Semaglutide (Novo Nordisk)

A decades-old compound may point to a new way of treating obesity by making the body burn more energy rather than simply reducing appetite. In mice, TOFA increased energy use by as much as 18%, reduced body fat without significant muscle loss, and improved blood sugar, triglycerides, and fatty liver disease. It also produced stronger results when combined with GLP-1 drugs such as Ozempic, Wegovy, Mounjaro, and Zepbound.GLP-1 medications have transformed the treatment of obesity, diabetes, and fatty liver disease over the past several years. Drugs sold as Ozempic, Wegovy, Mounjaro, and Zepbound can produce substantial weight loss while helping patients control blood sugar. But these medications can also cause problems. Some patients experience nausea and other gastrointestinal side effects. Because GLP-1 drugs reduce appetite and food intake, they may also contribute to nutritional deficiencies and loss of muscle, potentially increasing the risk of frailty and other long-term health issues. Researchers at UC Berkeley are now investigating a very different strategy for treating obesity and diabetes. Instead of reducing the amount of energy a person consumes, their approach is designed to increase the amount of energy the body uses by raising metabolic activity. A Different Way to Target Weight Loss In a study published August 21 in Science Advances, the team reports that a molecular compound called 5-tetradecyloxy-2-furoic acid (TOFA) can interfere with the production of lipids such as cholesterol and triglycerides. At the same time, it activates genes that encourage cells to use fat for fuel and produce more energy. In experiments with mice, TOFA improved insulin sensitivity and glucose control, reduced triglyceride levels, and improved signs of fatty liver disease. Obese mice treated with the compound lost fat while showing no significant reduction in lean muscle mass. "Body weight responds to two levers: taking in fewer calories, or spending more energy," said Anders Näär, a professor of metabolic biology and nutrition at UC Berkeley and senior author of the study. "GLP-1s work almost entirely on the first, so we went after the second." Reviving a Compound First Discovered Decades Ago TOFA was initially discovered in the 1970s and belongs to a group of compounds known as ACC inhibitors. These compounds reduce the body's production of lipids. Several ACC inhibitors have advanced into mid-stage clinical trials, but none has been approved to treat metabolic disease. One important obstacle is that many of these compounds can increase triglyceride levels, which may raise cardiovascular risk. The UC Berkeley team found that TOFA behaves differently. In addition to acting as an ACC inhibitor, it activates PPARα and PPARδ, cellular receptors that switch on genes involved in taking up fat and burning it for energy. In mice, this effect increased energy use by as much as 18% without causing the animals to become more physically active or increasing their body temperature. The researchers also found that TOFA did not produce the rise in triglycerides seen with some other ACC inhibitors, possibly because of its combined effects on lipid production and energy metabolism. "TOFA appears to engage a coordinated metabolic response," said study first author Justin Y. Lee, a postdoctoral student at UCSF who conducted the research as a Ph.D. student at Berkeley. "It is not simply blocking lipid synthesis. It is also activating energy expenditure pathways that may help the body handle excess lipid and glucose more effectively." One Compound Outperformed a Two-Drug Approach The researchers also tested whether they could reproduce TOFA's effects with two separate compounds. They gave mice one compound designed to suppress lipid production and another intended to increase energy expenditure. That combination did not improve overall metabolic health as effectively as TOFA by itself, suggesting that TOFA's particular combination of actions may be important to its effects. The team then examined whether TOFA could be paired with existing GLP-1 medications. These included semaglutide, sold under the brand names Ozempic or Wegovy, and tirzepatide, sold as Mounjaro and Zepbound. In mice, combining TOFA with these GLP-1 drugs produced larger improvements in body weight, glucose control, insulin levels, and triglycerides than either treatment produced on its own. "In our combination experiments, TOFA worked additively or synergistically with the GLP-1 appetite-suppressing drugs, so we view it as complementary rather than as a replacement," Näär said. Human Testing Is Still Needed Despite the promising results, the researchers emphasize that TOFA has so far been studied only in animals. Its safety and effectiveness in humans remain unknown and will need to be evaluated in future studies. With support from Berkeley's life sciences entrepreneurship ecosystem, including Nucleate and Berkeley SkyDeck, the researchers have created a company called ReRx Therapeutics to help move the research toward potential use in patients. The research was funded through discretionary funds from UC Berkeley, with additional assistance from the UCSF Liver Center and the University of Michigan Animal Phenotyping Core. Additional authors include Chi Zhu, Melissa A. Boldridge, Rachelle L. Stark, Lei Xu, Federico Gonzalez, Xin Tang, Kaitlyn T. Dang and Kook Son of Berkeley; Gracia Bonilla, Kashish Chetal and Ruslan I. Sadreyev of Massachusetts General Hospital; Kosuke Watari and Michael Karin of the University of California, San Diego; Christina Papa and Bilal N. Sheikh of the Helmholtz Center Munich; Prabha Ibrahim of ReRx Therapeutics.