Losing weight can happen via two paths: eating less, or spending more energy. Today’s blockbuster GLP-1 drugs are well-known for their ability to help people eat less, but finding drugs that increase energy expenditure could add another effective option to treat obesity and related metabolic disorders.
Now, researchers at the University of California, Berkeley, have shown that an old drug could be up to the task. In new work published in Science Advances, a team led by Anders Näär, with first author Justin Lee, demonstrated that giving mice the molecular compound called 5-tetradecyloxy-2-furoic acid (TOFA) led to weight loss without also losing lean muscle — known to be a common issue with GLP-1 drugs — and also decreased triglycerides and improved glucose control and features of fatty liver disease.
“We compared a panel of compounds known to act on lipid and energy metabolism for their effect on mitochondrial respiration in liver cells, and TOFA, an inhibitor of ACC1 and ACC2, lipid production enzymes that promote fatty-acid biosynthesis, stood out from the rest,” Näär told DDN.
Though the work is only preclinical for now, and TOFA has not been clinically evaluated for obesity or metabolic disease, the researchers founded ReRx Therapeutics with support from Berkeley’s life sciences entrepreneurship ecosystem, to hopefully move it closer to patients.
Why TOFA is different from the rest
The mechanism behind TOFA — an acetyl-CoA carboxylase (ACC) inhibitor — came as a surprise.
The drug was first studied in the 1970s, and unlike other ACC inhibitors, it lowers blood lipids rather than raising them, a discrepancy that went unexplained for decades. “TOFA was developed in the 1970s to lower blood lipids and tested in rodent and nonhuman primate models, but had never been evaluated against modern metabolic disease, because the disease framing and the tools to interrogate the mechanism did not exist when it was made,” said Näär.
His team found that TOFA doesn’t act like a regular ACC inhibitor because it also activates PPAR (peroxisome proliferator-activated receptor) alpha and PPAR delta, which are receptor proteins that turn on genes that promote fatty-acid oxidation and energy expenditure. Näär said it was exciting to discover that a fifty-year-old compound has an activity that had not been directly demonstrated before.
The mice in the new study showed an increased whole-body energy expenditure of up to 18 percent while on the drug, with no change in physical activity or rise in body temperature. The amount of food intake remained constant throughout the experiment. “We also saw significant beneficial effects of TOFA on fatty liver diseases such as Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD) and Metabolic dysfunction-Associated Steatohepatitis (MASH), with markedly decreased liver fat, inflammation and fibrosis in mouse models of those diseases,” said Näär.
The researchers were also surprised to find that pairing the ACC inhibitor firsocostat with the dual PPAR alpha/delta agonist elafibranor did not lead to the same results in the mice. “It did not work out the way we anticipated; TOFA was superior to that combination. We do not yet have a complete account of why, and that is an open question we are actively working on,” said Näär.
Combining with GLP-1 drugs
The research team also studied the effects of TOFA in combination with the GLP-1 drugs semaglutide and tirzepatide, which Näär noted led to even further improvements in body weight, glucose control, insulin levels, and triglycerides than either agent alone — suggesting that TOFA could be used alongside these drugs, rather than replacing them. “Energy balance has two sides and these agents work on opposite ones, which is a reason to expect them to add rather than overlap,” said Näär.
There’s also the potential for a drug like TOFA to allow patients to take a lower dose of a GLP-1 drug and reduce unwanted gastrointestinal side effects, though Näär emphasized that would need to be tested in humans.
Moving forward, Näär’s team is now completing safety and dosing studies in rats and preparing subsequent large-animal studies, as well as making progress on the pharmacology side to determine the proper human dose. They are also designing next-generation compounds that could achieve the same dual mechanism as TOFA with a lower dose, and Näär added that ReRx is open to discussions with potential development and investment partners on that front.
“On the science side, the open question is why one molecule does what two do not,” said Näär. “That is the part I most want to understand.”
