TOFA

TOFA is a cell-permeable, multifunctional modulator of lipid and energy metabolism. TOFA inhibits acetyl-CoA carboxylase 1 and 2 (ACC1/ACC2; ACACA/ACACB), key enzymes controlling malonyl-CoA production and de novo fatty acid synthesis (lipogenesis). By reducing malonyl-CoA formation, TOFA inhibits fatty acid synthesis and alters the balance between lipid synthesis and fatty acid oxidation. TOFA is further an agonist of the nuclear receptors PPARα and PPARδ, important transcriptional regulators of fatty acid oxidation, mitochondrial metabolism and energy expenditure. This combined targeting of ACC1/2 and PPARα/δ enables TOFA to coordinately modulate lipid synthesis and energy metabolism. In preclinical mouse models of diet-induced obesity and metabolic dysfunction, TOFA increased energy expenditure and reduced body fat without significantly affecting food intake or lean muscle mass. TOFA treatment also improved insulin sensitivity, glucose homeostasis, circulating triglycerides and features of fatty liver disease. Interestingly, combination treatment with TOFA and the incretin analogs semaglutide or tirzepatide produced more-than-additive improvements in obesity, dyslipidemia and insulin resistance.

TOFA is therefore a useful research compound for studying, Acetyl-CoA carboxylase (ACC1/ACC2) inhibition, PPARα and PPARδ activation, de novo lipogenesis and fatty acid synthesis, fatty acid oxidation and energy expenditure (Fatty acid synthase (FASN) inhibitor), obesity and metabolic disease research, insulin resistance and glucose metabolism, dyslipidemia and lipid homeostasis, MASLD/fatty liver research, immunometabolism and metabolic reprogramming and cancer metabolism. TOFA is a valuable tool for investigating the interplay between lipid metabolism, glycolysis, cellular activation, proliferation and survival.