A new study conducted by researchers at Stanford Medicine and Harvard Medical School has found that the diabetes medication metformin causes weight loss by triggering the production of an “anti-hunger” molecule called lac-phe, which is also produced after vigorous exercise. This discovery may lead to the development of a new class of weight loss drugs.
Lac-phe, short for lactate-phenylalanine, was first discovered by Stanford Medicine researchers in 2022. The molecule is formed when lactate, a byproduct of muscle fatigue, combines with the amino acid phenylalanine. The researchers found that lac-phe is not only more abundant after exercise but also causes people, mice, and even racehorses to feel less hungry immediately after a hard workout.
“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 and co-senior author of the study. “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.”
The researchers discovered that obese laboratory mice given metformin had increased levels of lac-phe in their blood, ate less than their peers, and lost about 2 grams of body weight during the nine-day experiment. They also analyzed blood plasma samples from people with Type 2 diabetes before and after they began taking metformin and found significant increases in lac-phe levels after treatment.
Further research revealed that lac-phe is made by intestinal epithelial cells in animals, and blocking the ability of mice to make lac-phe erased the appetite suppression and weight loss previously observed. A statistical analysis of people in a large, multi-ethnic study of atherosclerosis who lost weight during the study found a meaningful 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 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?”
Long believes that these findings suggest there may be a way to optimize oral medications to affect hunger and energy balance pathways to control body weight, cholesterol, and blood pressure, potentially leading to new types of weight loss drugs.