Researchers have identified an oral small molecule that increases energy expenditure, potentially offering a new strategy to fight obesity. The molecule, 5-tetradecyloxy-2-furoic acid (TOFA), was found to produce substantial weight loss in mouse models of obesity while preserving lean mass.
The study, conducted by researchers from the University of California, Berkeley, found that TOFA increased energy expenditure without reducing food consumption, unlike incretin drugs such as semaglutide and tirzepatide, which primarily reduce energy intake by suppressing appetite.
TOFA was found to combine two metabolic actions in a single molecule, inhibiting acetyl-CoA carboxylases 1 and 2 (ACC1/2), enzymes involved in fatty-acid synthesis, while partially activating PPARα and PPARδ, nuclear receptors that regulate lipid metabolism and energy expenditure.
In mice with high-fat diet-induced obesity, oral TOFA produced an average 18% reduction in body weight, primarily due to a loss of fat mass, with no significant change in lean mass or food intake.
Treatment with TOFA also lowered fasting glucose and insulin, improved glucose tolerance, reduced liver fat, and lowered circulating triglycerides and cholesterol.
The researchers also tested TOFA in combination with semaglutide and tirzepatide, finding that the combination produced significantly greater weight loss than individual treatments, with the additional loss reflecting fat rather than lean mass.
They found that combination therapy also produced greater improvements in glucose control, insulin levels, and serum and liver triglycerides, suggesting that TOFA could be a useful addition to existing therapies.
The authors suggest that the distinct mechanisms of TOFA could make it particularly useful alongside incretin drugs, potentially allowing lower doses while addressing concerns such as lean-mass loss and weight regain.
The findings, although preclinical, could offer a different way to treat obesity, targeting how the body uses and stores energy rather than relying solely on reducing energy intake.
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TOFA also improved features of metabolic dysfunction-associated steatotic liver disease and steatohepatitis in mouse models, reducing hepatic fat accumulation, inflammation, and markers of fibrosis.
As researchers continue to investigate obesity treatments, the discovery of TOFA offers a promising new avenue for investigation.
The study’s results were published in Science Advances.
Metabolic-cage experiments provided valuable insights into the mechanisms underlying TOFA’s effects, revealing that the molecule increased energy expenditure by enhancing fat oxidation, without relying on increased physical activity or changes in body temperature.
The dual mechanism of action of TOFA, combining ACC1/2 inhibition and PPARα/δ activation, may contribute to its ability to produce metabolic benefits that are not achieved by targeting either pathway alone, and could help to minimize potential side effects associated with conventional ACC inhibitors.
The potential for TOFA to be used in combination with other therapies, such as semaglutide and tirzepatide, could allow for more effective and sustainable weight loss, while also addressing related metabolic disorders, such as type 2 diabetes and non-alcoholic fatty liver disease.
Further research is needed to fully elucidate the effects of TOFA in humans, but the preclinical findings suggest that this molecule could represent a significant advancement in the treatment of obesity and related metabolic disorders.
The discovery of TOFA highlights the importance of continued research into the complex mechanisms underlying obesity and metabolic disease, and the potential for innovative therapeutic approaches to improve human health.
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