TOFA Helps Obese Mice Lose Weight by Burning More Energy

Most weight-loss medicines work chiefly by suppressing appetite and reducing how much people eat. An experimental compound, however, seems to take a different route: in mice, it enables the body to use more of the energy it consumes.

This strategy could provide another means of addressing obesity. Rather than focusing solely on cutting calorie intake, a treatment could also raise the number of calories the body expends.

In research published in Science Advances, scientists reported that the compound led to average weight loss of 18 percent in obese male mice over four weeks, without altering the amount the animals ate.

Most of the reduction was in body fat, while muscle and other lean tissue were largely retained.

TOFA and its effects on energy use

The compound is known as 5-tetradecyloxy-2-furoic acid (TOFA).

Researchers at the University of California, Berkeley, gave the mice a high-fat diet until they became obese. They then administered TOFA orally twice daily for four weeks.

"Food intake was unchanged, physical activity was unchanged, and body temperature did not rise, yet whole-body energy expenditure increased by as much as 18 percent," senior author Anders Näär, a metabolic biologist at UC Berkeley, told ScienceAlert.

Anders Näär (centre), with metabolic biology graduate student Rachelle Stark (left), and nutritional scientist Chi Zhu (right) in the Anders Näär lab at Berkeley. (Mathew Burciaga/UC Berkeley)

TOFA neither caused the mice to become more active nor stopped them absorbing calories from food. Rather, it seemed to alter the way their bodies processed fat and expended energy.

The compound appears to have two actions: it reduces the formation of new fat, while helping cells absorb and burn fat as fuel.

Precisely which cellular mechanisms explain all of this extra energy expenditure, though, is still uncertain.

The team expected to recreate these effects by using two distinct methods: one to curb fat production and another to boost fat burning. Yet this combination did not achieve the same outcome as TOFA.

"Having both activities in one molecule appears to matter, and we still do not fully understand why," Näär said.

TOFA was first made in the 1970s and has long been used in laboratory studies. Näär said its capacity to switch on fat-burning programmes appears to have existed all along, but had not previously been investigated.

Metabolic benefits and muscle retention

The treatment seemed to offer advantages beyond weight loss. It reduced blood glucose and insulin levels, improved the mice's response to glucose, and lowered fat levels in their blood and livers.

In separate experiments, TOFA also lessened indicators of fatty liver disease, including fat accumulation, inflammation and scarring.

Näär emphasises that TOFA does not seem to preserve muscle directly. Since the mice maintained their usual food intake, the majority of the weight they lost probably came from fat.

"In our mice it simply did not produce the loss of lean mass that often accompanies weight loss," he said.

Combining TOFA with GLP-1-based drugs

The researchers next paired lower doses of TOFA with the GLP-1-based drugs semaglutide and tirzepatide. These medicines largely support weight loss by lowering appetite, which helps reduce food intake.

Semaglutide promotes weight loss by reducing appetite. (imyskin/Canva)

The combined treatments achieved greater weight loss and metabolic gains than any treatment on its own.

The two strategies work on opposite sides of the body's energy balance. Semaglutide and tirzepatide lower energy intake, whereas TOFA raises energy expenditure in mice.

"That makes combination therapy interesting, because the mechanisms could complement one another instead of duplicating," Näär said.

In another experiment, mice treated with TOFA also kept their weight off for longer once treatment had stopped. By contrast, mice given semaglutide regained weight quickly as their food intake increased.

However, the combination studies were brief and used small groups of mice. Every live animal in the study was male, meaning it remains unknown whether TOFA would produce similar effects in females.

TOFA has not been tested in humans. Its lowest effective dose is not known, and it has not completed the safety assessments needed for medical use.

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Näär and two other study authors are co-founders and shareholders of ReRx Therapeutics, which is developing TOFA as a possible treatment.

The researchers intend to carry out toxicology and efficacy research in rats and larger animals with physiology more similar to humans. Such work is required before human clinical trials can start.

At present, TOFA is not a new weight-loss treatment. Nevertheless, the results suggest an intriguing possibility: fat loss might be supported not just by eating less, but by altering how the body uses the energy it receives.

The study was published in Science Advances.

This article was fact-checked by Rebecca Dyer and edited by Rebecca Dyer. While we take pride in our process, we are only human. If you spot an error, please let us know.