Most of today's highly effective weight-loss medications work partly by reducing appetite and helping people eat less. Scientists are now exploring a very different strategy: helping the body use more energy instead.
In a study published in Science Advances, researchers found that an experimental compound called TOFA increased energy use in mice without reducing how much they ate or how active they were. Obese mice given the compound lost body fat without a significant loss of lean mass and also showed improvements in blood sugar control and other measures of metabolic health.
The results are intriguing, but very preliminary. TOFA has not been tested for safety or effectiveness in humans. Several researchers involved in the study also have a financial interest in a company created to develop the compound.
“Body weight responds to two levers: taking in fewer calories, or spending more energy,” said Anders Näär, a professor of metabolic biology and nutrition at the University of California, Berkeley, and senior author of the study. “GLP-1s work almost entirely on the first, so we went after the second.”
Drugs such as semaglutide, sold as Ozempic and Wegovy, and tirzepatide, sold as Mounjaro and Zepbound, can lead to substantial weight loss. Reduced appetite and food intake are important parts of how those medications work, although their effects on the body are more complex than appetite suppression alone.
TOFA works differently.
The compound has been studied by scientists since the 1970s. It interferes with the body's production of certain fats, but the researchers found that it also appears to switch on processes that help cells use fat for energy.
That combination may be important. Earlier drugs designed to interfere with fat production have sometimes caused triglyceride levels to rise, which could increase cardiovascular risk. In the new mouse experiments, TOFA did not produce that effect.
“TOFA appears to engage a coordinated metabolic response,” said first author Justin Y. Lee, who conducted the research as a doctoral student at UC Berkeley and is now a postdoctoral researcher at the University of California, San Francisco. “It is not simply blocking lipid synthesis. It is also activating energy expenditure pathways that may help the body handle excess lipid and glucose more effectively.”
In some experiments, mice treated with TOFA used as much as 18% more energy. That increase did not appear to come from greater physical activity or higher body temperature.
When researchers tested the compound in mice with obesity, the animals lost fat without a significant decline in lean mass. That could make the approach particularly interesting because weight loss can involve losing both body fat and muscle.
Maintaining muscle matters for strength, mobility and long-term health, particularly as people get older. But the mouse findings do not establish that TOFA would protect muscle during weight loss in people.
The researchers also reported improvements in insulin sensitivity, blood sugar regulation and triglyceride levels, along with improvements in features of fatty liver disease.
Another set of experiments examined what happened when TOFA was paired with existing weight-loss drugs.
Mice receiving TOFA along with either semaglutide or tirzepatide had greater improvements in body weight and several metabolic measures than mice receiving either treatment alone.
“In our combination experiments, TOFA worked additively or synergistically with the GLP-1 appetite suppressing drugs, so we view it as complementary rather than as a replacement,” Näär said.
That does not mean TOFA is ready to be combined with GLP-1 medications in people. Researchers have not yet established whether the compound is safe in humans, what dose might be appropriate or whether the effects seen in mice will translate to people at all.
That is a major hurdle. Many experimental drugs that appear promising in animals never become treatments because later studies find they are ineffective, cause unacceptable side effects or work differently in humans.
The researchers have formed a company, ReRx Therapeutics, to pursue further development of TOFA. Näär, Lee and study co-author Prabha Ibrahim are co-founders, officers or equity holders in the company, which has optioned UC Berkeley intellectual property related to the research.
For now, the study offers evidence for a different way scientists might approach weight management: targeting how much energy the body uses rather than relying primarily on reducing how much a person eats. Whether that strategy can safely help people lose fat while maintaining muscle remains an unanswered question.
The research was supported by discretionary funds from the University of California, Berkeley, with assistance from the UCSF Liver Center and the University of Michigan Animal Phenotyping Core.
Several researchers have a commercial interest in the findings. Anders Näär, Justin Y. Lee and Prabha Ibrahim are co-founders, officers or equity holders of ReRx Therapeutics, which has optioned UC Berkeley intellectual property related to TOFA and this research.