Natural metabolites convert "bad" fats into "good" fats

"Metabolism" describes chemical changes
in the body that produce the substances it needs for growth and overall health.
Metabolites are substances that are produced and used during these metabolic processes — or, as a new finding by Scripps Research and its drug development arm, Calibr, they may also be effective molecules
for treating serious diseases.

In a study published in the journal Metabolites in August 2022, researchers used new drug discovery techniques to discover a metabolite that converts white fat cells ("bad" fat) into brown fat cells ("good" fat).

This finding offers a potential approach
to address metabolic diseases such as obesity, type 2 diabetes and cardiovascular disease.
What's more, it shows the promise
of using this creative approach to drug discovery to identify countless other potential therapies.

Co-senior author Gary Siuzdak, senior director of the Scripps Center for Metabolomics and professor of chemistry, molecular and computational biology at Scripps Research Center, said: "The reason many types of molecules don't make it to the market is toxicity
.
With our technology, we can extract endogenous metabolites – metabolites that the body produces itself – that can have the same effects as drugs, but with fewer
side effects.
The potential of this approach was even demonstrated by the recently approved FDA's Relyvrio, a combination of two endogenous metabolites for the treatment of amyotrophic lateral sclerosis (ALS).

”

Metabolic diseases are often caused by an energy homeostasis imbalance – in other words, when
the body absorbs more energy than it expends.
This is why some treatments center on
the conversion of white fat cells, called fat cells, into brown fat cells.
White fat cells store excess energy, which can eventually lead to metabolic diseases such as obesity, while brown fat cells break down stored energy into heat, ultimately increasing the body's energy expenditure and helping the body regain balance
.

To discover a therapy that could stimulate brown fat cell production, the researchers searched Calibr's ReFRAME Drug Reuse Library — a library of 14,000 known drug compounds that have been approved by the FDA for other diseases or have been extensively tested for safety in
humans.
Using high-throughput screening — an automated drug discovery method that searches through large amounts of information — the scientists scanned ReFRAME for drugs
with these specific functions.

That's how they discovered zafirlukast, an FDA-approved drug
for asthma.
Through a series of cell culture experiments, they found that zafirlukast can transform adipocyte precursor cells, called preadipocytes, into major brown adipocytes, and white adipocytes into brown adipocytes
.

While this is an encouraging finding, zafirlukast is toxic when taken in high doses, and it's not entirely clear how zafirlukast transforms
fat cells.
At this time, the researchers worked with Siuzdak and his team of
metabolite experts.

"We need to use additional tools to break down chemicals in the zafirlukast mechanism," said
Kristen Johnson, Ph.
D.
, co-senior author of the paper and director of the Calibr Translational Drug Discovery Study.
"In other words, can we find a metabolite that provides the same functional effects as zarluxert, but without the side effects?"

Siuzdak and his team designed a new set of experiments, called drug-initiated active metabolomics (DIAM) screening, to help answer Johnson's question
.
DIAM uses techniques such as liquid chromatography, a tool for separating components in a mixture, and mass spectrometry, an analytical technique that separates particles by weight and charge, to aggregate and identify specific metabolites through thousands of molecules
.
In this case, the researchers are looking for metabolites
in adipose tissue that may cause brown fat cells to produce.

After reducing 30,000 metabolic signatures to 17 metabolites, they discovered that nutmelyl glycine, an endogenous metabolite, promotes the production of brown fat cells without harming the cells
.
Of the thousands of metabolic signatures measured in the analysis, only myrgyl glycine has this particular characteristic, even in metabolites that are almost identical in structure
.

Johnson added: "The identification of myristoylglycine from thousands of other molecules is a testament to the Siuzdak method and the power of
these techniques.
Our findings illustrate what happens
when an analytical chemistry team and a drug discovery team work closely together.
”

Carlos Guijas, Andrew To, J.
Rafael Montenegro-Burke, Xavier Domingo-Almenara, Zaida Alipio-Gloria, Bernard P.
Kok, Enrique Saez, Nicole H.
Alvarez, Kristen A.
Johnson, Gary Siuzdak.
Drug-Initiated Activity Metabolomics Identifies Myristoylglycine as a Potent Endogenous Metabolite for Human Brown Fat Differentiation.
Metabolites, 2022; 12 (8): 749