Drug discovery method identifies naturally occurring metabolite that converts 'bad' fat to 'good' fat
Zafirlukast induces the production of brown adipocyte tissue. For preadipocytes treated with zafirlukast (right image), brown adipocytes (shown in red) were much more prevalent than preadipocytes grown with the DMSO control (left image). Credit: Scripps Research and Calibr

The body's chemical changes create the necessary materials for growth. Metabolites are substances made and used during these processes, and as a new discovery out of Scripps Research and its drug development arm, Calibr, indicates, they could also be potent molecule for treating severe diseases.

The Metabolites researchers used novel drug discovery technologies to find a metabolite that converts white fat cells to brown fat cells. There is a potential way to address metabolic conditions such as obesity and type 2 diabetes. It speaks to the promise of using this drug discovery method to find other potential drugs.

Toxicity is one of the reasons that many types of molecule don't go to market. We can pull out the ones that the body makes on its own, which can have the same effect as a drug with less side effects. The FDA's recent approval of Relyvrio is an example of the potential of this approach.

When the body takes in more energy than it excretes, it's called a metabolic disease. White fat cells are converted into brown fat cells in certain therapeutic approaches. White adipocytes store excess energy and can eventually lead to diseases such as Obesity, while brown adipocytes help bring it back into balance by dissolving excess energy into heat.

The researchers searched through Calibr's ReFRAME drug-repurposing collection to find a therapy that stimulates the production of brown adipocytes. The scientists used high-throughput screening to find a drug with certain capabilities.

This is how they found the FDA approved drug. Through a series of cell culture experiments, they were able to turn preadipocytes into brown adipocytes.

It wasn't clear how the fat cells were being converted by the drug. The researchers collaborated with the team of experts.

The co-senior author of the paper says that they needed to use more tools to break down the chemicals in the drug. Couldn't we find a metabolite that provided the same effect without the side effects?

Drug discovery method identifies naturally occurring metabolite that converts 'bad' fat to 'good' fat
DIAM uses technologies such as liquid chromatography and mass spectrometry to pool through thousands of molecules and identify specific metabolites. In this case, the researchers first reduced 30,000 metabolic features to just 17 metabolites, and then found myristoylglycine—an active endogenous metabolite that was able to convert white fat cells to brown fat cells, similar to the drug zafirlukast. Credit: Scripps Research and Calibr

A novel set of experiments was designed by Siuzdak and his team to answer Johnson's question. Liquid chromatography is a tool that separates components in a mixture, and mass spectrometry is an analytical method that separates particles by weight and charge. The researchers were looking for compounds that could lead to the production of brown adipocytes.

They found myristoylglycine after reducing the number of metabolic features to 17. Myristoylglycine was the only one of the thousands of features that had this characteristic.

The power of Siuzdak's approach and these technologies is demonstrated by the identification of myristoylglycine among the thousands of other molecules. The findings show what happens when a chemistry team and a drug discovery group work together.

More information: Carlos Guijas et al, Drug-Initiated Activity Metabolomics Identifies Myristoylglycine as a Potent Endogenous Metabolite for Human Brown Fat Differentiation, Metabolites (2022). DOI: 10.3390/metabo12080749