‘Anti-Hunger’ Molecule May Transform Weight Loss

The ‘anti-hunger’ molecule lac-phe was discovered by Stanford Medicine in 2022, it is produced after vigorous exercise and it is responsible for the moderate weight loss that is caused by the diabetes medication metformin, according to a new study in mice made jointly by Stanford Medicine and Harvard Medical School. 

“Until now, the way metformin, which is prescribed to control blood sugar levels, also brings about weight loss has been unclear,” said Jonathan Long, PhD, an assistant professor of pathology. “Now we 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 lower body mass and improve health in millions of people.”

Some people with diabetes who are prescribed metformin lose 2-3% of their body weight within a year of taking the drug. This amount may be modest compared to the 15% or more that some people experience when taking semaglutide drugs like Wegovy or Ozempic, but the discoveries that led to the development of those drugs also began with modest but reproducible begins of weight loss in those taking first generation version of those medications. Also, another difference between the drugs is that semaglutide drugs are injected into the bloodstream while metformin is an oral drug that is already being prescribed to millions of people. 

The research in 2022 found that a byproduct of muscle fatigue and an amino acid called phenylalanine dubbed lac-phe was more abundant after exercise and caused people, mice, and even racehorses to feel 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 to think about other aspects of lactate metabolism.”

Metformin was selected as a candidate because it stimulates the breakdown of glucose and can trigger the generation of lactate: First, obese mice given metformin were found to have increased levels of lac-phe in their blood, and they ate less than their untreated peers, losing weight during the 9-day experiment.  Next, blood plasma samples from participants with type 2 diabetes who took metformin for 12 weeks to control their blood sugar experienced significant increases in the levels of lac-phe compared to levels before treatment. Finally, 79 participants in a study of atherosclerosis taking metformin were found to have higher levels of lac-phe circulating in their blood than those not taking the drug. 

Additional research revealed that lac-phe is made by intestinal epithelial cells in animals, blocking the ability of mice to produce the molecule voided the appetite suppression and weight loss benefits that were previously observed. A statistical analysis of those in the atherosclerosis study found a meaningful association between metformin use, lac-phe production, and weight loss among the participants who were treated with metformin. 

“It was nice to confirm our hunch experimentally,” Long said. “The magnitude of effect of metformin on lac-phe production in mice was as great as 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.”

“The fact that metformin and sprint exercise affect your body weight through the same pathway is both weird and interesting,” Long said. “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?”

“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.”

Accompanying video: https://www.youtube.com/watch?v=S7o9I1sP5rY&t=1s