A clerodane diterpene inhibit adipogenesis by cell cycle arrest and ameliorate obesity in C57BL/6 mice
•For the first time, we report a Clerodane diterpene class of compound as an anti-adipogenic molecule.•Compound-1 exhibit beneficial effects as an anti-obesitic agent in high fat fed high BMI mice studies.•Anti-dyslipidemic and anti-obesitic properties of compound-1 proves it a potent translational...
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Veröffentlicht in: | Molecular and cellular endocrinology 2015-01, Vol.399, p.373-385 |
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Sprache: | eng |
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Zusammenfassung: | •For the first time, we report a Clerodane diterpene class of compound as an anti-adipogenic molecule.•Compound-1 exhibit beneficial effects as an anti-obesitic agent in high fat fed high BMI mice studies.•Anti-dyslipidemic and anti-obesitic properties of compound-1 proves it a potent translational lead candidate for metabolic disorders.
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. |
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ISSN: | 0303-7207 1872-8057 |
DOI: | 10.1016/j.mce.2014.09.024 |