Common diabetic drug linked to “anti-hunger” molecule causes weight loss

It’s been unknown until now how the medication metformin, which is recommended to manage blood sugar levels, also reduces weight. Scientists now understand that it reduces appetite via the same mechanism as intense exercise. Knowing how these pathways are regulated may help develop practical methods for reducing body mass and enhancing millions of people’s health.

A recent study in humans and animals found that the diabetic drug metformin causes moderate weight loss, which is related to the production of an “anti-hunger” molecule during intense exercise.

Researchers at Stanford Medicine, in collaboration with Harvard Medical School, made the finding. It further cements the critical role the molecule, lac-phe, plays in metabolism, exercise, and appetite. It may pave the way for a new class of weight loss drugs.

When using metformin for diabetes, many patients lose two to three percent of their body weight in the first year. While this weight loss is not as significant as that of patients taking semaglutide drugs like Wegovy and Ozempic (15%), the observations that led to the discovery of those drugs also included a relatively small but consistent weight loss in patients taking first-generation versions of the medications.

In 2022, scientists discovered lac-phe while hunting for small molecules responsible for curtailing hunger after vigorous exercise. They discovered phenylalanine, an amino acid, and lactate due to muscle fatigue. The hybrid molecule, which they named lac-phe, was then demonstrated to be more plentiful and reduce hunger in humans, mice, and even racehorses just after a hard workout.

Jonathan Long, Ph.D., an assistant professor of pathology, said, “There is an intimate connection between lac-the production and lactate generation. Once we understood this relationship, we started to think about other aspects of lactate metabolism.”

The drug metformin was an obvious choice since it can produce lactate and stimulate the breakdown of glucose, lowering blood sugar levels.

The investigators discovered that the blood levels of lac-phe were elevated in obese lab mice administered metformin. During the nine-day experiment, they consumed less food than their colleagues and lost roughly 2 grams of body weight.

In addition, Long and colleagues examined preserved blood plasma samples from Type 2 diabetics 12 weeks before and after patients started taking metformin to regulate their blood sugar. When comparing the levels of lac-phe in patients following metformin to those before therapy, they observed statistically significant increases. Lastly, compared to those not taking the medication, 79 individuals in a large, multi-ethnic study on atherosclerosis who were also taking metformin had significantly higher blood levels of lac-phe.

Long said, “It was nice to confirm our hunch experimentally. The magnitude of metformin’s effect on lac-phe production in mice was as great as or greater than what we previously observed with exercisefwe. If you give mouse metformin at levels comparable to what we prescribe for humans, their lac-phe levels go through the roof and stay high for many hours.”

Subsequent investigations indicated that animal intestinal epithelial cells produce lac-phe. Inhibiting the mice’s ability to produce lac-phe reverses the previously seen hunger suppression and weight loss.

Ultimately, a statistical examination of the atherosclerosis research participants who had weight loss throughout the several-year study and follow-up period revealed a significant correlation between the usage of metformin, lac-phe synthesis, and weight loss.

Long said, “The fact that metformin and sprint exercise affect your body weight through the same pathway is weird and interesting. And the involvement of the intestinal epithelial cells suggests a layer of gut-to-brain communication that deserves further exploration. Are there other signals involved?”

“While semaglutide drugs are injected into the bloodstream, metformin is an oral drug that is already prescribed to millions of people. These findings suggest there may be a way to optimize oral medications to affect these hunger and energy balance pathways to control body weight, cholesterol, and blood pressure. I think what we’re seeing now is just the beginning of new types of weight loss drugs.”

Journal Reference:

TeSlaa, T. Metformin induces a Lac-Phe gut–brain signalling axis. Nat Metab (2024). DOI: 10.1038/s42255-024-01014-x

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