Researchers at UC Berkeley have identified an experimental compound, 5-tetradecyloxy-2-furoic acid (TOFA), that increases energy expenditure to burn fat without causing the lean muscle loss associated with GLP-1 medications. Published August 21 in Science Advances, the animal study shows potential for combining TOFA with drugs like Ozempic and Wegovy.
Targeting Energy Expenditure Rather Than Restricting Calories
While blockbuster medications such as Ozempic, Wegovy, Mounjaro, and Zepbound have revolutionized obesity and diabetes management over the past several years, they operate primarily on a single mechanism. By mimicking GLP-1 hormones, these drugs suppress appetite and reduce food intake, effectively lowering calorie consumption. Yet that reliance on appetite suppression creates distinct trade-offs for patients, including gastrointestinal side effects, nutritional deficiencies, and a notable drop in lean muscle mass.
Researchers at the University of California, Berkeley are investigating an alternative approach designed to attack the problem from the opposite direction. Instead of lowering the amount of energy a person takes in, their strategy seeks to raise the amount of energy the body burns. In a study published August 21 in Science Advances, the research team demonstrated that a molecular compound known as TOFA interferes with the production of lipids like cholesterol and triglycerides while simultaneously driving up cellular energy use.
In experiments with mice, animals treated with TOFA burned up to 18% more energy without eating less or exercising more.
Unlike GLP-1 medications, which primarily work by suppressing appetite, TOFA appears to boost the body’s metabolism, allowing it to burn more energy without reducing food intake. The compound also blocks two enzymes involved in the production of fat and cholesterol.
Muscle plays a critical role in regulating blood sugar and maintaining metabolism. When people lose muscle along with fat, they can become weaker and may find it more difficult to maintain weight loss over time. According to researchers at UC Davis, people taking GLP-1 medications can lose significant amounts of lean muscle mass during rapid weight loss.
US GLP-1 use for overweight or obesity climbed 587% between 2019 and 2024, and about 18% of adults reported using one by late 2025, according to KFF tracking data.
Doctors have used GLP-1 drugs for weight loss for about five years, and researchers say some of the benefits are catching them off guard. Dr. Steven Heymsfield, a professor at Pennington Biomedical Research Center and director of the Metabolism Body Composition Laboratory, has studied GLP-1 drugs for 15 years.
“Some were predicted beforehand and others were completely surprising,” Heymsfield said. “The unpredictable type is that people report less desire to drink alcohol. And now there are studies beginning to show that that’s been confirmed.”
Heymsfield said people with arthritis have unexpectedly reported improved symptoms, less pain and less inflammation, and can walk better. He said studies have shown people need fewer knee replacements as a result. Heymsfield also pointed to cardiovascular improvements.
“We’ve already shown with GLP-1s that they reduce the risks of heart attacks, cardiovascular disease and mortality,” he said. “And it’s thought that it’s not just the weight loss, but processes like inflammation also are improving that might mediate these effects on the heart.” He said not all benefits are tied directly to weight loss.
“In simple terms, when you lose weight, you are decreasing caloric intake in terms of proteins, carbohydrates, and fats. The brain needs glucose. Fat by itself cannot be turned into glucose, and that is the major reason why muscle loss is inevitable when you decrease caloric intake,” said Dr. Caroline Apovian, co-director of the Center for Weight Management and Wellness at Brigham and Women’s Hospital, via Massachusetts General Hospital.
Strength training and high protein intake are the two most important habits for anyone on a GLP-1, according to Dr. Chuck Svendsen, chief medical officer at Astride Health and a former bariatric surgeon.
Unlocking a Compound First Discovered in the 1970s
TOFA has only been tested in mice so far, but researchers say the early findings could point to a new approach to treating obesity and diabetes.
When obese mice were treated with TOFA, they improved insulin sensitivity and glucose control, reduced triglycerides, and targeted fatty liver disease.
Synergy with Existing GLP-1 Medications
GLP-1 medications have transformed the treatment of obesity, diabetes, and fatty liver disease over the past several years. Drugs sold as Ozempic, Wegovy, Mounjaro, and Zepbound can produce substantial weight loss while helping patients control blood sugar. But these medications can also cause problems. Some patients experience nausea and other gastrointestinal side effects. Because GLP-1 drugs reduce appetite and food intake, they may also contribute to nutritional deficiencies and loss of muscle, potentially increasing the risk of frailty and other long-term health issues.
Readers should consult qualified healthcare professionals regarding metabolic treatments, weight management strategies, and individual health risks.
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