A clerodane diterpene inhibit adipogenesis by cell cycle arrest and ameliorate obesity in C57BL/6 mice. (5th January 2015)

• Record Type: Journal Article
• Authors: Beg, Muheeb; Shankar, Kripa; Varshney, Salil; Rajan, Sujith; Singh, Suriya Pratap; Jagdale, Pankaj; Puri, Anju; Chaudhari, Bhushan P.; Sashidhara, Koneni V.; Gaikwad, Anil Nilkanth
• Is Part Of: Molecular and cellular endocrinology. Volume 399(2015)
• Page Start: 373
• Page End: 385
• Publication Date: 2015-01-05
• Subjects: Clerodane diterpene -- Statins -- 3T3-L1 adipocyte -- Obesity -- Orlistat; Endocrinology -- Periodicals; Molecular biology -- Periodicals; Cytology -- Periodicals; Endocrinology -- Periodicals; Hormones -- Periodicals; Endocrinologie -- Périodiques; Cytology; Endocrinology; Molecular biology; Periodicals; 573.4
• DOI: 10.1016/j.mce.2014.09.024
• Languages: English
• ISSNs: 0303-7207

Abstract

Highlights: 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. Abstract: A clerodane diterpene, 16 α -Hydroxycleroda-3, 13 (14) Z-dien-15, 16-olide (compound1 ) 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 compound1 and lovastatin (polyketide class of compound) prompted us to investigate effects of diterpene compound1 on adipogenesis and thereby obesity. High content microscopy proved diterpene compound1 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 compound1 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 compound1 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 compound1 inhibit adipocyte hypertrophy and decreased steatosis in hepatocytes. Both in vivo and in vitro results demonstrate a potential value of compound1 as a novel anti-adipogenic and anti-obesity agent.