Researchers found that the molecule lac-phe, which is produced after intense exercise, is responsible for the weight loss seen in metformin users and is associated with appetite control and metabolism. Research shows that metformin increases lac-phe levels, reflecting the effects of intense exercise, suggesting a new avenue for weight loss drug development.
A Stanford Medicine study found that metformin, a commonly prescribed diabetes drug associated with moderate weight loss, stimulates the production of the molecule lac-phe, which is abundant after exercise.
A new study in mice and humans has found that “anti-hunger” molecules produced after intense exercise are responsible for modest weight loss induced by the diabetes drug metformin. The molecule lac-phe is discovered By researchers at Stanford Medicine in 2022.
The discovery, made jointly by researchers at Stanford University School of Medicine and Harvard Medical School, further solidifies that a molecule called lac-phe plays an important role in metabolism, exercise, and appetite. It could pave the way for a new class of weight loss drugs.
“The fact that metformin and sprinting exercise affect body weight in the same way is both strange and interesting.” — Dr. Jonathan Long
Metformin’s weight loss mechanism revealed
“Until now, it was unclear how metformin, which is prescribed to control blood sugar levels, results in weight loss,” said Dr. Jonathan Long, assistant professor of pathology. “We now know that it acts on the same pathways as strenuous exercise to reduce hunger. Understanding how these pathways are regulated could help millions of people… may lead to actionable strategies to lose weight and improve health.”
Long and Mark Benson, MD, assistant professor of medicine at Harvard Medical School, are co-senior authors of the study, which is scheduled to be published on March 18. natural metabolism. Postdoctoral researcher Dr. Shuke Xiao is the study’s lead author.
Many diabetic patients prescribed metformin lose about 2% to 3% of their body weight within a year of starting the drug. Although this amount of weight loss is modest compared to the 15% or more often seen in people taking semaglutide drugs such as Ozempic and Wigovy, the findings leading to these drugs are relatively mild but reproducible. It was also developed from observations of weight loss. People taking first-generation versions of the drug.
Loss of appetite after training
When Baylor University’s Long and his colleagues discovered Lacfe in 2022, they were looking for a small molecule that could play a role in suppressing hunger after intense exercise. What they discovered was a frankenbaby of lactate and amino acids, a byproduct of muscle fatigue. acid It’s called phenylalanine. They named this hybrid molecule lac-phe and showed that it was not only abundant after exercise, but also reduced hunger in humans (as well as mice and racehorses) immediately after intense exercise.
“There is a close relationship between the production of lac-phe and the production of lactic acid,” Long says. “Once we understood this relationship, we started thinking about other aspects of lactate metabolism.”
Effects of metformin on Lac-Phe and body weight
Metformin was an obvious candidate because it stimulates the breakdown of glucose (lowering blood sugar levels) and can cause the production of lactic acid.
Researchers found that obese laboratory mice given metformin had elevated blood lac-phe levels. During the nine-day experiment, they ate less than the other animals and lost about 2 grams of body weight.
Long and his colleagues also analyzed stored blood. plasma Samples taken from type 2 diabetic patients before and 12 weeks after starting to take metformin for blood sugar control. They observed a significant increase in lac-phe levels in people after metformin compared to pre-treatment levels. Finally, 79 participants in a large multiethnic study of atherosclerosis were taking metformin, and those participants had lower circulating lac-phe levels than participants not taking metformin. It was significantly higher.
Future direction of weight loss treatment
“It was great to be able to experimentally confirm our hunch,” Long said. “The magnitude of the effect of metformin on lac-phe production in mice was comparable to or greater than that previously observed with exercise. “The mouse’s lac-phe levels then go through the roof and remain high for hours.”
Further research revealed that lac-phe is produced by intestinal epithelial cells in animals. Inhibiting the ability of mice to make lac-phe abolished the previously observed appetite suppression and weight loss.
Finally, statistical analysis of subjects in the atherosclerosis study who lost weight over several years of study and follow-up found a significant association between metformin use, lac-phe production, and weight loss. It turned out that there is a sex.
“The fact that metformin and sprinting exercise affect body weight in the same way is both strange and interesting,” Long says. “And the involvement of intestinal epithelial cells suggests a layer of gut-brain communication that deserves further investigation. Are there other signals involved?”
Long pointed out that the drug semaglutide is injected into the bloodstream, while metformin is an oral medication already prescribed to millions of people. “These findings suggest that there may be ways to optimize oral medications that influence hunger and energy balance pathways to control weight, cholesterol, and blood pressure.” I think what we’re seeing now is just the beginning of a new type of weight loss drug. ”
Reference: “Lac-Phe mediates the effects of metformin on food intake and body weight” Shuke Xiao, Veronica L. Li, Xuchao Lyu, Xudong Chen, Wei Wei, Fahim Abbasi, Joshua W. Knowles, Alan Sheng- Hwa Tung, Shuliang Deng, Gaurav Tiwari, Xu Shi, Shuning Zheng, Laurie Farrell, Zsu-Zsu Chen, Kent D. Taylor, Xiuqing Guo, Mark O. Goodarzi, Alexis C. Wood, Yii-Der Ida Chen, Leslie A. Lange, Stephen S. Rich, Jerome I. Rotter, Clary B. Klish, Usman A. Tahir, Robert E. Gershten, Mark D. Benson, Jonathan Z. Long, March 18, 2024. natural metabolism.
DOI: 10.1038/s42255-024-00999-9
Researchers at Beth Israel Deaconess Medical Center in HavreUniversity of California Los Angeles Medical Center, Cedars-Sinai Medical Center, Baylor College of Medicine, University of Colorado, University of Virginia, and Broad Institute contributed to this research.
This research was funded by: National Institutes of Health (GM113854, K08HL145095, DK124265, DK136526, HHSN2682015000031, HSN26800004, UM1DK078616, 1R01HL151855), Stanford Medicine Dean’s Fellowship and American Heart Association.
