title: A withanolide coagulin-L inhibits adipogenesis modulating Wnt/β-catenin pathway and cell cycle in mitotic clonal expansion.
abstract: Obesity is a result of adipocyte hypertrophy followed by hyperplasia. It is a risk factor for several metabolic disorders such as dyslipidemia, type-2 diabetes, hypertension, and cardiovascular diseases. Coagulanolides, particularly coagulin-L isolated from W. coagulan has earlier been reported for anti-hyperglycemic activity. In this study, we investigated the effect of coagulin-L on in vitro models of adipocyte differentiation including 3T3-L1 pre-adipocyte, mouse stromal mesenchymal C3H10T1/2 cells and bone marrow derived human mesenchymal stem cells (hMSCs). Our results showed that, coagulin-L reduces the expressions of peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα), the major transcription factors orchestrating adipocyte differentiation. Detailed analysis further proved that early exposure of coagulin-L is sufficient to cause significant inhibition during adipogenesis. Coagulin-L inhibited mitotic clonal expansion (MCE) by delayed entry in G1 to S phase transition and S-phase arrest. This MCE blockade was caused apparently by decreased phosphorylation of C/EBPβ, modulation in expression of cell cycle regulatory proteins, and upregulation of Wnt/β-catenin pathway, the early stage regulatory proteins of adipogenic induction. Taken together all evidences, a known anti-hyperglycemic agent coagulin-L has shown potential to inhibit adipogenesis significantly, which can be therapeutically exploited for treatment of obesity and metabolic syndrome.
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 Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Parul
authors.initials: P
authors.lastname: Chauhan
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.
authors.forename: Kripa
authors.initials: K
authors.lastname: Shankar
authors.affiliation: Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research, CSIR-CDRI, 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: Deepika
authors.initials: D
authors.lastname: Saini
authors.affiliation: Division of Botany, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: M N
authors.initials: MN
authors.lastname: Srivastava
authors.affiliation: Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow 226031, India. Electronic address: pp_yadav@cdri.res.in.
authors.forename: Prem P
authors.initials: PP
authors.lastname: Yadav
authors.affiliation: Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research, CSIR-CDRI, India. Electronic address: anil_gaikwad@cdri.res.in.
authors.forename: Anil Nilkanth
authors.initials: AN
authors.lastname: Gaikwad
mesh_terms: D041721:3T3-L1 Cells; D050156:Adipogenesis / Q000187:drug effects*; D000818:Animals; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000037:antagonists & inhibitors*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D006801:Humans; D051379:Mice; D008938:Mitosis / Q000187:drug effects; D009765:Obesity / Q000188:drug therapy; D047495:PPAR gamma / Q000037:antagonists & inhibitors; D008517:Phytotherapy; D010936:Plant Extracts / Q000494:pharmacology / Q000627:therapeutic use; D013234:Stem Cells / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D032341:Withania; D054358:Withanolides / Q000494:pharmacology* / Q000627:therapeutic use; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: D022763:CCAAT-Enhancer-Binding Protein-alpha; D047495:PPAR gamma; D010936:Plant Extracts; D054358:Withanolides; D051153:Wnt Proteins; D051176:beta Catenin; C000593591:coagulin-L; D050760:Cyclin-Dependent Kinase Inhibitor p27; D058570:TOR Serine-Threonine Kinases
keywords: 3T3-L1; Adipocytes; Adipogenesis; Coagulin-L; Mitotic clonal expansion; Obesity; Withania coagulans