The accurate and timely exchange of information between our brains and our organs is essential for life. These exchanges direct a range of bodily functions, including maintaining a balance between energy expenditure (e.g. physical activity), and energy intake in the form of food. When this particular communication link breaks down, metabolic diseases such as type 2 diabetes and obesity can occur.
“A breakdown in communication between the brain and the rest of the body is also a sign of disorders such as Alzheimer’s disease,” explains Vincent Prevot from Inserm in France, one of the three principal investigators of the WATCH project. “These disorders often occur with age.”
Understanding exactly how the brain regulates bodily functions is therefore a critically important step in tackling metabolic disorders and neurodegenerative diseases. The prevalence of these conditions is increasing in many parts of the world, due to lifestyle changes (increasing consumption of fast food for example), and the ageing of populations.
Understanding neural behaviour
The 7-year EU-funded WATCH project, supported by the European Research Council, tackles this challenge by focusing on the behaviour of certain neural functions.
“We know that energy balance in the body is maintained by brain cells (neurons and glia) found in the hypothalamus, a small and highly specialised part of the brain,” says joint principal investigator Markus Schwaninger from the University of Lübeck, Germany. “These cells detect glucose or hormones produced by organs that signal hunger or satiety, and adapt the brain’s response accordingly.”
These signals and hormones are able to pass the blood-brain barrier, a tightly sealed wall of blood vessels that protects the brain from unwanted intrusions.
“This is where tanycytes come into play,” adds Prevot. “Tanycytes are peculiar glial cells present in the hypothalamus, which ‘shuttle’ signals into the brain, bypassing the normal barriers.” This enables the signals to reach neurons that regulate food intake, and other critical bodily functions.
The WATCH project has made a number of groundbreaking discoveries in the space of a couple of years. The team has shown for example how tanycytes ‘shuttle’ leptin, a hormone produced by fat cells, into the hypothalamus. The team found that blocking the ‘shuttling’ of this hormone can lead not only to obesity, but also to diabetes due to interference with the function of the pancreas.
In addition, tanycytes translate glucose from the blood into another molecule that can be ‘understood’ by the neurons that control appetite. The team also found that weight loss in certain diseases is mediated by tanycytes through a molecule involved in inflammation, called NFκB.
“Since the beginning of the COVID-19 pandemic, we have diverted part of our resources to studying the impact of the SARS-CoV-2 virus,” notes joint principal investigator Ruben Nogueiras from the University of Santiago de Compostela, Spain.
“We have shown, for instance, that it breaks down the blood vessel walls in the brain. Also, the liver of obese individuals expresses molecules that the virus docks to. This explains why these individuals are particularly vulnerable to severe forms of the disease.”
Tackling neurological diseases
While it is still early days – the project is scheduled to run until 2026 – the discoveries made so far are highly promising. “Some of our discoveries are being patented, and, we hope, will be put to good use in the future, whether it be to improve the lives of people with metabolic diseases, or COVID-19,” say the principal investigators.
“In fact, you could say that we are almost rewriting history. Even though a lot of our discoveries are new, we are also challenging dogma in the field – assumptions that people have made for years, sometimes decades, simply because they could not find proof of anything else.”
A key reason for this has been the dedication of the project team, which includes PhD students and postdocs. “Except during lockdown, our young scientists have been constantly travelling to other labs to learn new techniques, solve new problems, or discuss aspects of their work with someone from a different field,” says Sowmyalakshmi Rasika, who acts as scientific coordinator between the three laboratories.
“Our hope is that this work will lead to evidence-based treatments, or changes in behaviour that could limit the impact of neurological or brain-based diseases in our rapidly ageing and vulnerable populations,” the investigators conclude.