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Metformin Tied to Production of “Anti-Hunger” Molecule

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The same “anti-hunger” molecule stimulated by vigorous exercise can also be produced by the common diabetes drug metformin, according to a new study from Stanford University. This could be the cause of moderate weight loss when taking metformin, the research suggests.

The study is published in Nature Medicine.

Understanding the relationship between metformin and weight loss

Stanford researcher Dr. Jonathan Long has been investigating the role of a molecule called lac-phe, which plays an important role in metabolism, exercise and appetite.

Long and colleagues previously found that lac-phe is more abundant after vigorous exercise and curbs feelings of hunger in people, mice and even racehorses after a hard workout. It is a combination of lactate – a byproduct of muscle fatigue – and an amino acid called phenylalanine.

“There is an intimate connection between lac-phe production and lactate generation,” said Long, assistant professor of pathology at Stanford and co-senior author of the study. “Once we understood this relationship, we started to think about other aspects of lactate metabolism.”

Metformin, a commonly prescribed diabetes drug, reduces blood sugar by stimulating the breakdown of glucose and can also trigger lactate generation. Many people with diabetes who start taking metformin can lose 2–3% of their body weight within the first year of taking the drug.

In the new study, Long and colleagues investigated the potential link between lac-phe and metformin on weight loss.

Metformin induces lac-phe production

In their investigation, the researchers found that obese laboratory mice had increased lac-phe in their blood when treated with metformin. These mice also ate less than the control mice and lost approximately 2 grams of body weight over a 9-day study period.

“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.”

However, blocking the production of lac-phe – which takes place in intestinal epithelial cells, the cells that line the intestines – in the mice also blocked the effects on appetite and weight loss.

“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?”

To compare these results to humans, the researchers analyzed stored blood samples from people with type 2 diabetes before and after beginning metformin treatment, finding significantly higher lac-phe levels by 12 weeks of treatment.

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Next, they analyzed data from 79 participants receiving metformin who took part in a multi-ethnic atherosclerosis study. This revealed significantly higher lac-phe levels in the blood compared to those not taking metformin.

Statistical analysis of those who lost weight during the atherosclerosis study and follow-up period found a meaningful association between metformin use, lac-phe production and weight loss.

“Until now, the way metformin, which is prescribed to control blood sugar levels, also brings about weight loss has been unclear,” said Long. “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.”

“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,” Long added.

Reference: Xiao S, Li VL, Lyu X, et al. Lac-Phe mediates the effects of metformin on food intake and body weight. Nat Metab. 2024:1-11. doi: 10.1038/s42255-024-00999-9

This article is a rework of a press release issued by Stanford University. Material has been edited for length and content.