title: A clerodane diterpene inhibit adipogenesis by cell cycle arrest and ameliorate obesity in C57BL/6 mice.
abstract: A clerodane diterpene, 16α-Hydroxycleroda-3, 13 (14) Z-dien-15, 16-olide (compound 1) isolated from Polyalthia longifolia had previously been reported as a new structural class of HMG-CoA reductase inhibitor apart from statins. Statins are known to be anti-adipogenic in nature. The distant structural similarity between compound 1 and lovastatin (polyketide class of compound) prompted us to investigate effects of diterpene compound 1 on adipogenesis and thereby obesity. High content microscopy proved diterpene compound 1 exhibits better anti-adipogenic activity and less toxicity in differentiating adipocytes. Moreover, it reduced expression levels of PPARγ, C/EBPα and GLUT4 during differentiation in a time and concentration dependent manner. Diterpene compound 1 during early differentiation reduced MDI induced-Akt/mTOR phosphorylation and expression of cell cycle proteins, and thereby halted mitotic clonal expansion, the decisive factor in early adipogenesis. Further, its anti-adipogenic activity was validated in murine mesenchymal cell-line C3H10T1/2 and human mesenchymal stem cell models of adipogenic differentiation. When compound 1 was administered along with HFD, for another 8 weeks in 2 month HFD fed overweight mice (with BMI > 30 and impaired glucose tolerance), it attenuated weight gain and epididymal fat accumulation. It improved body glucose tolerance, reduced HFD induced increase in total cholesterol and leptin/adiponectin ratio. All these effects were comparable with standard anti-obesity drug Orlistat with added edge of potently decreasing circulating triglyceride levels comparable with normal chow fed group. Histological analysis shows that compound 1 inhibit adipocyte hypertrophy and decreased steatosis in hepatocytes. Both in vivo and in vitro results demonstrate a potential value of compound 1 as a novel anti-adipogenic and anti-obesity agent.
authors.affiliation: Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Muheeb
authors.initials: M
authors.lastname: Beg
authors.affiliation: Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Kripa
authors.initials: K
authors.lastname: Shankar
authors.affiliation: Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Salil
authors.initials: S
authors.lastname: Varshney
authors.affiliation: Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Sujith
authors.initials: S
authors.lastname: Rajan
authors.affiliation: Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Suriya Pratap
authors.initials: SP
authors.lastname: Singh
authors.affiliation: Pathology Laboratories, CSIR-Indian Institute of Toxicology Research, M.G. Road, Lucknow 226001, India.
authors.forename: Pankaj
authors.initials: P
authors.lastname: Jagdale
authors.affiliation: Division of Biochemistry, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Anju
authors.initials: A
authors.lastname: Puri
authors.affiliation: Pathology Laboratories, CSIR-Indian Institute of Toxicology Research, M.G. Road, Lucknow 226001, India.
authors.forename: Bhushan P
authors.initials: BP
authors.lastname: Chaudhari
authors.affiliation: Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow 226031, India. Electronic address: kv_sashidhara@cdri.res.in.
authors.forename: Koneni V
authors.initials: KV
authors.lastname: Sashidhara
authors.affiliation: Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research, CSIR-Central Drug Research Institute, Lucknow 226031, India. Electronic address: anil_gaikwad@cdri.res.in.
authors.forename: Anil Nilkanth
authors.initials: AN
authors.lastname: Gaikwad
mesh_terms: D050156:Adipogenesis / Q000187:drug effects*; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D002460:Cell Line; D045785:Diterpenes, Clerodane / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D051379:Mice; D009765:Obesity / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D047495:PPAR gamma / Q000378:metabolism
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; C530718:CEBPA protein, mouse; D045785:Diterpenes, Clerodane; D051275:Glucose Transporter Type 4; D047495:PPAR gamma; C495693:Slc2a4 protein, mouse
keywords: 3T3-L1 adipocyte; Clerodane diterpene; Obesity; Orlistat; Statins