Immunoregulatory functions of appetite controlling brain circuits

It is widely known that changes in our diet can significantly impact our immune system. Fasting or consuming fewer calories can aid in recovery from inflammatory and infectious diseases. However, overeating and obesity can increase our susceptibility to illness. Generally, it is believed that this is because the food we eat provides the fuel our body needs to function properly, including our immune system. So, changes in our diet can directly affect how well our immune system works.

What's is also becoming well understood is that our brain controls our food intake and that when we eat too much or too little, in addition to impacting on the body energy levels, we also affect how the brain and its metabolic-sensing network work. Indeed, specialised nerve cells in our brain sense how much food we have consumed and signal when we are hungry or full. These cells work together to regulate our feelings of hunger and satiety, to regulate our food intake and make sure our body gets the nutrients it needs. However, whether these nerve cells can also affect our immune system is completely unknown.

Surprisingly, our initial research supports the idea that the nerve cells in the brain that control hunger and fullness can also directly regulate our immune system. In this project, we are investigating this new idea further. To learn more, we will use the latest technologies to selectively activate or deactivate these specific nerve cells and study their effects on the immune system and how these effects take place.
We hope that our research will advance current knoledge, providing a new understanding of how the brain controls the immune system and how dietary changes can impact our health. This could lead to new treatments for immune-related diseases such as inflammation and infection, as well as a better understanding and potential future treatments for inflammatory diseases, which are highly prevalent in people leaving with obesity and metabolic syndrome.

Technical Summary
The immune system is influenced by metabolic states, and changes in nutrient availability have a significant impact on immune response. However, it is also well established that alterations in nutrient levels - whether due to increased or reduced intake - lead to changes in discrete brain networks that regulate feelings of hunger and satiety.
Given the tight connections between metabolic states and the brain networks that encode and sustain their central represenations, it remains unknown whether the nutritional modulation of immune functions is solely due to altered nutrient availability or whether it also involves brain-initiated responses.
To address this question, we plan to use a combination of chemo- and optogenetic circuit manipulations and immunological approaches that allow us to definitively separate nutrient levels from the activity of metabolic-sensing circuitry to investigate their immunoregulatory functions.
Our pilot findings indicate the existence of a previously unknown immunoregulatory framework, in which neurons encoding feelings of hunger and satiety directly control the dynamics of circulating inflammatory monocytes in response to nutritional changes.
With this proposed work, we will first define the biological mechanisms through which this novel immunoregulatory mechanism occurs. Next, we will delineate the brain circuitries and the key biological substrates that integrate their immunomodulatory signals in the periphery. Finally, we will study the operating logic of this emerging immunoregulatory mechanism and test the hypothesis that central mechanisms encoding hunger and satiety - beyond classic homeostatic principles - may control monocyte dynamics in a feed-forward manner.
The proposed work has the potential to uncover a completely novel mechanism for neuro-immune-metabolic interactions and lead to a better understanding of how nutritional states influence immune function.