Metformins Secret Unleashed: The Mirror Exercise of Anti-Hunger Molecules

Researchers have discovered that the lac-phe molecule, produced after intense exercise, is responsible for the weight loss seen in metformin users, linking it to appetite control and metabolism. Studies show that metformin increases lac-phe levels, mirroring the effects of vigorous exercise, suggesting new avenues for developing weight-loss drugs.

A Stanford Medicine study found that metformin, a commonly prescribed diabetes drug associated with moderate weight loss, stimulates the production of lac-phe, a molecule abundant after exercise.

An “antifame” molecule produced after vigorous exercise is responsible for moderate weight loss caused by the diabetes drug metformin, according to a new study in mice and humans. The molecule, lac-phe, was discovered by Stanford Medicine researchers in 2022.

The finding, made jointly by researchers at Stanford Medicine and Harvard Medical School, further solidifies the critical role that the molecule, called lac-phe, plays in metabolism, exercise and appetite. It may pave the way for a new class of weight-loss drugs.

“The fact that metformin and sprint exercise affect your body weight through the same pathway is strange and interesting.” — Jonathan Long, PhD

Mechanism of metformin weight loss presented

“So far, the way metformin, which is prescribed to control blood sugar levels, also causes weight loss,” said Jonathan Long, PhD, assistant professor of pathology. “We now know that it is acting through the same pathway as vigorous exercise to reduce hunger. Understanding how these pathways are controlled may lead to viable strategies to reduce body mass and improve the health of millions of people.”

Long and Mark Benson, MD, PhD, assistant professor of medicine at Harvard Medical School, are co-lead authors of the study, which will be published March 18 in Metabolism of nature. Postdoctoral scholar Shuke Xiao, PhD, is the lead author of the study.

Many people with diabetes who are prescribed metformin lose about 2% to 3% of their body weight during the first year of starting the medication. While this amount of weight loss is modest compared to the 15% or more often seen by people taking semaglutide drugs like Ozempic and Wegovy, the discoveries that led to these drugs also grew out of observations of relatively less, but reproducible, weight loss in people taking first-generation versions of the drugs.

Loss of appetite after training

When Long and his colleagues at Baylor University discovered lac-phe in 2022, they were looking for small molecules responsible for reducing hunger after vigorous exercise. What they found was a Frankenbaby of lactate, a byproduct of muscle fatigue, and an amino acid called phenylalanine. They named the hybrid molecule lac-phe and showed that not only is it more abundant after exercise, but it also makes people (as well as mice and even racehorses) less hungry immediately after ‘a hard workout.

“There is an intimate connection between lac-phe production and lactate generation,” Long said. “Once we understood this relationship, we started thinking about other aspects of lactate metabolism.”

The impact of metformin on Lac-Phe and weight

Metformin was an obvious candidate because since it stimulates the breakdown of glucose (thereby lowering blood sugar levels) it can trigger the generation of lactate.

The researchers found that obese laboratory mice given metformin had increased levels of lac-phe in their blood. They ate less than their peers and lost about 2 grams of body weight during the nine-day experiment.

Long and his colleagues also analyzed stored blood plasma samples from people with type 2 diabetes before and 12 weeks after they started taking metformin to control their blood sugar. They saw significant increases in lac-phe levels in people after metformin compared to their levels before treatment. Finally, 79 participants in a large multi-ethnic study of atherosclerosis who were also taking metformin had significantly higher levels of circulating lac-phe in their blood than those not taking the drug.

Future directions in the treatment of weight loss

“It was nice to confirm our intuition experimentally,” Long said. “The magnitude of the effect of metformin on lac-phe production in mice was as great or greater than what we previously observed with exercise. If you give a 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.”

Further research revealed that lac-phe is made by animal intestinal epithelial cells; blocking the mice’s ability to make lac-phe erased the previously observed appetite suppression and weight loss.

Finally, a statistical analysis of people in the Atherosclerosis Study who lost weight during the multi-year study and follow-up period found a significant association between metformin use, lac-phe production and weight loss.

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

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

Reference: “Lac-Phe Mediates the Effects of Metformin on Food Intake and Body Weight” by 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. Clish, Usman A. Tahir, Robert E. Gerszten, Mark D. Benson, and Jonathan Z. Long, 18 Mar 2024, Metabolism of nature.
DOI: 10.1038/s42255-024-00999-9

Researchers at Beth Israel Deaconess Medical Center, Harbor-UCLA Medical Center, Cedars-Sinai Medical Center, Baylor College of Medicine, the University of Colorado, the University of Virginia, and the Broad Institute contributed to the work.

The study was financed by the National Institutes of Health (grants GM113854, K08HL145095, DK124265, DK136526, HHSN2682015000031, HSN26800004, UM1DK078616, and 1R01HL151855), a grant from the American Medical Association, and the Dean of the Stanford School of Medicine.

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