Researchers from the University of California, Berkeley (USA) have identified a possible innovative therapy against obesity and diabetes that, unlike GLP-1 drugs, promotes fat burning without causing a significant loss of muscle mass.
In a study with mice, published in the journal "Science Advances," the team details that a molecule called 5-tetradecyloxy-2-furoic acid (TOFA) manages to halt the synthesis of lipids such as cholesterol and triglycerides, while activating genes involved in allowing cells to use fat as fuel and generate energy.
In the last five years, treatments known as GLP-1 have transformed the approach to metabolic disorders such as obesity, diabetes, and fatty liver disease. Under the brands "Ozempic," "Wegovy," "Mounjaro," and "Zepbound," these medications have proven to be very effective in promoting weight loss and stabilizing blood sugar levels.
However, their use is not without drawbacks. A percentage of patients treated with GLP-1 suffer from nausea and other difficult-to-manage digestive symptoms. Additionally, by reducing appetite and the amount of food ingested, nutritional deficits and a loss of muscle mass may occur, which, in the long term, is associated with frailty and other health problems.
In contrast to this approach, the group from the University of California, Berkeley has described a molecular compound that, unlike GLP-1, increases energy expenditure by helping cells consume more energy without the need to decrease intake or alter physical activity, with encouraging results in the analyzed animal models.
The mice lost weight without losing muscle mass
In the trials with mice, scientists found that TOFA improves insulin sensitivity and glucose control, reduces triglycerides, and corrects several markers associated with fatty liver disease. In the obese animals treated with this compound, the weight loss primarily came from fat tissue, while lean muscle mass remained virtually intact.
"Body weight responds to two factors: ingesting fewer calories or expending more energy. GLP-1 acts almost exclusively on the first, so we focused on the second," explained Anders Näär, professor of Metabolic Biology and Nutrition at UC Berkeley and the principal author of the study.
The TOFA was first identified in the 1970s and is part of a family of molecules called ACC inhibitors, whose function is to block lipid production in the body. Although several ACC inhibitors reached intermediate phases of clinical trials, none received approval to treat metabolic pathologies, largely because many of these compounds raised triglycerides, with the consequent cardiovascular risk.
In this new research, the team observed that TOFA not only acts as an ACC inhibitor but also activates PPARa and PPARd, cellular receptors that initiate genes responsible for capturing fat and using it to generate energy. In mice, this mechanism caused cells to increase their energy expenditure by up to 18 percent, with no changes in physical activity level or body temperature.
Probably thanks to this dual mode of action, TOFA also did not increase triglyceride levels, unlike other previously tested ACC inhibitors.
"TOFA seems to activate a coordinated metabolic response," emphasized the first author of the study, Justin Y. Lee, a postdoctoral researcher at the University of California in San Francisco (UCSF), who conducted the research while he was a doctoral student at Berkeley. "It is not limited to blocking lipid synthesis. It also activates pathways related to energy expenditure that could help the body manage excess lipids and glucose more effectively," he added.
When scientists administered two molecules separately to the mice—one aimed at inhibiting lipid production and another at increasing energy expenditure—they found that the combination did not achieve the same efficacy as TOFA alone in improving the overall metabolic parameters.
It acted synergistically with GLP-1 drugs
The authors also analyzed whether TOFA could be administered alongside GLP-1 treatments, such as semaglutide, marketed as "Ozempic" and "Wegovy," and tirzepatide, sold as "Mounjaro" and "Zepbound." In mouse models, they verified that the combination of TOFA with these GLP-1 medications generated greater improvements in body weight, glucose control, insulin levels, and triglycerides than any of the treatments separately.
"In our combination experiments, TOFA acted additively or synergistically with the GLP-1 drugs that suppress appetite, so we consider it a complementary treatment, rather than a substitute," Näär has pointed out.
The researchers emphasize that, for the moment, TOFA has only been evaluated in laboratory animals and its safety and efficacy in humans have not yet been determined.