New research published in the journal Science Advances has revealed an innovative approach to combating obesity, focusing on increasing the body’s energy expenditure rather than just reducing appetite. Unlike well-known treatments, such as Ozempic and Wegovy, which aim to reduce calorie intake, this study opens a new path by proposing a method that increases energy burning without changing diet.

The compound in question, identified as TOFA (5-tetradecyloxy-2-furoic acid), was the subject of investigation by scientists at the University of California at Berkeley, who tested it in mice that developed obesity.

Details of the experiment carried out with the TOFA compound

During the research, male mice were subjected to a high-fat diet for a period of seven weeks, which led them to develop obesity. Subsequently, for four weeks, these animals received oral doses of TOFA twice a day.

The results obtained showed an average loss of 18% in the body weight of the mice, notably without any change in the amount of food consumed, the intensity of physical activity or the internal temperature of the animals.

“Food intake didn’t change, physical activity didn’t change, body temperature didn’t increase – and yet total energy expenditure increased by up to 18%,” said Anders Näär, a metabolic biologist at the University of California at Berkeley and senior author of the study.

The majority of weight reduction was attributed to fat loss, with muscle mass and other lean tissue being largely preserved. This is a crucial aspect, as maintaining muscle mass represents a significant difference compared to restrictive diets and medications such as Ozempic, which often cause muscle loss.

Understand the mechanism of action of the TOFA compound

TOFA works through a dual mechanism. It works by inhibiting the ACC1 and ACC2 enzymes, which are fundamental in the production of fat by the body, while simultaneously activating the PPARα and PPARδ receptors, which in turn stimulate genes involved in the absorption and burning of fat to generate energy.

Previous research on ACC inhibitors in clinical trials has failed due to increased blood triglyceride levels, which pose a serious cardiovascular risk. Unlike these compounds, TOFA has not been shown to cause this effect in the animals studied.

“TOFA appears to trigger a coordinated metabolic response. It not only blocks lipid synthesis, but also activates energy expenditure pathways that can help the body process excess lipids and glucose more efficiently,” explained Justin Y. Lee, the study’s first author, in a statement from the University of California at Berkeley.

It was observed that when researchers tried to replicate the effects of TOFA using the combination of two different compounds — one to prevent the production of fat and the other to increase energy expenditure — this approach did not prove to be as efficient as TOFA administered alone.

“Having both activities in a single molecule seems to be relevant, and we still don’t fully understand why,” said Näär.

Results of combining TOFA with Ozempic and Mounjaro

In a complementary stage of the research, scientists tested TOFA in conjunction with medications such as semaglutide, present in Ozempic and Wegovy, and tirzepatide, found in Mounjaro and Zepbound.

The combination of these substances showed more favorable results compared to treatments administered alone, demonstrating improvements in body weight, glucose control, insulin levels and a reduction in triglycerides.

This synergy is based on complementarity of action: while GLP-1 medications act by reducing calorie intake, TOFA works to increase energy expenditure, addressing both sides of the energy equation jointly.

“This characteristic makes combined therapy particularly interesting, as the mechanisms of action can complement each other, not duplicate each other,” commented Näär.

It was observed that mice that received TOFA were able to maintain their weight for a longer period after the end of treatment. In contrast, those who were treated with semaglutide alone experienced rapid weight regain when returning to a higher calorie diet.

Additional Health Benefits of TOFA Compound

In addition to weight loss, TOFA has been shown to improve blood sugar control and insulin sensitivity in animals, as well as reduce triglyceride levels and the amount of fat in the liver.

In separate experiments, the compound was also able to attenuate indicators of fatty liver disease, including fat accumulation, inflammatory processes and the formation of fibrosis.

Although TOFA was discovered in the 1970s and used in laboratory studies for decades, it has never been tested in humans. The minimum effective dosage remains unknown, and the compound has not yet undergone the safety tests required for medical use.

All of the mice used in the experiments were males, which means that the effects of TOFA on females are not yet known.

The researchers’ next steps include carrying out toxicology and efficacy studies in rats and larger animals, before proceeding to clinical trials in humans. Anders Näär, along with two other authors of the research, are co-founders and shareholders of ReRx Therapeutics, a company dedicated to the development of TOFA as a potential treatment.