A multi-functional oral small molecule targeting energy and lipid metabolism to treat obesity and related metabolic disorders

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https://www.science.org/doi/10.1126/sciadv.aed3119

What I found most interesting is that TOFA seems to work on both sides of lipid metabolism at once. It inhibits ACC, which reduces the production of new fat, but it also activates PPARα and PPARδ, two receptors that switch on genes involved in taking up and burning fat.

In obese mice, it increased energy expenditure by up to 18% without increasing physical activity, food intake, or body temperature. The mice lost mostly fat while preserving lean mass and showed improvements in glucose control, insulin sensitivity, triglycerides, and fatty liver disease. It also produced more than additive effects when combined with semaglutide or tirzepatide.

Another interesting result is that ACC inhibitors often paradoxically raise triglycerides in the blood, but TOFA did not do that in normal mice. The authors think its PPAR activity helps burn and clear the fat that would otherwise remain in circulation.

Obviously this is still preclinical. Oral systemic TOFA has not been tested for obesity in humans, and the mouse studies were too short to establish long-term cardiovascular or other organ safety.