What Optogenetics Reveal About the Role of the Vagus Nerve in Appetite Suppression

Two new studies shed light on new approaches to reducing habitual overeating

With Carlos Campos PhD and Sung Il Park PhD

Vagus nerveResearchers are using light to study how stimulation of the vagus nerve could help patients dealing with obesity in the future.

Eating can seem like a pretty simple behavior, but fresh technologies continue to reveal how complex it truly is. Two new studies explore the use of the light technologies optogenetics and optoelectronics to control eating behaviors. The results could eventually have important effects on how we treat obesity by controlling sensory afferents of the vagus nerve.

Shedding light on optogenetic and optoelectronic technology

Optogenetics refers to the incorporation of genes into cells which code for opsins, light-gated ion channels. In humans, opsins are abundant in the retina but for applications purposes, researchers use opsins found in bacteria and microalgae. In the newest of the studies, the gene for Channelrhodopsin (ChR2) was used with an adeno-associated virus (AAV9) vector to create sodium ion channels that open in the presence of blue light (470l). The AAV9-DIO-ChR2 vector was injected into the nodose ganglion of mutant CalcCre mice. The nodose ganglion, or inferior ganglion of the vagus nerve, contains the cell bodies of the vagal sensory neurons that innervate the gastrointestinal (GI) tract. These sensory afferents were now poised to express a light-gated ion channel in the presence of Cre (cAMP response element) expression which could then be controlled by light.

Specific to that study, the CalcCre mice express Cre in the Calc sensory afferents, localizing ChR2 expression to these nerve endings. Calc sensory afferents innervate the lesser curvature of the corpus and the pyloric antrum of the stomach and contain chemoreceptors. While there are multiple types of vagal sensory afferents in the GI tract defined by region specific innervation (stomach, intestine, or both) and by sensory receptors (mechanoreceptors or chemoreceptors)2, this study focused only on the very specific nerve endings, Calc.

What is optogenetics?

Optoelectric technology, then, refers to the means by which light is introduced to manipulate the light-gated ion channels. The brain has been an ideal organ for developing optoelectric technology mainly because it is a relatively stable organ. Historically, a microLED light was inserted into the brain, which was wired to an external power source, tethering the animal by a wire bundle cemented on the skull. In the second study, microLED lights were implanted into the nucleus of the solidary tract within the medulla to activate ChR2 sodium channels expressed in terminal ends of the vagal afferents. Like the first study, the second study used similar optogenetic techniques for ChR2 expression.

Tethering makes optoelectronic technology clinically unfeasible. The first study, however, developed a wireless system by which the microLED was sutured into the lining of the stomach and a wireless radiofrequency (RF) powered device was used to control the microLED (see figure). This innovation to optoelectric technology could allow optogenetics to be used in organs and tissue that are subject to movement, like the GI tract. Since it is also untethered, there is clinical potential for its use.

In discussing this advancement with author Carlos Campos PhD of the Division of Metabolism, Endocrinology and Nutrition at the of University of Washington, he said, “A major advancement of our studies was the development of a wireless optogenetic device that allows us to probe the function of distinct stomach sensory pathways.”

Cardia

Optogenetics allow Calc-sensory vagal afferents to express light-gated ion channels (blue dots), which can be activated by turning on a microLED light inserted into the stomach and controlled through a wireless RF device. 

Study design

The first study identified the three classical sensory vagal endings in the GI tract using optogenetics:

  • Intraganglionic laminar endings (ILGEs) with mechanoreceptors, or stretch receptors, found along the fundus, corpus, and pyloric antrum of the stomach as well as throughout the intestine
  • Intramuscular array endings also containing mechanoreceptors limited to the sphinctal areas of the cardia and pyloric regions
  • Mucosal endings with chemoreceptors in the corpus, cardia, and antrum of the stomach and intestine

Results

When the mechanoreceptors of the ILGE afferents were stimulated in food-restricted mice, they did not eat as much food as the unstimulated control mice. In contrast, when the chemoreceptors of the mucosal endings were stimulated, both groups of mice ate similar volumes of food. The researchers concluded that stimulation of receptors which respond to gastric and intestinal distension, or stretch, were sufficient for reducing eating behaviors.

To further explore this idea of distension within the GI tract, mice were fed foods which induced distension in the whole GI tract, the intestine only, or the stomach only. They found that both lipids and glucose caused an increase in fluid content in the stomach and intestine. Hyperosmolar and non-nutritive solutions (salty or the artificial sweetener, mannitol) increased intestinal volume, while methylcellulose increased stomach volume only. When food-deprived mice were again given free-access to food, only those that experienced intestinal distension limited their food consumption compared to controls or those given methylcellulose. Thus mechanoreceptor stimulation within the intestine may help limit food consumption.

Chemoreceptors play a more important role in eating that previously thought

The idea that chemoreceptors play a less important role in eating behaviors is challenged by these results. It is important to note that this series of experiments focused on the chemosensitive afferents found only in the stomach, known as Calc sensory afferents. Using optogenetics and optoelectric technology, the sensory afferents were preferentially stimulated in food deprived mice. Compared to unstimulated controls, these mice ate significantly less food. Additional behavioral tests found that stimulating these specific nerve endings was associated with a negative valence mechanism rather than a positive one. When asked what this means in clinical terms, Dr. Campos told us:

“We discovered that activation of the Calc vagal afferents suppress appetite by producing a robust aversion to food, suggesting that these sensory neurons might be involved in pathological conditions that cause loss of appetite, such as food poisoning. Food poisoning causes inflammation and increases the acidity within the stomach to fight off bacteria, all of which may be detected by chemosensitive vagal afferents. Consequently, activation of these vagal afferents suppresses further intake of that food and might even produce a taste aversion memory that prevents future consumption of the harmful diet.”

Is there a future for optogenetics and optoelectronic technology in treating obesity?

Using “opto-tech,” both groups studied the vagal mechanisms behind what turned out to be two different eating behaviors: reduced eating caused by physical distension of the GI tract and reduced eating caused by chemosensory-controlled aversion.

While these studies hint at interesting clinical applications for opto-tech in the future, we asked author Sung Il Park PhD of the Department of Electrical and Computer Engineering at Texas A&M University about the feasibility of using their technology in humans. Regarding optoelectric technology, Dr. Sung said, “I don’t see any technical difficulties or barriers to the adoption of the wireless optotechnology, but optogenetics requires expression of light sensitive proteins to targeted regions in the stomach.”

Dr. Campos agreed, adding, “Optogenetic therapy to control appetite in humans is feasible but would require several additional advancements. In particular, the gene that encodes for the light-activated opsin protein would need to be delivered to the sensory neurons of interest using a vector. Our colleagues in gene therapy have been making light-speed advancements in this research area.”  

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