Researchers have identified an oral compound, known as TOFA, that induced substantial weight loss in obese mice by increasing energy expenditure rather than suppressing appetite. The study, led by scientists at the University of California, Berkeley, and published in Science Advances, found that TOFA reduced body weight by an average of 18% in mice without altering their food intake or leading to a significant loss of lean muscle.
This approach contrasts with some current popular weight-loss medications, such as semaglutide, which primarily reduce food intake. While effective for weight loss, these injectable drugs can sometimes cause gastrointestinal side effects and a loss of lean mass, a critical component for daily function and combating aging. Preserving muscle during weight loss is a significant challenge in obesity medicine.
How TOFA Works
Unlike appetite suppressants, TOFA operates within cells by blocking enzymes involved in lipid production, including fats like triglycerides. Simultaneously, it activates cellular receptors that promote fat burning and energy production. In experiments, treated mice burned up to 18% more energy under normal and mildly warm conditions without showing increased activity or a dangerous rise in body temperature.
When TOFA was administered in combination with existing obesity drugs like semaglutide or tirzepatide, the combined treatments resulted in greater reductions in body weight and improvements in blood sugar, insulin, and triglyceride levels compared to either drug alone. Furthermore, mice treated with TOFA maintained their reduced body weight after the treatment concluded, whereas mice previously treated with semaglutide began to regain weight rapidly.
The compound also demonstrated potential benefits in mouse models of metabolic dysfunction-associated steatohepatitis (MASH), a form of fatty liver disease. Mice treated with TOFA showed reduced liver fat, inflammation, and scarring. Importantly, TOFA achieved these liver benefits without increasing blood triglyceride levels, a side effect sometimes associated with other metabolic drugs that can raise cardiovascular concerns.
Study Limitations and Future Considerations
Scientists noted that all animal experiments were conducted on male mice, and further studies are needed to determine if TOFA yields similar results in female animals. The drug has not yet been tested in humans, leaving questions about appropriate dosage, long-term safety, potential toxicities, and subtle side effects unanswered. Experts urge caution, emphasizing that early animal data should be carefully considered against potential unforeseen effects in humans. The complexity of metabolic processes means that manipulating lipid production could have downstream consequences that are not yet understood.
Despite these caveats, the compound could eventually offer benefits to patients, either as a standalone treatment or in combination with other therapies. Some researchers involved in the study have disclosed financial ties to a company that holds an option to develop the discovery.