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. GLP-1s work almost entirely on the first, so we went after the second."
Anders Näär, professor of metabolic biology and nutrition at UC Berkeley and senior author of the study
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.
Source:
Journal reference:
Lee, J. Y., et al. (2026). A multi-functional oral small molecule targeting energy and lipid metabolism to treat obesity and related metabolic disorders. Science Advances. DOI: 10.1126/sciadv.aed3119. https://www.science.org/doi/10.1126/sciadv.aed3119
Facts Only
* GLP-1 medications include Ozempic, Wegovy, Mounjaro, and Zepbound.
* GLP-1s are effective for weight loss and blood sugar management in treating obesity, diabetes, and fatty liver diseases.
* Some users experience nausea and other gastrointestinal side effects from GLP-1s.
* GLP-1s suppress appetite and reduce food intake, posing a risk of nutritional deficiencies and muscle loss long term.
* Researchers found that 5-tetradecyloxy-2-furoic acid (TOFA) blocks lipid production (cholesterol and triglycerides).
* TOFA activates genes that promote fat burning and energy generation.
* In mice, TOFA improved insulin sensitivity, glucose control, and lowered triglycerides while preserving lean muscle mass during weight loss.
* TOFA caused mouse cells to burn up to 18% more energy in experiments without changes in physical activity or body temperature.
* Combining TOFA with GLP-1 drugs resulted in greater improvements in weight, glucose control, insulin levels, and triglycerides in mice.
* TOFA was discovered in the 1970s as part of ACC inhibitors.
Executive Summary
Medications known as GLP-1s, including Ozempic, Wegovy, Mounjaro, and Zepbound, have been used for five years to treat metabolic disorders such as obesity, diabetes, and fatty liver diseases, demonstrating efficacy in weight loss and blood sugar management. These treatments carry risks, including gastrointestinal side effects and the potential for nutritional deficiencies or muscle loss due to appetite suppression. Researchers at UC Berkeley investigated an alternative approach by focusing on increasing energy expenditure rather than limiting caloric intake for obesity and diabetes treatment.
A study published in *Science Advances* found that a molecular compound called 5-tetradecyloxy-2-furoic acid (TOFA) can simultaneously block the production of lipids like cholesterol and triglycerides while activating genes responsible for fat burning and energy generation. In mouse experiments, TOFA improved insulin sensitivity and glucose control, lowered triglycerides, and improved fatty liver disease markers without causing significant loss of lean muscle mass when obese mice took the compound. Furthermore, combining TOFA with GLP-1 medications in mice resulted in greater improvements in weight, glucose, insulin levels, and triglycerides compared to using either treatment alone, suggesting a complementary effect.
Full Take
The narrative pivots on challenging the current paradigm where weight management is primarily addressed by energy restriction (GLP-1s) versus increasing energy expenditure (TOFA). The finding that TOFA engages a coordinated metabolic response—blocking lipid synthesis while activating energy expenditure pathways—suggests a deeper mechanistic understanding than simply blocking appetite. The crucial observation in the mouse studies is the successful decoupling of weight loss from muscle loss, which directly addresses the primary concern with current GLP-1 therapy regarding potential frailty.
The combination study suggests that the failure to achieve optimal metabolic health might stem from addressing only one lever (calorie intake) rather than engaging both lipid regulation and energy expenditure simultaneously. The synergy observed between TOFA and GLP-1s implies a necessary shift toward integrated metabolic strategies. However, the limitation remains in extrapolating these positive findings from animal models to human populations, necessitating caution regarding the safety and efficacy of this approach for humans until further testing is conducted by the newly formed company, ReRx Therapeutics.
The potential implication is that treating obesity and diabetes might require a multifaceted intervention that targets both hormonal appetite regulation *and* systemic energy regulation. The focus shifts from purely caloric control to orchestrating the body's metabolic machinery. What underlying assumptions about human physiology allow for such seamless integration of lipid management and energy expenditure signaling in the context of treatment? How does the potential loss of muscle mass, even when minimized in the study, weigh against the gains in glucose and triglyceride control in a long-term human context?
Sentinel — Human
This text reads like a factual summary of a scientific publication, characterized by detailed citation and layered explanation, suggesting human authorship synthesizing primary research.