Rutaecarpine Analogues Reduce Lipid Accumulation in Adipocytes via Inhibiting Adipogenesis/Lipogenesis with AMPK Activation and UPR Suppression

Obesity is characterized by expansion of adipose tissue, which results from an increase in adipocyte number (adipogenesis) and adipocyte size (lipogenesis). A reversal of these processes has been suggested to be a potential antiobetic therapy. Rutaecarpine (Rut) and its novel analogues (R17 and R18) were identified to exert potent effect in reducing lipid accumulation during adipocyte differentiation in 3T3-L1 adipocytes with little cytotoxicity. All three compounds reduced lipid accumulation in a dose-dependent manner, while R17 and R18 exhibited much more potent inhibitory effects compared to that of Rut. Further studies showed that R17 suppressed both adipogenesis and lipogenesis during all stages of adipocyte differentiation as indicated by the reduced protein and mRNA levels of key regulators of adipogenesis/lipogenesis, including PPARγ, C/EBPα, SREBP-1c, ACC, FAS, and SCD-1. We next examined the effect of R17 on the UPR pathway and the results showed that the UPR markers (PERK, eIF2α, IRE1α, and spliced XBP1 mRNA) were all significantly reduced by R17. Further studies revealed that R17 persistently activated AMPK during differentiation, suggesting that the AMPK may be an upstream mechanism for the effect of R17 on adipogenesis and lipogenesis via the adipogenic/lipogenic markers and the UPR pathway. Finally, studies in fast/refeeding mice demonstrated that R17 administration was able to reduce epididymal fat mass and the levels of plasma TG and FFA in vivo. Our results suggest that rutaecarpine analogues may have therapeutic potential for obesity and related metabolic disorders. The mechanism involves the suppression of adipogenic/lipogenic proteins and the suppression of the UPR pathway possibly via the AMPK.