Over the past five years, medications called GLP-1s have revolutionized the treatment of metabolic disorders like obesity, diabetes and fatty liver diseases. Sold under the brand names Ozempic, Wegovy, Mounjaro and Zepbound, these drugs are highly effective at helping people lose weight and manage their blood sugar levels. However, they do come with some risks. Some people taking GLP-1s experience nausea and other gastrointestinal side effects that can be difficult to manage. And, by suppressing appetite and reducing food intake, they have the potential to cause nutritional deficiencies and muscle loss, which can lead to frailty and other problems long term.
At UC Berkeley, researchers have found a new potential treatment for obesity and diabetes that works by increasing energy expenditure — boosting the body's metabolic rate — rather than limiting energy intake.
In a study published online today in the journal Science Advances, the researchers show that a molecular compound called 5-tetradecyloxy-2-furoic acid (TOFA) is able to block the production of lipids like cholesterol and triglycerides while simultaneously turning up genes that help cells burn fat and generate energy.
In experiments in mice, the researchers found that TOFA is effective at improving insulin sensitivity and glucose control, lowering triglycerides and improving features of fatty liver disease. When obese mice took the compound, they lost weight from fat but experienced no significant loss of 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."
TOFA was first discovered in the 1970s and is known for being part of a class of compounds called ACC inhibitors, which help block the production of lipids in the body. Though several ACC inhibitors reached mid-stage clinical testing, none has been approved for metabolic disease. This is largely because many of these compounds can also raise triglycerides, posing a significant risk to heart health.
In the new study, the researchers found that TOFA doesn't just act as an ACC inhibitor, but also activates PPARα and PPARδ, cellular receptors which turn on genes that let cells take up fat and burn it for energy. In mice, this caused the cells to burn up to 18% more energy with no change in physical activity or increase in body temperature. Perhaps because of this dual mechanism, TOFA also did not raise triglycerides like other ACC inhibitors.
"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."
When the researchers tried giving mice two separate compounds — one to block lipid production and a second to boost energy expenditure — they found that the combination was not as effective at improving overall metabolic health as TOFA alone.
The researchers also explored whether TOFA could be used together with GLP-1 medications like semaglutide, which is sold under the brand names Ozempic or Wegovy, and tirzepatide, which is sold as Mounjaro and Zepbound. In mice, they found that combining TOFA with these GLP-1 drugs led to greater improvements in body weight, glucose control, insulin levels and triglycerides than either treatment alone.
"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.
The researchers caution that TOFA has only been studied in animals, and its safety and efficacy in humans has yet to be tested. With support from Berkeley's life sciences entrepreneurship ecosystem, including Nucleate and Berkeley SkyDeck , they have founded a new company ReRx Therapeutics to help carry this work to patients.
The work was supported by discretionary funds from UC Berkeley, with 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.
