Researchers at UC Berkeley have identified a compound called TOFA that may help burn fat without the muscle loss associated with GLP-1 drugs like Ozempic, Wegovy, and Zepbound, according to a study published August 21 in Science Advances. The compound, tested in mice, activates metabolic pathways to increase energy expenditure while preserving lean mass.
The study, led by Anders Näär, a professor of metabolic biology and nutrition at UC Berkeley and senior author of the research, highlights TOFA’s potential as a complementary therapy to GLP-1 medications, which primarily suppress appetite. Unlike these drugs, TOFA works by boosting the body’s metabolic rate, a strategy that avoids the muscle loss and nutritional deficiencies linked to current weight-loss treatments.
Experimental compound helps burn fat without muscle loss
TOFA, first discovered in the 1970s, belongs to a class of compounds known as ACC inhibitors. However, unlike other ACC inhibitors that can raise triglyceride levels, TOFA uniquely activates PPARα and PPARδ, receptors that promote fat burning and energy expenditure. In mouse trials, TOFA improved insulin sensitivity, reduced triglycerides, and enhanced fatty liver disease markers without depleting muscle mass. Body weight responds to two levers: taking in fewer calories, or spending more energy,
said Näär. GLP-1s work almost entirely on the first, so we went after the second.
In experiments, TOFA increased energy use by up to 18% in mice, with no increase in physical activity or body temperature. The compound also blocks two enzymes involved in the production of fat and cholesterol. In animal studies, combining TOFA with semaglutide, the active ingredient in Ozempic and Wegovy, or tirzepatide, the active ingredient in Zepbound, produced greater weight-loss results than either treatment alone. Näär emphasized that TOFA is envisioned as a complementary rather than replacement therapy for GLP-1 drugs.
GLP-1 medications, such as semaglutide and tirzepatide, are highly effective for weight loss but carry risks like gastrointestinal side effects and muscle loss. Researchers at UC Davis estimate that patients may lose up to 20% of lean mass during rapid weight loss, a concern highlighted in a report. Muscle loss is a critical issue because it can weaken the body and make maintaining weight loss more difficult. Muscle plays a critical role in regulating blood sugar and maintaining metabolism,
said a researcher cited in source 3. When people lose muscle along with fat, they can become weaker and may find it more difficult to maintain weight loss over time.
A promising new weight loss and diabetes treatment helps
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. He noted that some benefits of GLP-1 drugs are unexpected, such as reduced alcohol consumption. Some [benefits] 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 also highlighted cardiovascular improvements linked to GLP-1 drugs. 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 added that GLP-1 drugs may already be prescribed off-label to treat inflammation, though this carries risks due to unknown effects in non-approved populations.
Adverse effects reported with GLP-1 drugs include gastrointestinal issues, but Heymsfield noted that the long-term risks of muscle loss and nutritional deficiencies remain under study. It looks like it’s not just the weight loss, but these drugs that actually have themselves some properties that improve inflammation,
he said, adding that this effect is being actively studied.
New weight loss drug may burn fat without muscle
Despite promising results, TOFA has only been studied in animals. Researchers caution that human trials are needed to confirm safety and efficacy. The study’s authors, including Näär, emphasized that TOFA is in the early stages of development. We need to determine whether these findings translate to humans, Näär said, noting that the compound’s mechanism differs from existing therapies.
The research team is exploring ways to preserve muscle mass in obesity treatment, such as increased protein intake and drugs like androgen-type therapies.
The study’s authors stress that further research is required to evaluate long-term effects and safety.
