Researchers at the University of California, Berkeley have identified a chemical compound that causes weight loss in mice by boosting metabolism rather than suppressing appetite.
In a four-week laboratory study, obese mice given the compound known as 5-tetradecyloxy-2-furoic acid, or TOFA, lost 18 percent of their body weight. The weight loss occurred even though the rodents maintained their normal food intake and physical activity levels.
Further analysis revealed that virtually all of the weight lost by the mice came from fat tissue rather than muscle mass. This contrasts with popular GLP-1 weight loss drugs, such as Ozempic and Wegovy, which often cause patients to lose significant amounts of muscle alongside body fat.
Dr Anders Näär, a metabolism researcher and senior author of the study, explained the fundamental difference between the two approaches to weight management.
"Body weight responds to two levers: taking in fewer calories, or spending more energy," Näär said. "GLP-1s work almost entirely on the first, so we went after the second."
Speaking to ScienceAlert, Näär noted that the treated animals maintained their baseline habits and body temperature while burning energy at a significantly higher rate.
"Food intake was unchanged, physical activity was unchanged, and body temperature did not rise, yet whole-body energy expenditure increased by as much as 18 percent," Näär said.
The University of California, Berkeley is a major public research university located in Berkeley, California. Weight loss medications have seen surging demand across the United States in recent years. Popular injectable drugs like Ozempic and Wegovy contain semaglutide and belong to a class of medications known as glucagon-like peptide-1, or GLP-1, receptor agonists. These drugs work by mimicking natural gut hormones that signal fullness to the brain and delay stomach emptying.
While GLP-1 medications have taken America by storm for their ability to cause weight loss by suppressing appetite, they are associated with several side effects. Patients frequently report nausea, nutritional deficiencies, and muscle loss. Preserving muscle tissue is critical because muscle loss can lead to physical frailty and increase the risk of dangerous falls in later life.
Fat Burning and Cellular Metabolism
The study, published in the peer-reviewed journal Science Advances, examined the impact of oral TOFA administration on mice that had previously developed obesity after being fed a high-fat diet. Science Advances is an open-access scientific journal published by the American Association for the Advancement of Science. Researchers administered the compound orally to the obese rodents twice a day over a period of four weeks.
Analysis during the trial suggested that TOFA caused cells to take up more fat and burn up to 18 percent more energy than normal. The researchers confirmed there was no evidence that the compound stopped the mice from absorbing calories or prompted them to move more than previously.
In addition to losing fat, the mice exhibited greater insulin sensitivity and improved blood sugar control. Insulin sensitivity describes how effectively body tissues respond to insulin to clear glucose from the bloodstream. High insulin sensitivity helps regulate blood sugar levels and reduces the risk of metabolic complications.
Scientists noted that because the mice continued to consume the exact same amount of food as before, they avoided nutritional deficiencies and successfully maintained their muscle mass. Retaining lean muscle mass is essential for supporting overall metabolic health and physical mobility.
The research paper reported no evidence that TOFA caused a rise in body temperature or elevated triglycerides in the test mice. The paper did not state whether the treatment caused vomiting in the rodents.
History of TOFA and Past Challenges
TOFA is not a newly created molecule; it was first discovered in the 1970s and tested previously as a potential treatment for metabolic disease. Metabolic disease refers to a cluster of conditions, including high blood pressure, high blood sugar, excess body fat around the waist, and abnormal lipid levels, that raise the risk of cardiovascular illness and stroke.
However, TOFA was not developed as a medical treatment at the time after scientists found that it raised blood levels of triglycerides. Triglycerides are a common type of fat found in the blood, and elevated triglyceride levels can harden arteries, increasing the risk of a heart attack or stroke. The scientists in the new study emphasized that their test mice showed no signs of elevated triglycerides.
Combining TOFA with GLP-1 Medications
In a second arm of the study, researchers administered both TOFA and GLP-1 drugs to a separate group of obese mice. Overall, researchers recorded greater weight loss and superior metabolic improvements in this group compared to mice given only TOFA or only a GLP-1 drug.
Mice receiving the dual treatment lost about 10 percent of their body weight compared to mice on single treatments over a shorter period than the main study. Researchers believe this enhanced result occurred because the mice were both burning more energy due to TOFA and eating less due to the GLP-1 drug.
Next Steps and Human Development
The scientists emphasized that their research remains in its early stages and that TOFA has only been tested in mice. It is not yet clear whether the compound will prove safe and effective when administered to human patients.
Researchers now plan to conduct further investigations into TOFA for potential use in humans. Näär and two of his co-authors are co-founders of ReRx Therapeutics, a biotechnology company that is developing TOFA as a potential clinical treatment, although they noted that bringing the drug through human trials could take several years.
