Rohitukine inhibits in vitro adipogenesis arresting mitotic clonal expansion and improves dyslipidemia in vivo

We developed a common feature pharmacophore model using known antiadipogenic compounds (CFPMA). We identified rohitukine, a reported chromone anticancer alkaloid as a potential hit through in silico mapping of the in-house natural product library on CFPMA. Studies were designed to assess the antiadipogenic potential of rohitukine. Rohitukine was isolated from Dysoxylum binacteriferum Hook. to ⬧95% purity. As predicted by CFPMA, rohitukine was indeed found to be an antiadipogenic molecule. Rohitukine inhibited lipid accumulation and adipogenic differentiation in a concentration- and exposure-time-dependent manner in 3T3-L1 and C3H10T1/2 cells. Rohitukine downregulated expression of PPARγ, CCAAT/enhancer binding protein α, adipocyte protein 2 (aP2), FAS, and glucose transporter 4. It also suppressed mRNA expression of LPL, sterol-regulatory element binding protein (SREBP) 1c, FAS, and aP2, the downstream targets of PPARγ. Rohitukine arrests cells in S phase during mitotic clonal expansion. Rohitukine was bioavailable, and 25.7% of orally administered compound reached systemic circulation. We evaluated the effect of rohitukine on dyslipidemia induced by high-fat diet in the hamster model. Rohitukine increased hepatic expression of liver X receptor α and decreased expression of SREBP-2 and associated targets. Rohitukine decreased hepatic and gonadal lipid accumulation and ameliorated dyslipidemia significantly. In summary, our strategy to identify a novel antiadipogenic molecule using CFPMA successfully resulted in identification of rohitukine, which confirmed antiadipogenic activity and also exhibited in vivo antidyslipidemic activity. We developed a common feature pharmacophore model using known antiadipogenic compounds (CFPMA). We identified rohitukine, a reported chromone anticancer alkaloid as a potential hit through in silico mapping of the in-house natural product library on CFPMA. Studies were designed to assess the antiadipogenic potential of rohitukine. Rohitukine was isolated from Dysoxylum binacteriferum Hook. to ⬧95% purity. As predicted by CFPMA, rohitukine was indeed found to be an antiadipogenic molecule. Rohitukine inhibited lipid accumulation and adipogenic differentiation in a concentration- and exposure-time-dependent manner in 3T3-L1 and C3H10T1/2 cells. Rohitukine downregulated expression of PPARγ, CCAAT/enhancer binding protein α, adipocyte protein 2 (aP2), FAS, and glucose transporter 4. It also suppressed mRNA expression of LPL, sterol-regulatory element binding protein (SREBP) 1c, FAS, and aP2, the downstream targets of PPARγ. Rohitukine arrests cells in S phase during mitotic clonal expansion. Rohitukine was bioavailable, and 25.7% of orally administered compound reached systemic circulation. We evaluated the effect of rohitukine on dyslipidemia induced by high-fat diet in the hamster model. Rohitukine increased hepatic expression of liver X receptor α and decreased expression of SREBP-2 and associated targets. Rohitukine decreased hepatic and gonadal lipid accumulation and ameliorated dyslipidemia significantly. In summary, our strategy to identify a novel antiadipogenic molecule using CFPMA successfully resulted in identification of rohitukine, which confirmed antiadipogenic activity and also exhibited in vivo antidyslipidemic activity. Obesity and associated disorders have shifted from an epidemic state to pandemic proportions (1Ginsberg H.N. MacCallum P.R. The obesity, metabolic syndrome, and type 2 diabetes mellitus pandemic: Part I. Increased cardiovascular disease risk and the importance of atherogenic dyslipidemia in persons with the metabolic syndrome and type 2 diabetes mellitus.J. Cardiometab. Syndr. 2009; 4: 113-119Crossref PubMed Scopus (196) Google Scholar). Although factors responsible for obesity are still unclear, the increase in lipid content of adipocytes is considered relevant. These cells constitute roughly 1/6 of body weight and are involved in both catabolic and anabolic processes. By virtue of their capacity to secrete various adipokines and cyto­kines, adipocytes have gained the status of an important endocrine tissue (2Adamczak M. Wiecek A. The adipose tissue as an endocrine organ.Semin. Nephrol. 2013; 33: 2-13Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar). In a constant renewal process, ∼50% of subcutaneous adipocytes are replaced every 8 years (3Taillan B. Fuzibet J.G. Garnier G. Pesce A. Vinti H. Saint-Paul M.C. Dujardin P. [Hepatic involvement in human immunodeficiency virus infection. 104 histologically documented cases].Ann. Med. Interne (Paris). 1991; 142 (French.): 226-227PubMed Google Scholar); thus, adipocytes are a good target for pharmacological intervention of obesity. 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Therefore, exploiting the literature on diverse antiadipogenic compounds, developed and a Hiphop model to common pharmacophore properties of antiadipogenic molecules feature pharmacophore model using known antiadipogenic compounds We model to virtual screening of an in-house natural compound library in with feature of pharmacophore reported for antiadipogenic We identified rohitukine as a potential hit Rohitukine is a chromone alkaloid reported to be isolated from Dysoxylum Hook. and It reported for various biological and properties inhibition by Med. Chem. 2012; PubMed Scopus Google Scholar, N. P. S. G. effect of compound of and 2012; PubMed Scopus Google Scholar, P. S. S. G. M. an from Dysoxylum rohitukine, a alkaloid 2012; PubMed Scopus Google Scholar, G. K. and properties of the of Dysoxylum in and docking analysis of rohitukine, the alkaloid isolated from 2007; Full Text Full Text PDF PubMed Scopus Google Scholar, K. A. N. M. A. In and in vivo activity of Dysoxylum and 2007; Full Text Full Text PDF PubMed Scopus Google Scholar, M. G. induces apoptosis of and potent activity in vivo human and Google Scholar). of and are evaluated in phase 2 for potential anticancer inhibition by Med. Chem. 2012; PubMed Scopus Google Scholar). Many natural compounds like genistein, and which antiadipogenic have also found to be anticancer Zhang T. gallate is the in 2012; 4: PubMed Scopus Google Scholar, J. M. A. of in Mol. Med. 2012; PubMed Scopus Google Scholar, J.W. K. and quercetin, of apoptosis in Res. PubMed Scopus Google Scholar). have an obesity and I. Obesity and and N. Y. Sci. 2012; PubMed Scopus Google Scholar, P. A. and a of their relationship to metabolic syndrome, cardiovascular and in 2013; PubMed Scopus Google Scholar, K. M. T. T. M. The via in Sci. 2013; PubMed Scopus Google Scholar). The target of is the both obesity and As antiadipogenic activity of rohitukine was reported was to assess antiadipogenic In the the effects of rohitukine on adipocyte differentiation in 3T3-L1 and C3H10T1/2 cells the of We effects in terms of lipid accumulation and in and protein expression for various the effect of rohitukine in a high-fat diet hamster model of rohitukine the phase of adipogenic differentiation by inhibiting and also to cycle during mitotic clonal at expression of PPARγ, CCAAT/enhancer binding protein α, adipocyte protein 2 (aP2), FAS, and glucose transporter and to inhibition of Rohitukine also exhibited in vivo antidyslipidemic effects in the hamster model. diverse compounds of antiadipogenic capacity were as a of and on the inhibition of adipogenesis in 3T3–L1 Chem. 2007; PubMed Scopus Google Scholar). was using the Hiphop of Catalyst in the compounds in the study were using and to These compounds were using the field Version 4.1 ed. 2006. Accelrys Inc., San Diego, CA.Google Scholar, S. M. a for and Comput. Chem. 4: Scopus Google Scholar, A. P. Comput. Chem. Scopus Google of diverse of molecules with the of the The potent compound in the inhibited and the compound of increased lipid accumulation during adipogenesis of and on the inhibition of adipogenesis in 3T3–L1 Chem. 2007; PubMed Scopus Google Scholar). The was a of 2 and of to features of molecule are considered for of the molecules of the and were as and The was to 2 from the of in to the are in the compounds as as 2 This was to the in the compounds and in acid, which are in of the compounds involved in the 3T3-L1 mapping was to identify the common features in the As lipid to to and to were during the pharmacophore Rohitukine was isolated and as N. P. S. G. effect of compound of and 2012; PubMed Scopus Google Scholar). of Dysoxylum was with by The were and to a It was to the of of was and and The on a known rohitukine The compound was using and with the was by and found to be The 3T3-L1 and C3H10T1/2 were from the were in a at and in and adipogenic cells were in was replaced with differentiation insulin and This was replaced with This was replaced and cells were in from and of cells lipid study the effect of rohitukine on adipogenic cells were at to rohitukine as in the 3T3-L1 or adipocytes were in The adipocyte lipid were with in for was using and was at were in and were and in and protein were using as were and an of protein was by It was to The were with in with the were with for at by with for The target were using using and was as was isolated from 3T3-L1 cells and using was performed using and for quantitative analysis on analysis of the quantitative was using the which the in expression of the to an in in and for in vivo and to a as a in are in for expression binding protein liver X sterol-regulatory element binding in a binding protein liver X sterol-regulatory element binding 3T3-L1 were in adipogenesis with or rohitukine at different The cells were and in cells were in cells were in for at were on a was performed using to the of cells in and assess was induction of differentiation of 3T3-L1 with or rohitukine in the of of for cells were with with and more with were in 2 and were by was from to dyslipidemia in body were as the of for the of and on on and by the of was in The with identification were for The of was with like diet and were with for to to diet and at was administered at the The diet of the was for the the body weight of the was and drug Rohitukine was in the and orally at a for to the and was administered to the The from the of was in and was and were from using The of adipose and liver were in and in tissue and liver were with and to the In vivo study was performed in weight and of rohitukine were at and for were on to were from the as at and was performed by the at for were by the phase using were with 2 and by 2 were to with and the were with of were with 2 of The were in and to in a at These were in and was to Rohitukine and were on a size with a was as The was in with a phase of at a of The was to and for rohitukine and The of were using the analysis of in vivo were as and for in were as the was for of of and were as of were on Inc., San Diego, The developed common feature pharmacophore of and the pharmacophore with from to the pharmacophore were for the of the of the pharmacophore features and the with and which different of in the the of was the which the predicted the and compounds the on the of the of the and the mapping of the and the compounds was for The of pharmacophore model was using an of reported compounds were in the These compounds were on using pharmacophore mapping using The of molecules were in the I. The compounds in their The based of compounds are in The compound with the of the the of and the at the model was as a for in-house virtual screening of compounds resulted in identification of the rohitukine, which was for in the activity. Rohitukine to the on as with the compound of the rohitukine to the pharmacophore model of at 8 of the to the the of feature as and at the of the the of of lipid or or a molecule every feature of the or a molecule to feature in the lipid or in a or a molecule every feature of the or a molecule to feature in the of rohitukine were added to the during rohitukine decreased lipid accumulation in 3T3-L1 and C3H10T1/2 adipocytes in a manner of in lipid rohitukine inhibits adipogenesis at a and of increased lipid accumulation was inhibited at a rohitukine was found to be in 3T3-L1 cells using based Rohitukine was added during and of rohitukine to decreased lipid accumulation in with a inhibition at of was to in lipid accumulation and adipogenesis in 3T3-L1 adipocytes 2 with at a mRNA expression of PPARγ, FAS, and LPL, were a was in the of in analysis This was also by the protein expression of PPARγ, aP2, FAS, and expression was found to be suppressed as with during phase and of adipogenesis and target of were in rohitukine during adipogenesis The expression of antiadipogenic factors and was increased and by of rohitukine of adipogenic mRNA of LPL, aP2, FAS, PPARγ, and on of adipocyte differentiation was by in the and of rohitukine in Rohitukine to the phase protein expression of PPARγ, aP2, and in 3T3-L1 adipocytes on and of Rohitukine inhibits of and by Rohitukine the mRNA of and on 2 by The were by of the and rohitukine an antiadipogenic potential in and was for of was added to cells to of the cycle is for of rohitukine to a of rohitukine of adipogenesis was of cells were in S phase with of cells with This increase cells either S phase or in S was in expression analysis of cycle performed at and Rohitukine of and protein These are to in to of rohitukine in of of as as a expression of which can be to inhibition of and was also confirmed by Rohitukine inhibited at a The with drug in systemic circulation. in rohitukine have reported was in the which rohitukine was and of rohitukine systemic administered It be in and in for more of rohitukine and the from to of in a the from to of were designed to in vivo effects of rohitukine at and We the of lipid like and and diet as as body weight These the lipid be associated with decreased to regulation of or a study to the of rohitukine associated lipid was for in and The was with an of diet was by the in body weight was in the from the was a and comparative lipid was performed and We in and We also in in the rohitukine to lipid the was increased We and adipose of Rohitukine increased hepatic mRNA expression expression of and SREBP-2 were significantly. in the hepatic mRNA expression of and tissue weight was increased in the was in the expression in adipose tissue expression was was in FAS, aP2, and the effects of rohitukine on were to and hamster adipocytes were with the We also more lipid accumulation in the liver as in hepatic in were in In also more accumulation in which was in the In developed for the a CFPMA. We the potential of an in-house library of natural compounds and identified rohitukine as a molecule. rohitukine antiadipogenic activity in more model of in Rohitukine inhibition was added in the phase of by in In vivo in rohitukine antidyslipidemic activity both liver and adipocyte clonal 3T3-L1 is considered an model to identify molecules Many have in for their potential to adipogenesis lipid accumulation and have (11Rayalam S. Della-Fera M.A. Baile C.A. Phytochemicals and regulation of the adipocyte life cycle.J. Nutr. Biochem. 2008; 19: 717-726Crossref PubMed Scopus (331) Google Scholar). many and compounds are to and adipogenesis of and on the inhibition of adipogenesis in 3T3–L1 Chem. 2007; PubMed Scopus Google Scholar). 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In of intervention adipocyte as as weight which was in the Rohitukine also expression of PPARγ, FAS, aP2, and in gonadal decreased lipid accumulation was increased in in the and rohitukine decreased lipid accumulation and to Although is the of to the to antiadipogenic molecules antidyslipidemic activity, rohitukine also in vivo antidyslipidemic and are in for activity. The compounds on and CFPMA predicted of and for This to novel antiadipogenic for The pharmacophore mapping of compounds in the In summary, our to the of the pharmacophore model of antiadipogenic compounds for identification of rohitukine as the molecule. We rohitukine both antiadipogenic activity in and antidyslipidemic activity in of rohitukine for and is on many rohitukine is the pharmacophore of molecules in the anticancer drug and and both of also for feature of antiadipogenic It be to the antiadipogenic potential of molecules and their on the of with adipocyte protein 2 CCAAT/enhancer binding protein common feature pharmacophore model using known antiadipogenic compounds glucose transporter lipid high-fat diet receptor liver X receptor mitotic clonal and insulin diet sterol-regulatory element binding protein