Doctor of Philosophy (PhD)
First Advisor's Name
M. Alejandro Barbieri
First Advisor's Committee Title
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Fourth Advisor's Name
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Fifth Advisor's Name
Fifth Advisor's Committee Title
adipogenesis, obesity, sesquiterpene lactones, mitotic clonal expansion
Date of Defense
For the first time in human history, more people worldwide suffer from obesity than are undernourished. Numerous health complications are associated with obesity including cardiovascular disease, Type 2 Diabetes, cancers of reproductive tissues, stroke, depression, anxiety disorders, and Alzheimer’s disease. A deeper understanding of the anti-adipogenic effects and mechanism of action of sesquiterpene lactones may have pharmacological import in the continuing search for therapeutic modalities to ameliorate the effects of this global obesity epidemic.
Dehydroleucodine (DhL), 11,13-dihydro-dehydroleucodine (DH-DhL), and dehydroparashin-B (DhP), sesquiterpene lactones extracted from or derived from compounds extracted from Artemisia douglasiana, were investigated for their anti-adipogenic effects on 3T1-L1 preadipocytes.
Dehydroleucodine inhibited the expression of C/EBPa and PPARg, and also strongly blocked the expression of C/EBPβ, an early stage biomarker of early adipogenesis, in a concentration-dependent manner. Dehydroleucodine arrested the cell cycle at the G0/G1 phase, increased p27 and decreased both cyclins A and D and their partners (e.g., CDK2 and CDK4). Furthermore, DhL downregulated expression of histone demethylase JMJD2 as well as repressed the expression of histone methyltransferase MLL4, which in turn diminished the expression of C/EBPb and PPARg, respectively.
11,13-dihydro-dehydroleucodine blocked the accumulation of lipid droplets and inhibited the expression of PPARγ and C/EBPβ. Collectively, the results indicate that the inhibition of early stage preadipocyte differentiation by DH-DhL may be associated with cell cycle arrest at the G0/G1 phase.
Dehydroparashin-B significantly decreased the accumulation of lipid content and downregulated the expression of CEBPβ, PPARγ and CEBPα as well as FAS. Interestingly, the addition of DhP inhibited the number as well as the size of the lipid droplets during the differentiation of 3T3-L1 preadipocytes. Taken together, this data suggests that DhP has an important inhibitory effect on cellular pathways regulating adipocyte differentiation.
Abood, Steven, "The Effects of Artemisia Derived Natural Products on Adipogenesis" (2017). FIU Electronic Theses and Dissertations. 3383.
Available for download on Tuesday, July 23, 2019
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