Rather than eating less, burn more: Scientists identify a new approach to treating obesity

A drug that prompts the body to expend more energy rather than suppressing appetite could represent a new approach to treating obesity and metabolic diseases. Researchers at the University of California, Berkeley, tested the molecule TOFA in mice and found that it helped burn fat, improved insulin sensitivity and did not cause significant muscle loss.

The findings were published in the scientific journal Science Advances.

Over the past five years, GLP-1 drugs, including Ozempic, Wegovy, Mounjaro and Zepbound, have significantly transformed the treatment of obesity and diabetes. They effectively reduce appetite and help control blood sugar levels, but some patients experience nausea and other gastrointestinal side effects. In addition, because weight loss involves eating less, it can lead to a reduction in muscle mass as well as body fat.

Researchers at Berkeley decided to target a different mechanism — not how much energy enters the body, but how much it uses.

The molecule 5-tetradecyloxy-2-furoic acid, or TOFA, blocks the production of lipids, including cholesterol and triglycerides, while simultaneously activating genes involved in fat burning and energy production.

In experiments, mouse cells used about 18% more energy. The animals did not become more physically active, nor did their body temperature increase. In obese mice, treatment with TOFA reduced fat mass without causing significant loss of muscle tissue.

The drug also improved insulin sensitivity and glucose control, reduced triglyceride levels and improved several markers of fatty liver disease.

TOFA has been known to scientists since the 1970s and belongs to a class of compounds known as ACC inhibitors. These compounds block lipid production in the body.

However, earlier drugs in this class failed to become standard treatments for metabolic diseases. Many of them paradoxically increased triglyceride levels, potentially raising the risk of cardiovascular problems.

According to the researchers, TOFA’s potential advantage lies in its dual action. In addition to blocking lipid synthesis, it activates PPARα and PPARδ receptors, which trigger processes involved in the uptake and burning of fat by cells. This mechanism may help prevent an increase in triglyceride levels.

The researchers also examined what happens when TOFA is combined with GLP-1 drugs. In experiments involving mice, combining TOFA with semaglutide, sold under the brand names Ozempic and Wegovy, or tirzepatide, marketed as Mounjaro and Zepbound, resulted in greater weight loss and improved glucose, insulin and triglyceride control compared with either treatment alone.

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