Powerful weight-loss medicines have changed the treatment of obesity and type 2 diabetes in only a few years.
Drugs such as Ozempic, Wegovy, Mounjaro and Zepbound can help people eat less, lose substantial amounts of weight and improve blood sugar control.
Researchers are now exploring a very different strategy: helping the body use more energy rather than mainly reducing how much food a person eats.
A research team at the University of California, Berkeley, has studied a compound called 5-tetradecyloxy-2-furoic acid, or TOFA.
In experiments with mice, TOFA increased energy use while also improving several signs of poor metabolic health. The research was published in the journal Science Advances.
Obesity develops when the body stores more energy than it uses over a long period.
Biology is much more complicated than simply counting calories, because appetite, hormones, genes, sleep, activity and the environment all influence body weight.
Even so, researchers often describe weight control as involving two broad sides: energy coming in through food and energy being used by the body.
Today’s highly effective GLP-1-based medicines mainly work on the first side. They affect signals involved in appetite and digestion, helping many people feel full sooner and eat less.
This can produce major health benefits, but reduced food intake may also make it harder for some people to consume enough protein and other nutrients.
Weight loss can also include loss of muscle as well as fat. Maintaining muscle is important because muscle supports strength, movement, balance and healthy aging. Researchers are therefore interested in treatments that could reduce body fat while better preserving lean tissue.
Senior author Anders Näär, a professor of metabolic biology and nutrition at UC Berkeley, and his colleagues decided to investigate the other side of the energy equation.
Instead of concentrating on appetite, they studied whether metabolism could be shifted so that cells used more energy. Their experiments centered on TOFA, a compound that scientists have known about since the 1970s.
TOFA belongs to a group of compounds that can block enzymes called acetyl-CoA carboxylases, or ACCs. These enzymes help the body make fats such as fatty acids and triglycerides. Blocking them can reduce fat production, which has made ACC inhibitors interesting candidates for treating metabolic diseases.
However, earlier ACC inhibitors have faced an important problem. Some have caused triglycerides in the blood to rise, an unwanted effect because high triglyceride levels can contribute to cardiovascular risk. Although several ACC inhibitors reached clinical testing, none has been approved for treating metabolic disease.
The Berkeley researchers found that TOFA appeared to do more than simply reduce the body’s production of fat. It also activated two cellular switches called PPAR-alpha and PPAR-delta. These switches control genes that help cells take in fats and use them as fuel.
This combination appeared to create a coordinated change in metabolism. The cells made less fat while also increasing their ability to burn available fuel. In the mice, energy expenditure increased by as much as 18% without an increase in physical activity or body temperature.
The researchers also reported several improvements related to diabetes and metabolic disease. TOFA improved the animals’ response to insulin and helped control blood glucose. It lowered triglycerides and improved signs of fatty liver disease, a condition in which excess fat accumulates in the liver.
The effect on body composition was especially interesting. Obese mice treated with TOFA lost body fat without a significant reduction in lean muscle mass. If a similar effect could eventually be achieved safely in people, preserving muscle could be an important advantage during weight loss.
First author Justin Y. Lee, who carried out the work while a doctoral student at Berkeley, said TOFA seemed to produce a broader metabolic response rather than simply blocking fat production.
The researchers tested this idea by giving mice two separate compounds, one designed to reduce fat production and another designed to increase energy use. That combination did not produce the same overall metabolic benefits as TOFA alone.
The team then asked whether the new approach might work alongside existing weight-loss medicines. They combined TOFA with GLP-1-based drugs including semaglutide and tirzepatide in mice. The combined treatments produced greater improvements in weight, blood glucose, insulin and triglycerides than either approach used alone.
This suggests that the strategies could potentially complement each other. A GLP-1 medicine could reduce energy intake by lowering appetite, while a TOFA-like treatment could increase the amount of energy the body uses. Näär said the researchers view TOFA as a possible partner for GLP-1 therapy rather than a replacement.
The findings are promising, but there is a major reason for caution: the experiments were conducted in animals. A drug that works well in mice may behave very differently in humans. Researchers still need to determine whether TOFA is safe, what dose might be appropriate and whether the metabolic benefits would occur in people.
Increasing energy expenditure also needs careful study because metabolism affects many organs and biological systems. A treatment that changes fat production and fuel use could have unexpected effects that are not obvious in short animal experiments. Long-term safety would therefore be just as important as weight loss.
The researchers have founded a company called ReRx Therapeutics to help move the work toward possible human treatment.
Before TOFA or a related compound could become a medicine, it would need extensive laboratory testing followed by carefully controlled clinical trials. That process can take years, and many promising experimental drugs never reach patients.
Overall, the study offers an interesting new direction for obesity research. Rather than relying only on appetite suppression, it suggests that scientists may be able to target the body’s energy use while preserving more lean tissue.
The strongest finding is the combination of fat loss, better glucose control and higher energy expenditure in mice, but it remains far too early to know whether the same benefits will appear safely in humans.
The research is important because future obesity treatment may not depend on a single biological pathway. Combining medicines that influence different parts of metabolism could potentially produce stronger results or address some weaknesses of current treatments.
For now, however, TOFA should be viewed as an experimental research compound, not an available alternative to approved weight-loss medicines.
The study was conducted by researchers at the University of California, Berkeley, and was published in Science Advances.
Source: University of California, Berkeley.
