A novel tocopherol derivative suppresses obesity in high-fat diet-induced obese mice

Lipid accumulation plays a pivotal role in obesity pathogenesis, aggravating the metabolic and inflammatory burden. However, drugs targeting lipid accumulation inhibition remains limited. α-Tocopheryl succinate (TS), a succinic ester of α-tocopherol (T), inhibits lipid accumulation but exhibits cytotoxicity (Majima et al., Biol. Pharm. Bull 2021). We previously developed α-tocopheryl adipate (Tadi) as a potential anti-obesity drug candidate. Tadi is an adipic acid ester of T, and was found to inhibit lipid accumulation without cytotoxicity (Yamasaki et al., Biochem Biophys Rep 2022). However, hydrolysis of its ester moiety attached to the phenolic hydroxyl group of T raises concerns about its chemical stability and oral administration. Herein, we synthesized deoxo α-tocopheryl adipate (dTadi), a novel α-tocopherol derivative, which is an ether analog of Tadi, in which the ester bond is replaced by an ether bond. Structural modification enhances the stability of dTadi over Tadi. dTadi significantly reduced lipid accumulation without cytotoxicity in vitro. Moreover, oral administration of dTadi dose-dependently suppressed body weight increase (by 13 %-20 %) in high-fat diet (HFD)-fed C57BL/6J mice without altering food intake in vivo. Additionally, dTadi significantly reduced blood glucose levels and serum triglyceride concentrations in a dose-dependent manner. dTadi treatment reduced epididymal and retroperitoneal fat mass while also attenuating adipose hypertrophy and reducing lipid accumulation in the liver. Safety studies revealed that dTadi produced no adverse effects. Lastly, dTadi treatment significantly increased glycerol release, uncoupling protein1 (UCP1), and fatty acid β-oxidation in vitro. These results demonstrate that dTadi may be a potential candidate for an oral anti-obesity drug.