Glucophage Activates the Same Pathway as Sprint Exercise to Reduce Appetite

Glucophage (Metformin, Bristol-Myers Squibb) has shown weight loss effects by activating a hunger-reducing pathway, according to Jonathan Long, PhD, an assistant professor of pathology at Baylor University and co-senior author of a study published in Nature Metabolism. Glucophage, an oral medication, triggers an “anti-hunger” molecule called lac-phe, which is normally triggered after vigorous exercise.

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“Until now, the way glucophage, which is prescribed to control blood sugar levels, also brings about weight loss has been unclear,” said Long in the press release. “[But] understanding how these pathways are controlled may lead to viable strategies to lower body mass and improve health in millions of people.”

Compared with popular weight loss injections like semaglutide, glucophage only leads to a small amount of body weight loss (15% compared with 2%, respectively). However, understanding the mechanisms of weight loss can lead to the development of drugs that have a larger impact on weight loss.

In 2022, researchers from Baylor, Stanford, and associated universities first discovered lac-phe, a molecule made by intestinal epithelial cells—the name lac-phe is actually derived from the words ‘lactate’ and ‘phenylalanine.’ Phenylalanine is an amino acid that is produced as a byproduct during lactate production. Abundant after exercise (especially vigorous exercise), it also decreases feelings of hunger.

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

In a study of laboratory mice with obesity, glucophage increased lac-phe levels which resulted in the consumption of less food. In this animal cohort, “lac-phe levels go through the roof and stay high for many hours,” Long observed.

When investigators inhibited lac-phe production in mice, they no longer had any appetite suppression and they regained weight. “The involvement of the intestinal epithelial cells suggests a layer of gut-to-brain communication that deserves further exploration,” Long said in the press release.

In a separate study evaluating glucophage for people with type 2 diabetes, the drug significantly increased lac-phe in the blood after 12 weeks. These results were confirmed in a study evaluating glucophage for patients with atherosclerosis, with investigators observing meaningful association between weight loss, lac-phe production, and glucophage.

Glucophage affects weight the same as doing a sprinting exercise, since both activate the same pathway, Long said. Investigators should investigate if glucophage activates any other signals that aid in weight loss.

“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,” Long said in the press release. “I think what we’re seeing now is just the beginning of new types of weight loss drugs.”

REFERENCE

Weight loss caused by common diabetes drug tied to “anti-hunger” molecule in study. Stanford Medicine. News Release. March187, 2024. Accessed on March 18, 2024. https://www.eurekalert.org/news-releases/1037636