Researchers at UC Berkeley have identified a compound that could treat obesity, diabetes, and fatty liver disease differently than current GLP-1 drugs like Ozempic, Wegovy, Mounjaro and Zepbound.
How it works:
- GLP-1s work by reducing appetite and food intake, which can cause side effects like nausea, nutritional deficiencies, and muscle loss.
- The new compound, 5-tetradecyloxy-2-furoic acid (TOFA), works on the other side of the energy equation: it increases energy expenditure.
- TOFA has a dual mechanism. It is an ACC inhibitor that blocks production of lipids like cholesterol and triglycerides, AND it activates cellular receptors PPARα and PPARδ that turn on genes to help cells take up fat and burn it for energy.
Results in mice, published in Science Advances:
- Cells burned up to 18% more energy with no change in food intake, physical activity, or body temperature.
- Obese mice lost weight from fat with no significant loss of lean muscle mass.
- Improved insulin sensitivity, glucose control, lowered triglycerides, and improved features of fatty liver disease.
- Unlike other ACC inhibitors that reached mid-stage clinical trials, TOFA did not raise triglycerides, a major heart risk that has prevented approval of others in this class.
Combination potential:
- When researchers gave mice two separate drugs to replicate TOFA’s two actions, it was less effective than TOFA alone.
- When combined with GLP-1 drugs semaglutide and tirzepatide, TOFA worked additively or synergistically, leading to greater improvements in weight, glucose, insulin, and triglycerides than either alone. Researchers view it as complementary, not a replacement.
TOFA was first discovered in the 1970s. The study was led by senior author Anders Näär, professor of metabolic biology and nutrition at UC Berkeley, and first author Justin Y. Lee.