Abstract:
We developed a common feature pharmacophore model using known anti-adipogenic compounds (CFPMA). We identified rohitukine, a reported chromone anti-cancer alkaloid as potential hit through in silico mapping of in-house natural product library on CFPMA. Studies were designed to assess anti-adipogenic potential of rohitukine. Rohitukine was isolated from Dysoxylumbinacteriferum Hook. to> 95% purity. As predicted by CFPMA, rohitukine indeed found to be anti-adipogenic molecule. Rohitukine inhibited lipid accumulation and adipogenic differentiation in concentration and exposure time dependent manner in 3T3-L1 and C3H10T1/2 cells. Rohitukine down-regulated expression of PPARγ, C/EBPα, aP2, FAS and GLUT4. It also suppressed mRNA expression of LPL, SREBP-1c, FAS and aP2, the downstream targets of PPAR. Rohitukine arrests cells in S-phase during mitotic clonal expansion.
Rohitukine was bio-available and 25.7% of orally administered compound reached in systemic circulation. We evaluated effect of rohitukine on high fat diet induced dyslipidemia in the hamster model. Rohitukine increased hepatic expression of LXRα and decreased expression of SREBP2 and associated targets. Rohitukine decreased hepatic and gonadal lipid accumulation and ameliorated dyslipidemia significantly.
In summary, our strategy to identify novel anti-adipogenic molecule using CFPMA successfully resulted in identification of rohitukine, which confirmed anti-adipogenic activity and also exhibited in vivo anti-dyslipidemic activity.
