Breakthrough drug combats obesity and diabetes by transforming 'bad' fats to 'good' fats
[Mar. 31, 2023: JD Shavit, The Brighter Side of News]
“Metabolism” describes the body’s chemical changes that create the necessary materials for growth and overall health. (CREDIT: Creative Commons)
A new discovery out of Scripps Research and its drug development arm, Calibr, could offer a potential way of addressing metabolic conditions like obesity, type 2 diabetes, and cardiovascular disease. In a study published in Metabolites, researchers used novel drug discovery technologies to uncover a metabolite that converts white fat cells to brown fat cells. This breakthrough could lead to the development of countless potential therapeutics.
Metabolism is the process by which the body creates the necessary materials for growth and overall health. Metabolites are the substances made and used during these metabolic processes.
According to co-senior author Gary Siuzdak, PhD, the senior director of the Scripps Center for Metabolomics and professor of Chemistry, Molecular, and Computational Biology at Scripps Research, “The reason many types of molecules don’t go to market is because of toxicity. With our technology, we can pull out endogenous metabolites—meaning the ones that the body makes on its own—that can have the same impact as a drug with less side effects.”
Metabolic diseases are often caused by an imbalance in energy homeostasis—in other words, when the body takes in more energy than it expends. This is why certain therapeutic approaches have centered around converting white fat cells, known as adipocytes, into brown fat cells.
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White adipocytes store excess energy and can eventually result in metabolic diseases like obesity, while brown adipocytes dissolve this stored energy into heat—ultimately increasing the body’s energy expenditure and helping bring it back into balance.
To uncover a therapy that could stimulate the production of brown adipocytes, the researchers searched through Calibr’s ReFRAME drug-repurposing collection. This is a library of 14,000 known drug compounds that have been approved by the FDA for other diseases or have been extensively tested for human safety. Using high-throughput screening, an automated drug discovery method for searching through large pools of information, the scientists scanned ReFRAME for a drug with the specific capabilities they were looking for.
This is how they uncovered zafirlukast, an FDA-approved drug used for treating asthma. Through a set of cell culture experiments, they found that zafirlukast could turn adipocyte precursor cells, known as preadipocytes, into predominantly brown adipocytes, as well as convert white adipocytes into brown adipocytes.
High-throughput screening reveals an inducer of brown fat differentiation. (CREDIT: Scripps Research Institute)
However, zafirlukast is toxic when administered at higher doses, and it wasn’t entirely clear how zafirlukast was converting the fat cells. This is when the researchers partnered with Siuzdak and his team of metabolite experts.
“We needed to use additional tools to break down the chemicals in zafirlukast’s mechanism,” says Kristen Johnson, PhD, co-senior author of the paper and a director in Translational Drug Discovery Research at Calibr. “Framed another way, could we find a metabolite that was providing the same functional effect that zafirlukast was, but without the side effects?”
Siuzdak and his team designed a novel set of experiments, known as drug-initiated activity metabolomics (DIAM) screening, to help answer Johnson’s question. 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 were searching through adipose tissue for metabolites that could lead to brown adipocyte cell production.
Zafirlukast induces metabolically active brown adipocytes. (a) Quantification of the dose–response effect of zafirlukast in brown adipocyte differentiation based on HCI data. (CREDIT: Scripps Research Institute)
After reducing 30,000 metabolic features to just 17 metabolites, they found myristoylglycine—an endogenous metabolite that prompted the creation of brown adipocytes, without harming the cell. Of the thousands of metabolic features measured in the analysis, only myristoylglycine had this special characteristic, even among nearly structurally identical metabolites.
Excited about their discovery, the researchers conducted further experiments to test the effectiveness of myristoylglycine in promoting the conversion of white fat cells into brown fat cells. They found that myristoylglycine was indeed able to stimulate the production of brown adipocytes from white adipocytes, just like zafirlukast. However, unlike zafirlukast, myristoylglycine did not exhibit any toxic effects on the cells, making it a promising candidate for further development as a therapeutic agent for metabolic diseases.
Drug-Initiated Activity Metabolomics (DIAM) screening allows for the discovery of myristoylglycine, which recapitulates brown adipocyte differentiation. (a) Comparative dose–response effect of zafirlukast and montelukast in brown adipocyte differentiation based on HCI data. (CREDIT: Scripps Research Institute)
The researchers also explored the mechanisms by which myristoylglycine promotes the production of brown adipocytes. They found that myristoylglycine acts on a protein called peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1-alpha), which is a key regulator of brown adipocyte differentiation and function. By activating PGC1-alpha, myristoylglycine stimulates the conversion of white adipocytes into brown adipocytes, leading to increased energy expenditure and improved metabolic health.
The discovery of myristoylglycine as a potent and safe metabolic therapeutic has significant implications for the treatment of metabolic diseases like obesity, type 2 diabetes, and cardiovascular disease. These diseases are major public health concerns, affecting millions of people worldwide and contributing to significant morbidity and mortality. Current therapies for these diseases are limited and often associated with significant side effects, highlighting the urgent need for novel and effective treatments.
The researchers are now working on further preclinical studies to evaluate the safety and efficacy of myristoylglycine as a therapeutic agent for metabolic diseases. They are also exploring other endogenous metabolites that could have therapeutic potential using their novel drug discovery technologies.
“This discovery illustrates the power of metabolomics in identifying novel therapeutics for metabolic diseases,” says Siuzdak. “By leveraging the body’s own metabolic processes, we can develop safe and effective treatments that have the potential to transform the lives of millions of people worldwide.”
The discovery of myristoylglycine as a therapeutic agent for metabolic diseases is just one example of the exciting advances being made in the field of metabolomics. Metabolomics is a rapidly growing field that aims to understand the complex metabolic processes that underlie human health and disease. By studying the thousands of metabolites that are present in the body, metabolomics researchers can gain insights into the biochemical pathways that drive cellular function and identify novel targets for drug discovery.
The development of new technologies like DIAM and the ReFRAME drug-repurposing collection is also expanding the possibilities for drug discovery, allowing researchers to screen large libraries of compounds for potential therapeutic agents. These technologies have the potential to accelerate the drug discovery process and lead to the development of safer and more effective treatments for a wide range of diseases.
As the field of metabolomics continues to advance, it holds the promise of transforming the way we approach drug discovery and disease treatment. With the discovery of myristoylglycine as a safe and effective metabolic therapeutic, the future looks bright for the millions of people worldwide who suffer from metabolic diseases.
In addition to Siuzdak and Johnson, authors of the study, “Drug-Initiated Activity Metabolomics Identifies Myristoylglycine as a Potent Endogenous Metabolite for Human Brown Fat Differentiation” include Carolos Guijas, J. Rafael Montenegro-Burke, Xavier Domingo-Almenara, Bernard P. Kok and Enrique Saez of Scripps Research; and Andrew To, Zaida Alipio-Gloria and Nicole H. Alvarez of Calibr.
This research was partially funded by the National Institutes of Health and the NIH Cloud Credits Model Pilot.
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