An orally bioavailable small molecule reduced body weight and fat mass without affecting food intake or lean mass in a preclinical study.
Researchers evaluated 5-tetradecyloxy-2-furoic acid (TOFA) using cell-based experiments and multiple male mouse models of obesity and related metabolic diseases. In the primary diet-induced obesity experiment, male C57BL/6 J mice were fed a diet containing 60% fat for 7 to 12 weeks and then received oral TOFA or vehicle twice daily for 4 weeks. TOFA-treated mice had an average 18% decrease in body weight by the end of treatment. Food intake was unchanged, and weight reduction was attributable to fat-mass loss, with no statistically significant change in lean mass. TOFA improved fasting blood glucose and insulin levels, glucose tolerance, and insulin sensitivity. Treatment also reduced liver and serum triglycerides and cholesterol.
The researchers conducted metabolic-cage experiments in mice with diet-induced obesity. Following 1 week of treatment, TOFA-treated mice had reduced fat mass without a statistically significant change in lean mass. Energy expenditure was approximately 18% higher compared with controls at room temperature and under thermoneutral conditions but just 4% higher during cold exposure. Overall activity did not increase, and there was no evidence of hyperthermia, showing increased systemic energy expenditure rather than greater physical activity or cold-induced thermogenesis.
Mechanistic experiments showed that TOFA inhibited acetyl-CoA carboxylases 1 and 2 while partially activating peroxisome proliferator–activated receptor (PPAR) alpha and delta. RNA sequencing, knockout experiments, and receptor-specific interaction studies supported a role for both PPAR pathways in the compound’s metabolic activity. The researchers demonstrated direct biochemical interactions between TOFA and the ligand-binding domains of PPAR alpha and delta.
Male mice were fed a choline-deficient, amino acid–defined high-fat diet for 8 weeks followed by TOFA or vehicle for another 4 weeks. TOFA-treated mice lost an average of approximately 9% of their body weight without a change in food intake and had lower liver triglyceride levels. Histologic and molecular assessments showed reductions in hepatic steatosis, inflammation, collagen-related markers, oxidative stress, and fibrosis, with a more modest effect on hepatocyte ballooning.
Similar findings emerged in a second model designed to reproduce more advanced metabolic dysfunction-associated steatohepatitis. Following 10 weeks of high-fat feeding, male MUP-uPA mice received TOFA or vehicle for 6 weeks. The mice showed sustained weight loss without altered food intake, lower serum and hepatic triglycerides and hepatic cholesterol, and reductions in hepatic lipid accumulation and fibrosis.
The researchers assessed whether TOFA complemented incretin-based treatment in mice with diet-induced obesity that received vehicle, TOFA, semaglutide, tirzepatide, or TOFA combined with either incretin analog for 24 days. Each monotherapy produced an average weight reduction of approximately 10% compared with controls, but combination regimens produced greater weight loss as well as improvements in glucose control, fasting insulin, and serum and hepatic triglycerides. Changes in body weight reflected fat-mass loss without a statistically significant loss of lean mass.
In a separate treatment-withdrawal experiment, mice previously treated with TOFA maintained body weight near control levels following treatment cessation, whereas mice previously treated with semaglutide showed an immediate increase in body weight.
All in vivo experiments involved male mice, and the researchers noted that female models are needed to assess efficacy and safety. Other metabolic targets or tissues may also contribute to TOFA’s effects. The minimum efficacious dose for weight loss remains undetermined, and the safety profile at the doses used was incompletely characterized for subclinical toxicity.
“Our findings suggest that the coordinated multitargeting of energy metabolism and lipid homeostasis by TOFA is an effective approach to address multiple associated metabolic diseases,” wrote lead study author Justin Y. Lee, of the Department of Nutritional Sciences & Toxicology at the University of California, Berkeley, and colleagues.
Full disclosures of the study authors can be found in the study.
Source: Science Advances
