Obesity: meet Tofa – it speeds up the metabolism and increases energy expenditure

When a person is struggling with obesity or being overweight, from a purely metabolic perspective – and without going into cognitive-behavioural approaches – they essentially have two ways of shedding excess weight and reducing the metabolic and inflammatory risks associated with it. Restricting calorie intake or increasing energy expenditure. On this second front, regular physical activity is essential. But finding a pharmacological solution is arduous, tremendously difficult. Consequently, for decades science has been searching for an effective ‘fat-burner’ that demonstrates, in clinical trials, a real effect on metabolism as well as on the disheartening figures shown on the scales. But now there is a glimmer of hope. It is important to remember, however, that we are still only at the animal trial stage.

The research carried out by experts at the University of California, Berkeley, published in Science Advances and led by Anders Näär, a professor of metabolic biology and nutrition, opens up interesting prospects for the future. This is partly because the compound in question, TOFA (an acronym for 5-tetradecyl-2-furoic acid), could be combined with drugs that are already available today for obesity, diabetes and liver problems – namely GLP-1 agonists such as semaglutide and tirzepatide, as well as those due to be launched in oral formulations, such as orforglipron and others.

The study shows that the compound has a dual action: on the one hand, it helps to inhibit the production of lipids such as cholesterol and triglycerides; on the other, it ‘switches on’ the genes that promote fat utilisation by cells, resulting in the release of energy. In particular, according to the research, in mice, TOFA is thought to improve tissue sensitivity to insulin through these mechanisms, leading to better blood glucose control, and to help reduce triglyceride levels and improve liver function. All of this, based on observations in mice, occurs without a significant loss of lean body mass and therefore results in a truly interesting metabolic profile. “Body weight is determined by two factors: consuming fewer calories or expending more energy,” commented Näär in a statement from the Californian university. “GLP-1s act almost exclusively on the first factor, so we focused on the second.”

TOFA was first discovered in the 1970s. It is one of a group of active substances that inhibit the activity of acetyl-CoA carboxylase (ACC), a key enzyme in the regulation of fat metabolism. It must be said, however, that none of these potential drugs has yet become a treatment for metabolic disorders, due to potential adverse effects on cardiovascular risk. According to the study, TOFA not only acts as an ACC inhibitor but also activates PPARα and PPARδ, cellular receptors that trigger the genes enabling cells to absorb fats and burn them to produce energy. In mice, this led cells to burn up to 18 per cent more energy without any changes in physical activity or increases in body temperature. Crucially, there were no effects on triglyceride levels – and therefore no increase in cardiovascular risk, as observed with other drugs in this class. To top it all off, there is a potential synergistic effect with conventional GLP-1 receptor agonists. In experiments (again on animals), TOFA acted additively or synergistically with GLP-1 drugs that reduce appetite, suggesting it could be a possible addition to future treatments.

“Today, strategies for managing obesity, including the latest pharmacological treatments, focus primarily on reducing energy intake,” comments Daniela Martini, lecturer in Human Nutrition at the University of Milan. The possibility of using medication to influence the other component of energy balance – by increasing the energy expended by the body – could therefore open up a particularly interesting complementary avenue, not least because, in animal models, TOFA appears to promote weight loss whilst preserving lean body mass, which is an extremely important consideration. However, it is important to emphasise that it is far too early to hail this as a miracle or to think we have finally found the ‘fat-burner’: these are results obtained in animals, still a long way from clinical application. Today, where individual circumstances allow, staying physically active remains the key strategy for increasing energy expenditure whilst, at the same time, preserving muscle mass and function.”