A molecule that has been mostly disregarded since the Nixon administration recently received a second look in a Berkeley lab, and the preliminary findings are making metabolic researchers take notice.
Since the 1970s, biochemists have recognized TOFA, short for 5-tetradecyloxy-2-furoic acid, as an ACC inhibitor, a class of molecules that prevent the body from producing fats like triglycerides and cholesterol. Once, the category showed promise. The majority of ACC inhibitors ended up raising triglyceride levels, which is precisely the wrong direction for a medication intended to treat metabolic disease, after a series of clinical trials ran into the same brick wall. The entire field of study essentially came to a standstill.
Professor Anders Münär and his colleagues at UC Berkeley discovered that TOFA performs a function that the older compounds did not. In addition to acting as an ACC inhibitor, it also activates two cellular receptors called PPARα and PPARδ, which turn on genes that draw fat into cells and burn it as fuel. Energy expenditure increased by up to 18% in obese mice given the compound, but neither the animals’ food intake nor their movement patterns changed. The fat was removed. Lean muscle mass remained largely unaltered. And the issue with triglycerides that caused earlier ACC inhibitors to fail? It didn’t show up. It appears to be prevented by the dual mechanism.
More attention should be paid to that muscle detail than it typically receives in these kinds of announcements. Over the past five years, GLP-1 drugs like Ozempic, Wegovy, Mounjaro, and Zepbound have significantly changed how obesity is treated. They function, frequently in dramatic ways, and at this point, patient demand for them verges on becoming a cultural phenomenon.
However, they function by decreasing food intake, suppressing appetite, and putting the body in a calorie deficit. The body doesn’t always make a clear decision between muscle and fat when confronted with that shortfall. Researchers at UC Davis have calculated that when GLP-1 medications cause rapid weight loss, some patients lose about 20% of their lean mass. Physical weakness, a slower metabolism, and a body that is more difficult to maintain at a lower weight over time are all consequences of muscle loss. This is the portion of the GLP-1 story that isn’t always featured on the front page.
Áär used almost purposefully simple language to explain the difference. “Eating fewer calories or expending more energy are the two levers that affect body weight. We pursued the second since GLP-1s focus almost entirely on the first. Although it is clean, the framing is sturdy. TOFA differs mechanistically from all currently approved treatments for obesity because it acts on the expenditure side of metabolism rather than the intake side.
In order to determine whether the effects of TOFA could be repeated by combining two different medications—one that suppresses lipid production and another that increases energy use—the researchers also conducted a controlled experiment. The performance of the combination was inferior to that of TOFA alone. This discovery suggests something significant: rather than two separate effects occurring simultaneously, TOFA’s actions appear to function as an integrated metabolic response. After 50 years on the shelf, this molecule is gaining significant attention, which may be explained by the fact that such coordination is genuinely hard to replicate artificially.
Combining TOFA with currently available GLP-1 drugs is the most immediately useful discovery. In mice, weight, glucose, insulin sensitivity, and triglycerides all improved more when TOFA was combined with semaglutide or tirzepatide than when either treatment was used alone. According to Rodríguezär, TOFA is “complementary rather than a replacement,” which likely reflects both the science and a certain level of commercial realism. Given the size of the GLP-1 market, a compound that improves rather than replaces those medications has a much more promising future.
Human testing has not yet been done on any of this, and that is a significant gap. There is a long history of promising outcomes from mouse models that were not translated. The Berkeley team acknowledges that they are aware of this. Nevertheless, they have already established ReRx Therapeutics, a company supported by Nucleate and Berkeley SkyDeck, to continue the research.
That is not insignificant. Typically, scientists don’t take the time to start a startup because they have private doubts about the results. The underlying concept—burning more rather than eating less—is one that metabolic medicine has been circling for years without a clear solution, regardless of whether TOFA eventually makes it to a clinic or subtly joins the long list of substances that appeared to be beneficial in animals. This may be the closest to one to date.
