An “anti-hunger” molecule produced after vigorous exercise is responsible for the moderate weight loss caused by the diabetes medication metformin, according to results from a study in mice and humans, carried out by researchers at Stanford Medicine and at the Harvard Medical School. The molecule, lac-phe, was discovered by Stanford Medicine researchers in 2022.

The latest finding adds new weight to the notion of a critical role for lac-phe, in metabolism, exercise and appetite, and could also help pave the way to development of a new class of weight loss drugs.

“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.”

Long and Mark Benson, MD, PhD, an assistant professor of medicine at the Harvard Medical School, are co-senior authors of the team’s published study in Nature Medicine. Shuke Xiao, PhD, is lead author of the report, which is titled “Lac-Phe mediates the effects of metformin on food intake and body weight.”

Many people with diabetes who are prescribed metformin lose around two to three percent of their body weight within the first year of starting the drug. “The effects of metformin on body weight appear to be associated with suppression of food intake rather than changes in nutrient absorption or energy expenditure,” the authors noted. Although this amount of weight loss is modest when compared with the 15% or more often seen by people taking semaglutide drugs, the discoveries that led to those drugs also grew from observations of relatively minor, but reproducible, weight loss in people taking first-generation versions of the medications.

When Long and colleagues at Baylor University discovered lac-phe in 2022, they were on the hunt for small molecules responsible for curtailing hunger after vigorous exercise. What they described as the “Frankenbaby” of lactate—a byproduct of muscle fatigue—and the amino acid phenylalanine. They dubbed the hybrid molecule lac-phe and went on to show that it’s not only more abundant after exercise but it also causes people (as well as 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 an obvious candidate because as it stimulates the breakdown of glucose (thus reducing blood sugar levels) it can trigger the generation of lactate.

In their newly reported study the researchers found that diet-induced obese laboratory mice given metformin had increased levels of lac-phe in their blood. The animals ate less than their peers and lost about two grams of body weight during the nine-day experiment. “We also observe that lac-phe levels are reduced by fasting and increased by re-feeding,” the investigators pointed out.

Long and his colleagues also analyzed stored blood plasma samples from people with type 2 diabetes before and 12 weeks after they had begun taking metformin to control their blood sugar. The results confirmed significant increases in the levels of lac-phe in people after metformin compared with their levels before treatment. “Robust increases in lac-phe levels were observed in individuals after 12 weeks of metformin therapy,” they wrote. The scientists similarly found that 79 participants in a large, multi-ethnic study of atherosclerosis who were also taking metformin had significantly higher levels of lac-phe circulating in their blood than those who were not taking the drug. “In multivariable regression analyses (adjusted for age, sex, fasting glucose, total cholesterol and hypertension status), participants on metformin had significantly higher circulating levels of lac-phe compared to participants who were not on metformin,” the team noted.

“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.”

CNDP2 is the principal biosynthetic enzyme for basal and exercise-inducible lac-phe, the team explained. Their research using CDNP2-knockout (KO) animals demonstrated that Lac-Phe is made by intestinal epithelial cells in the animals. “Intestinal epithelial CNDP2+ cells, not macrophages, are the principal in vivo source of basal and metformin-inducible lac-phe,” they stated. Blocking the ability of mice to make lac-phe by knocking out the enzyme erased the appetite suppression and weight loss previously observed. Following metformin intake the food intake and body weight changes of the CDNP2-knockout animals were the same as those of control mice. Interestingly, the team also pointed out, “Our data, along with our previous study, shows that CNDP2-KO mice are resistant to both the anti-obesity effects of exercise as well as that of metformin.”

Finally, a statistical analysis of the people in the atherosclerosis study who lost weight during the several-year study and follow-up period found a meaningful association between metformin use, lac-phe production and weight loss. “… mediation analyses support a role for lac-phe as a downstream effector of metformin’s effects on body mass index in participants of a large population-based observational cohort,” the investigators stated. “The collective data, they reported, demonstrate that lac-phe is a critical mediator of metformin’s effects on energy balance.”

“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?”

While acknowledging the limitations of their study, the team further noted that research outlined in a report published in parallel also showed that lac-phe is increased postprandially and also following metformin administration in humans, “thereby confirming and extending the findings reported here.”

Long also noted that, while semaglutide drugs are injected into the bloodstream, metformin is an oral drug that is already prescribed to 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.”

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