal small intestine, so-called neuropod cells, abolishes the vagal afferent signal to intestinal sucrose and prevents mice from distinguishing non-nutritive sweeteners from nutritive sucrose. Elaborate in vitro and in vivo studies further identified a mechanism by which luminal glucose is transported into the EECs selectively through sodium-glucose transporter-1 (SGLT1), which leads to cell depolarization, the release of glutamate from the neuropods, and rapid activation of glutamate receptors on vagal afferent terminals.
Potential for Targeted Therapies
Approaches and molecular targets to develop future pharmacotherapy targeted to the vagus nerve for the treatment of obesity are proposed. These advancements pave the way for the development of highly targeted therapies that selectively modulate vagal afferent activity to promote weight loss and improve metabolic health.
Correlated Vagus Nerve Stimulation System
A correlated VNS system that is battery free and automatically generates electrical stimulations in correlation to stomach movement. A flexible nanogenerator device is developed to be attached to the stomach surface and produce biphasic electrical pulses in response to the peristalsis of stomach. The electric signals can stimulate the vagal afferent fibers to reduce food intake and eventually achieve weight control.
Development and Working Principle
The correlated VNS system for weight control is designed following the principle depicted in Fig. 1a. The stomach motion is used as the sole source to generate pulsed voltage signals, which in response will stimulate the vagus nerves to reduce food intake. This self-responsive function is enabled by a triboelectric nanogenerator (TENG) attached on the surface of stomach, which generates biphasic electric pulses when the stomach is in peristalsis. Here, a bilateral VNS is implemented by wrapping the two gold (Au) leads around the anterior vagus nerves (AVNs) and posterior vagus nerves (PVNs) at the proximity of the gastroesophageal junction (Fig. 1b).
Lifestyle Adjustments to Stimulate the Vagus Nerve
Beyond medical interventions, lifestyle adjustments can also play a significant role in stimulating the vagus nerve and promoting overall health.
Relaxation Techniques
Stimulating the vagus nerve has been shown to improve conditions including:
- Anxiety
- Alcohol addiction
- Migraines
- Alzheimer’s
- Leaky gut
- Bad blood circulation
If finding moments of true relaxation in your life are hard to come by, that could be the key factor that is driving your digestive issues and weight gain.
Meditation
Meditation can increase the positive emotions you experience and the social connection you feel with those around you. The influx of positive emotions increases your vagal activity, which transitions you into “rest and digest” mode, helping to alleviate symptoms of both anxiety and depression.
Deep Breathing
A simple breathing exercise in which you’re breathing through your belly rather than your chest has been shown to stimulate the vagus nerve. Belly breathing, like this box breath exercise, allows you to interrupt your stress response system and bring down your heart rate and blood pressure.
Probiotics
The mind-gut connection is more than just a saying, but an actual communication channel. It’s through the autonomic nervous system, where the vagus nerve lies, that the brain and gut send signals to one another. Probiotics may positively impact your vagus nerve by reducing inflammation in the gut microbiota. Certain strains of probiotics have shown to increase GABA, the relaxation neurotransmitter in the brain, via stimulation of the vagus nerve.
Yoga
In general, yoga increases your vagus nerve activity and parasympathetic system. Yoga breathing directly stimulates the vagus nerve and improves your autonomic regulation, which is your ability to react to environmental cues without thinking. This form of breathing can also your improve cognitive function and mood. Studies have shown that yoga increases your GABA levels as well.
Conditions and Disorders Affecting the Vagus Nerve
Various conditions and disorders can affect the vagus nerve, leading to a range of symptoms.
Gastroparesis
Gastroparesis occurs when damage to a vagus nerve stops food from moving into your intestines from your stomach. This vagal nerve damage can result from diabetes, viral infections, abdominal surgery, and scleroderma.
Vasovagal Syncope
Vasovagal syncope occurs when a vagus nerve to your heart overreacts to certain situations like extreme heat, anxiety, hunger, pain, or stress. Blood pressure drops very quickly (orthostatic hypotension), making you feel dizzy or faint.
Signs of Vagus Nerve Problems
Vagus nerve conditions cause different symptoms depending on the specific cause and affected part of your nerve. You may experience:
- Abdominal pain and bloating
- Acid reflux (gastroesophageal reflux disease, GERD)
- Changes to heart rate, blood pressure, or blood sugar
- Difficulty swallowing or loss of gag reflex
- Dizziness or fainting
- Hoarseness, wheezing, or loss of voice
- Loss of appetite, feeling full quickly, or unexplained weight loss
- Nausea and vomiting