An experimental compound from the 1970s, known as TOFA, is showing potential to significantly enhance the efficacy of current weight-loss drugs and mitigate their side effects, according to early research. Unlike popular medications such as Wegovy and Mounjaro, which primarily suppress appetite, TOFA appears to increase the body's energy expenditure by promoting fat metabolism.
Researchers at the University of California, Berkeley, rediscovered TOFA, a synthetic compound initially developed to reduce blood fats. Their recent study, published in Science Advances, found that TOFA causes cells to burn fat for energy. It achieves this by blocking enzymes involved in fat production and activating proteins that regulate fat burning and energy generation. In obese mice, TOFA treatment led to an approximate 18% body weight loss over four weeks without reducing food intake. Crucially, the weight lost was predominantly fat, with no significant decrease in lean tissue, including muscle, which is a common challenge with traditional weight-loss methods.
Enhanced Efficacy in Combination Therapy
Further experiments explored the combination of TOFA with existing weight-loss medications semaglutide (Ozempic, Wegovy) and tirzepatide (Mounjaro). When administered at significantly lower doses than those used in human obesity trials, TOFA combined with semaglutide resulted in a 26.9% body weight loss in mice, and TOFA with tirzepatide led to a 37.1% loss. For comparison, the drugs alone resulted in 6.7% and 4.5% weight loss, respectively. In some cases, the combined therapy was so effective that researchers had to halve the drug doses to prevent excessive weight reduction.
Justin Lee, the study's lead researcher, explained that the synergistic effect is due to the drugs targeting complementary pathways. While tirzepatide and semaglutide work on appetite suppression through gut hormones, TOFA increases energy expenditure. This dual action creates a substantial negative energy balance, leading to significant weight loss and metabolic improvements. Lee suggested that using lower doses of these drugs in combination could reduce gastrointestinal side effects, such as nausea, vomiting, diarrhea, and constipation, which are common with current weight-loss injectables.
Potential Broader Health Benefits and Safety Considerations
Beyond weight loss, TOFA alone demonstrated improvements in blood sugar control in mice, potentially lowering the risk of type 2 diabetes. It also reduced triglyceride levels, a type of blood fat linked to heart disease, and decreased fat accumulation in the liver.
Despite the promising findings in mice, TOFA has not yet been tested in humans, and its full safety profile remains unknown. Experts caution that further rigorous safety assessments are essential. Naveed Sattar, professor of metabolic medicine at the University of Glasgow, highlighted the need to ensure TOFA does not cause excessive heat production or strain the heart, given its mechanism of increasing energy expenditure. Additionally, historical concerns with drugs targeting similar pathways include potential increases in triglyceride levels, raising the risk of heart disease and pancreatitis, and effects on platelet levels that could increase bleeding risk.
Alex Miras, a clinical professor of medicine and obesity specialist, described the findings as exciting, particularly noting the unmet need for alternative or enhanced treatment options for individuals who do not respond adequately to current GLP-1-based drugs.