A 1970s Lipid-Lowering Compound May Offer a New Approach to Obesity 

By Irene Yeh 

September 15, 2026 | Obesity can cause metabolic conditions, including abnormal blood lipid levels, insulin resistance, and diabetes. Incretin-based drugs, such as glucagon-like peptide-1 receptor agonists (GLP-1 RAs), continue to see widespread use for obesity and to achieve weight loss. These incretin-based medications primarily suppress appetite and increase feelings of fullness but have side effects, including gastrointestinal issues and muscle loss. A new question arises: are there treatments that can address the broader metabolic issues of obesity? 

Researchers at the University of California, Berkeley, have identified a potential therapeutic candidate for obesity that boosts the body’s metabolic rate: 5-tetradecyloxy-2-furoic acid or TOFA. TOFA is a known oral small-molecule compound that lowers blood lipid levels and inhibits ACC1 and ACC2, enzymes involved in fat production and the regulation of fatty-acid breakdown (Science Advances, DOI: 10.1126/sciadv.aed3119).  

According to Anders M. Näär, Ph.D., professor of metabolic biology and nutrition and senior author of the study, TOFA behaves differently from other ACC inhibitors in two important ways. First, whereas all other known ACC inhibitors increase blood triglycerides, TOFA lowers them—a discrepancy that had gone unexplained for decades. Second, simply blocking ACC enzymes does not produce weight loss. Therefore, TOFA must have additional mechanisms of action. 

How Does TOFA Work? 

TOFA was developed back in the 1970s and was tested then on rodents and nonhuman primates, but it was not evaluated with modern metabolic disease framing in mind. It was known to inhibit ACC1 and ACC2, albeit at low micromolar doses, while inexplicably decreasing blood triglycerides. In the new study, Näär and colleagues discovered that TOFA also increased oxygen consumption and mitochondrial proton leakage, indicating an ability to enhance cellular energy expenditure. This feature was not seen for other ACC inhibitors. 

Testing TOFA in Obese Mice 

To determine if this increased energy expenditure would yield weight loss, male mice were fed a high-fat diet for seven weeks to establish obesity and then given TOFA or a control treatment twice daily for four weeks. The mice on TOFA lost weight soon after treatment started and continued to lose weight even after researchers reduced the dose to prevent rapid weight loss. By the end of four weeks, the mice on TOFA lost an average of 18% of their body weight.  

GLP-1 RAs suppress appetite and reduce energy intake, which can lead to weight loss that includes some loss of lean mass. In contrast, TOFA did not reduce appetite in the current mouse studies. The TOFA group maintained food intake, and weight loss was primarily from decreased body fat, with insignificant change to lean mass. TOFA also improved several obesity-related metabolic measures. It lowered fasting blood glucose levels and improved glucose tolerance, meaning the mice were able to bring their blood glucose levels down more quickly after receiving a glucose injection. The researchers also found that TOFA improved signs of fatty liver disease, including metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH), in mouse models, reducing liver fat, inflammation, and fibrosis. 

Other Mechanistic Targets 

For additional mechanistic insights, the researchers analyzed the transcriptional profiles of mice treated with vehicle or TOFA. The peroxisome proliferator activated receptor (PPAR) nuclear hormone superfamily stood out as a heavily enriched pathway. Specifically, PPARα and PPARδ, proteins that regulate genes involved in fat metabolism and energy use, were upregulated by TOFA, and RT-qPCR confirmed the upregulation of several target genes. In vitro binding assays also confirmed the ability of TOFA to directly bind these receptors. 

Because TOFA appeared to have stronger metabolic effects than other ACC inhibitors, the team believed that the combination of ACC1 and ACC2 inhibition and PPARα and PPARδ activation could account for TOFA’s unique effects. Blocking ACC1 and ACC2 reduces fat production and promotes the breakdown of fatty acids for energy, and activating PPARα and PPARδ may contribute to weight loss and improvements in metabolic problems associated with type 2 diabetes.  

To test this theory, they treated mice with two different drugs: firsocostat, an ACC inhibitor, and elafibranor, which activates PPARα and PPARδ. However, the combination did not reproduce TOFA’s effects, suggesting that simply targeting the two pathways with separate drugs is insufficient. Fircostat continued to increase blood lipid levels in the presence of elafibranor. Based on this result, either these two different activities must exist within a single molecule delivered to the same cells at the same time, or additional TOFA targets are involved. 

Combination with Incretins 

The team also investigated whether TOFA could be combined with injectable incretin drugs, such as semaglutide and tirzepatide. In the mouse studies, the mice received a control treatment, semaglutide, tirzepatide, TOFA, or a combination of TOFA with one of the two incretin drugs for 24 days. The mice treated with TOFA and tirzepatide rapidly lost weight, requiring the researchers to reduce their dose. The mice given TOFA and semaglutide lost weight more slowly after about a week. Overall, mice receiving either combination treatment lost significantly more weight than those receiving any single-agent treatment. Again, weight loss was entirely from decreasing body fat with no significant loss of lean mass. Combined treatment also showed improvements in glucose control, as well as the largest reductions in triglycerides in the blood and liver. Perhaps most impressively, during the washout period, the TOFA-treated mice largely maintained their body weight, whereas mice treated with semaglutide experienced a rapid increase in body weight. Näär said the findings raise the possibility that TOFA could eventually allow for a lower dose of an incretin-based drug, potentially reducing gastrointestinal side effects. However, he emphasized that this would need to be tested in humans. 

The Road to Human Trials 

Before TOFA can be considered for therapeutic use for obesity and weight loss, Näär said researchers must establish the lowest dose that produces an effect, understand how drug exposure scales from animals to people, and complete the longer-term safety studies required for a chronic metabolic drug. He and his team are currently working to advance TOFA toward clinical translation. Näär’s company, ReRx Therapeutics Inc., is raising funds for IND-enabling studies of TOFA in animals and initial human phase 1 trials. The earliest human trials could begin in the first quarter of 2028 if they complete the necessary preclinical and regulatory work and secure funding. 

Näär cautioned that compounds that increase energy expenditure require a carefully defined therapeutic window, the range in which a drug can produce its intended effect without causing serious harm. “There is no established safe or effective human dose,” he said. 

Though the research team will need to continue exploring the full effects of TOFA, the findings point to the potential of targeting energy expenditure as a complementary approach to treatments that reduce food intake. “We are also designing next-generation compounds that could achieve the same dual mechanism at a lower dose,” added Näär. 

But, again, Näär wanted to be very careful with how this information might be used. “Do not compound it. Do not dispense it. Do not recommend it to patients, and do not take it yourself. If a patient raises it, tell them plainly that this was a study in mice and that no human dose exists.”