Old oral drug triggers fat loss in mice while sparing muscle mass

A group of scientists from the University of California, Berkeley identified the decades-old oral compound TOFA as a potent inducer of weight loss in obese male mice, achieving an average 18% reduction in body weight without altering food consumption or causing significant loss of lean mass. The drug works by inhibiting enzymes that synthesize lipids and by stimulating cellular receptors that up-regulate genes involved in fat oxidation and energy production, resulting in up to 18% higher energy expenditure under normal temperatures.

Combining TOFA with existing obesity medicines like semaglutide or tirzepatide produced greater weight loss and better blood-sugar, insulin, and triglyceride profiles than either agent alone, and mice maintained their reduced weight after stopping TOFA, unlike those treated only with semaglutide. Additional experiments indicated that TOFA reduced liver fat, inflammation, and fibrosis in a mouse model of metabolic dysfunction-associated steatohepatitis without raising blood triglycerides.

The research was limited to male mice, and no human testing has occurred, leaving questions about appropriate dosing, long-term safety, and effects in females. Experts caution that early animal results may not translate directly to humans, but the findings suggest a potential new avenue for obesity treatment, possibly in combination with current drugs. Some study authors have equity stakes in ReRx Therapeutics, which holds rights to develop the Berkeley discovery.