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Potential Targets for Loss of Appetite/Cachexia Related to Interleukin 18 Activity Identified in Early Studies

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Key Points

  • IL-18 interferes with normal appetite control when it binds to its receptors on a specific subset of bed nucleus of the stria terminalis–lateral hypothalamus projecting neurons. IL-18 reduces glutamate release, leading to less activation of type III neurons, reduced GABA signaling, and a loss of appetite.
  • Mice with IL-18 injected directly into the anterior bed nucleus of the stria terminalis ate significantly less than mice that received a control substance.
  • Researchers believe the circuit affected by IL-18 may be a potential drug target for treating loss of appetite. 

Loss of appetite during illness is a common and potentially debilitating phenomenon. In cancer patients especially, it can even shorten lifespan. Scientists at The Scripps Research Institute (TSRI) have discovered how an immune system molecule controls a brain circuit and reduces appetite. Their research points to potential targets for treating loss of appetite and restoring a patient's strength. The findings were published by Francesconi et al in The Journal of Neuroscience.

“Treating loss of appetite won't cure an underlying disease, but it could help a patient cope,” said Bruno Conti, PhD, Professor in the Department of Chemical Physiology at TSRI. “Many times, loss of appetite can compromise clinical outcome. A weak individual is less likely to be able to cope with chemotherapy, for instance.”

Study Background

In patients with diseases such as cancer or AIDS, loss of appetite can turn into a wasting disease called cachexia, also known as “the last illness,” as it can accelerate a patient's decline.

Previous studies had identified the biologic players in loss of appetite. One was an immune molecule called interleukin 18 (IL-18), which activates other cells to fight disease. Another was a brain structure called the bed nucleus of the stria terminalis (BST)—which has a subset of neurons that project to the lateral hypothalamus (LH), a brain region that controls appetite. The challenge was to show how these elements interacted.

Study Findings

The new research began with the discovery of the expression of IL-18 receptors in neurons of the anterior BST. With this finding, the researchers had a starting point for tracking the effects of IL-18 in this part of the brain.

Researchers then used an electrophysiological technique called whole-cell patch clamp to record neuronal activity and uncovered a series of events regulating appetite.

In mouse BST brain slices not exposed to IL-18, an excitatory neurotransmitter called glutamate strongly activates a subset of BST neurons projecting to the LH. The activation of these BST-LH neurons leads to the release of an inhibitory neurotransmitter, called gamma-aminobutyric acid (GABA), on target neurons. The GABA release inhibits neuronal activity in the LH. In conclusion, normal amounts of GABA released into the LH lead to a normal appetite.

IL-18 interferes with this system when it binds to its receptors on a specific subset of BST-LH projecting neurons (type III), it reduces glutamate release, leading to less activation of type III neurons, reduced GABA signaling, and a loss of appetite.

“IL-18 regulates feeding by locking directly into the neuronal circuitry,” said Dr. Conti.

Studies of mouse behavior supported this finding. Mice with IL-18 injected directly into the anterior BST ate significantly less than mice that received a control substance.

The researchers believe the circuit affected by IL-18 may be a potential drug target for treating loss of appetite.

The researchers plan next to investigate the specific biochemical pathways in this brain circuit.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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