Targeting cellurlar dysfunction with green tea polyphenols to treat the underlying basis of the metabolic complications of obesity

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Obesity is a metabolic disease with high risk of severe complications, including type 2 diabetes, cardiovascular disease, and cancer conditions. To develop natural approaches to obesity-associated metabolic complications a series of in vitro studies were conducted to evaluate effects of green tea polyphenols (GTP) on cellular dysfunction related to the development of obesity and its complications. Increased differentiation of adipocytes from preadipocytes contributes to fat mass expansion and leads to obesity and type 2 diabetes. The effects of GTP on fat cell differentiation and lipids accumulation were investigated in Chapter 3 using 3T3-L1 preadipocytes. The results demonstrated that GTP suppressed the differentiation of 3T3-L1 preadipocytes into mature adipocytes through down-regulating adipogenic regulators of PPARγ, C/EBPα, and SREBP-1c at gene expression and post-transcriptional level. The findings from this study suggest that GTP can combat unnecessary adipogenesis at the cellular level to prevent obesity and subsequently reduce the risk of type 2 diabetes and cardiovascular disease. Accumulating evidence demonstrated an increase of adipogenesis accompanied by osteoporosis in obese populations. Adipocytes and osteoblasts originate from a common ancestor, pluripotent mesenchymal stem cells. Based on the anti-adipogenic effect of GTP, the study in Chapter 4 investigated whether GTP possesses the ability to limit human adipose tissue-derived stem cells (hADSCs) differentiation to adipogenic lineage and concomitantly enhance osteogenesis. The study utilising hADSCs and PPARγ agonist identified PPARγ and Runx2 as essential regulators involved in adipogenesis and osteogenesis, respectively. GTP treatment inhibited ADSCs differentiation to mature adipocytes and promoted osteogenesis through suppressing the PPARγ-induced adipogenesis and upregulating Runx2-Bmp2 mediated osteogenic pathway. Therefore, the enhancement of osteogenesis with preventing adipogenesis with GTP may provide a rational approach towards developing GTP as multifaceted therapeutic goods for the intervention of obesity-associated osteoporosis. Polycystic Ovarian Syndrome (PCOS) is a complex of the metabolic and reproductive disorder. Obesity associated with insulin resistance plays an important role in excessive androgenesis by ovarian theca cells. Based on our observations that GTP is capable of enhancing insulin-mediated glucose and lipid metabolism with anti-obese effect study in Chapter 5 investigated whether GTP would be able to alternate ovarian cell dysfunction led abnormal steroidogenesis using dexamethasone-induced hyperandrogenism in primary thecal cells from female mice. GTP treatment inhibited over-secretion of testosterone in theca cells through downregulation of the expression of the cytochrome P450 17a-hydroxylase (CYP17A1) additionally reduced CYP11A1 expression at the high concentration (25 μg/mL). These findings provide scientific evidence to support the use of GTP for ovarian dysfunction leading to hyperandrogenism in PCOS. DNA methylation is essential for healthy development and is also involved in aging and carcinogenesis. The recent study using genome-wide DNA methylation analysis has identified hypermethylation as a potential epigenetic change of obesity-related cancer. Based on the antiadipogenic effect of GTP during ADSCs differentiation, the study in Chapter 6 evaluated the effects of GTP on DNA methylation in deferent passages of ADSCs. This study discovered GTP enhanced DNA methyltransferase 1 (biomarker of DNA methylation) expression without changing MYC expression at early stage of ADSCs passages and downregulated DNMT1 expression at passage 12 of ADSCs culture. These findings suggest GTP possesses dual regulatory effects on DNA methylation during ADSCs expansion with genomic stability, which highlights the potential use of this naturally occurring compound in ADCSs expansion for regenerative medicine without carcinogenic risk. In summary, in vitro studies conducted in this thesis have demonstrated beneficial effects of and molecular mechanisms of GTP on obesity and obesity-associated osteoporosis and PCOS. To gain deeper insight into therapeutic application of GTP for obesity and its metabolic complications, the animal studies and clinical trials are warranted in the future study.
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