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A new review from Professor Ana Domingos’ lab and colleagues offers a fresh modern viewpoint on sympathetic neurons and their relation to immune cells and obesity.

The sympathetic nervous system orchestrates the activity of organs such as the pancreas, liver, and white and brown adipose tissues to maintain metabolic homeostasis. Thomas Willis provided the first identifiable images of the system back in the 17th century, yet modern neural atomical maps of the sympathetic nervous system used in education and research have not been developed much beyond these original descriptions.

According to Professor of Neuroscience Ana Domingos: “Copies of maps from the mid-1600s remain in textbooks taught to current university medical students. Some of this old knowledge may hold true today, but other pieces of information do not. Researchers have been using methods for studying the biology of sympathetic neurons that are a bit outdated and lead to conclusions that do not necessarily hold when utilising the modern tools of science.”

However, our understanding of the sympathetic nervous system has recently started to grow beyond the classical models. Professor Domingos said: “Previously, there were a lot of assumptions carried on through the available literature, as people were not able to visualise the nerves themselves. It’s only now that we have methods that enable the visualisation of these nerves in the whole intact tissue, and moreover, we can define the molecular identity of those nerves.”

Professor Domingos came across these challenges in her own research. In 2015, when she discovered the sympathetic innervation of the white adipose issue, there was a great deal of discussion around the topic in the scientific community, but there were no pictures available.

Professor Domingos said: “The power of modern imaging techniques is that finally we can start seeing things. That's why we framed our review in light of the 21st century, because now the tools are out there, while still not perfect, we can at least see things. First, we have to see the object that we want to study and then we manipulate the object that we want to study by perturbing its function, either to reduce the function or to increase the function. That's what I did in 2015: not just the visualisation, but also the functional manipulation of the sympathetic innervation of white adipose tissue. And now these findings can be generalised to other organs as well.”

In a new review published in a special issue of Neuron, Professor Domingos and her collaborating authors outline the evolution of these findings, and those of other contributing researchers to the field. One of them is Dr Henrique Veiga-Fernandes, who collaborated with Professor Domingos on a 2021 paper published in Nature, where they discovered a type of stromal cell that senses sympathetic neurons and in turn regulates immune cells that reside in adipose tissues.

Most notably, Professor Domingos and her team discovered new biology about sympathetic innervation. Alongside this, they offer an autonomic framework for the neuroendocrine loop of leptin action, and discuss the role of immune cells in regulating sympathetic terminals and metabolism. They also highlight potential anti-obesity therapeutic approaches that emerge from the modern appreciation of the sympathetic nervous system as a neural network.

The field of neuroimmunometabolism is still very new. The Domingos lab’s discovery that macrophages regulate sympathetic nerves in adipose tissue, as published in Nature Medicine, and can be credited with starting this field of study in 2017. Professor Domingos, with team members, examined the intersection between neuroimmunology and immunometabolism in 2019 in Nature Reviews Endocrinology, and later on in Annual Reviews thus proposing neuroimmunometabolism as an area of study for the first time. The field has since expanded and continues to gain momentum, with more and more scientists putting out papers within the subject. This new Neuron review concludes by critically appraising the field and where it needs to go.

The full review ‘The sympathetic nervous system in the 21st Century: neuro-immune interactions in metabolic homeostasis and obesity’ is available to read in a special issue of Neuron. Authors include former DPAG postdoctoral researcher Dr Noelia Martinez-Sanchez, former Oxford medical student Dr Owen Sweeney, and international collaborators Drs Davi Sidarta-0liveira, Alexandre Caron and Sarah Stanley.

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