Mapping of cell populations in the brainstem bodes well for future obesity treatment
Two years of research have resulted in an article in the respected journal Nature Metabolism. PhD student Mette Q. Ludwig is first author of the article, which has been produced in an international collaboration with, among others, the team led by Associate Professor Tune H. Pers at the Novo Nordisk Foundation Center for Basic Metabolic Research (CBMR).
When PhD student Mette Q. Ludwig had to choose a field for her master’s degree a few years ago, there was only one route. She had a Bachelor’s in Molecular Biomedicine under her belt and wanted to spend the next two years diving into a combination of mathematics, biology and computer science to study biological connections. The Master’s in Bioinformatics at the University of Copenhagen was the obvious choice.
‘What drives me is that, with computational tools, you can understand some cool biology. Looking for patterns in large volumes of data and finding connections that can provide more knowledge to help develop new types of treatments and drugs, for example, is exciting’, says Mette Q. Ludwig, who started working on her PhD in the spring of 2019 with financial support from the Danish Diabetes Academy.
Findings demonstrated by rat experiments in Michigan
In the days before Easter 2021, the article ‘A genetic map of the mouse dorsal vagal complex and its role in obesity’ was published in the respected journal Nature Metabolism. It was preceded by a great deal of work in Tune H. Pers’ group at the CBMR to map cell populations in the mouse brainstem that are involved in appetite regulation. From the University of Michigan, USA, Professor Martin G. Myers’ team joined in with a series of experiments on rats designed to demonstrate the findings.
‘The brain plays a key role in the regulation of appetite and weight, but a large proportion of obesity research concentrates on the hypothalamus. While also acknowledged as an area of importance, the same level of attention has not been paid to the brainstem, and a comprehensive understanding of the cellular identities has been lacking’, explains Mette Q. Ludwig.
The findings from this study are therefore ground-breaking. Using bioinformatics and single-cell sequencing tools, the researchers succeeded in characterising cell populations in the brainstem that are activated by drug treatment for obesity and are associated with genetic predisposition to the disease. This knowledge may help develop new anti-obesity drugs.
One area of the brainstem was particularly affected
The research was carried out on obese mice where the lower part of the brainstem was isolated and the genetic activity of the cells was mapped. The mice were administered with drugs that are used to treat obesity. These imitate the hormone GLP-1 and are known as GLP-1 receptor agonists. The treatment altered one area of the brainstem in particular, namely the area postrema. This single-cell atlas was then cross-referenced with data from studies of genes associated with body weight in humans.
‘Using single-cell sequencing tools, we mapped 25 neuronal populations and eight types of glial cells in the area postrema and two adjacent areas that together make up the dorsal vagal complex. Two neuronal populations expressed GLP-1 receptors, while another population expressed receptors for the hormone amylin, which is already being investigated as a possible treatment for obesity. These three populations all expressed genes that predispose to obesity in humans’, says Mette Q. Ludwig.
To test the Danish findings, a collaboration was set up with Professor Martin G. Myers of the University of Michigan. Using genetically modified rats, brainstem populations that expressed amylin receptors were activated, causing a drop in food intake. This confirmed the hypothesis that these neurones reduce appetite.
The results of the research on the two species represent interesting progress. By identifying cells that anti-obesity drugs activate in the brain, new insight has been generated into the way these drugs act. For Mette Q. Ludwig, this is a trail she wants to pursue further: there are more patterns and connections to be found.
Read the article from Nature Metabolism, ‘A genetic map of the mouse dorsal vagal complex and its role in obesity’: https://www.nature.com/articles/s42255-021-00363-1
Read the abstract of Mette Q. Ludwig’s PhD project, which is supported by the Danish Diabetes Academy. The PhD is planned to be completed in the spring of 2022: https://www.danishdiabetesacademy.dk/sites/default/files/media/upload/mette_ludwig_dk_uk.pdf
/ By Pernille Fløjstrup Andersen, Communications Officer, Danish Diabetes Academy