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Anti-obesity study of Indonesian medicinal plants : an in vitro study in adipocytes

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Title: Anti-obesity study of Indonesian medicinal plants : an in vitro study in adipocytes
Other Titles: 脂肪細胞を対象としたインドネシア薬用植物の抗肥満研究
Authors: Lahrita, Lucy Browse this author
Issue Date: 25-Sep-2018
Publisher: Hokkaido University
Abstract: Obesity has become a global health problem due to its association with major life-threatening diseases including cardiovascular diseases, type 2 diabetes and numerous cancers. Over the past decades, only few anti-obesity drugs have been developed and approved. In fact, some drugs have been withdrawn from the market due to their serious side-effects. With the alarming rise of obese individuals globally and in view of the dissatisfactions with synthetic drugs, there is a growing shift towards natural product-based medications. In this study, investigation of potential anti-obesogenic agents was conducted from Indonesian medicinal plants. Indonesia, a Southeast Asian country, is rich in flora diversity which have been used as herbal medicines. Two plants, Eurycoma longifolia and Brucea javanica (both from family Simaroubaceae) were investigated for their lipolytic activity, a bioactivity to break down triglyceride into glycerol in adipocytes. Several lipolytic compounds were isolated from these plants and were further studied for their cellular mechanisms of actions. In addition, an anti-obesogenic screening was conducted to explore different mode of action from Indonesian medicinal plants. 1. Study of lipolytic activity from E. longifolia The roots extract of E. longifolia have been widely used as aphrodisiac in Southeast Asian traditional medicine. Our previous study demonstrated its activity to reduce lipid accumulation in 3T3-L1 white adipocytes without cytotoxicity, indicating an antiobesogenic activity. In current study, further investigation on lipolytic activity from this plant was conducted, including isolation of its active compounds, and lipolytic mechanisms for its extract and active compounds. Additionally, explorative study on the bioactivities of the active compounds in brown adipocytes, different type of adipocytes known for its thermogenesis, was studied. Based on glycerol release assay, the extract of E. longifolia (EL) exerted lipolytic activity in 3T3-L1 adipocytes in a concentration-dependent manner. Subsequent molecular mechanistic study using several specific inhibitors to lipolytic signaling pathways showed that PKA and ERK inhibitors attenuate the lipolytic activity of EL. Further immunoblotting analysis confirmed that EL activates PKA and ERK phosphorylation by 200% and 250%, respectively. Based on bioassay-guided fractionation, two lipolytic compounds, eurycomanone (1) and 13β,21-epoxyeurycomanone (2), were isolated from E. longifolia. Compound 1 enhanced lipolysis in adipocytes with an EC50 of 14.6 μM, while its epoxy derivate, compound 2, had a stronger activity with an EC50 of 8.6 μM. Molecular mechanistic study found that PKA inhibitor totally diminishes the lipolytic activity of 1 and 2. Furthermore, immunoblotting analysis confirmed the activation of phosphorylated PKA by both 1 and 2. When tested in WT-1 brown adipocytes, compounds 1 and 2 also reduced lipid accumulation and exerted lipolytic activity, suggesting a potential of thermogenesis stimulation. 2. Lipolytic activity of B. javanica The fruit of B. javanica has been used by local Indonesian people in traditional medicine for the treatment of dysentery, malaria, and cancers. So far, there was not much research that studies its activity in glucose and lipid metabolisms. This is the first study to explore potential anti-obesity activity from B. javanica. In this study, B. javanica demonstrated strong lipolytic activity in white adipocytes, thus further study was conducted to identify its lipolytic compounds. Bioassay-guided fractionation from B. javanica has isolated several lipolytic compounds, including brucein A (5), brusatol (6), brucenatinol (7), brucein B (8), 3’-hydroybrucein A (9), and bruceine C (10). Some isolated compounds from this plant have demonstrated much stronger lipolytic activity compared to two isolated compounds from E. longifolia. 3. Anti-obesogenic screening of Indonesian medicinal plants The 76 selected Indonesian plant extracts were subjected to two bioassays, namely lipid accumulation and glycerol release assays. The results of this screening revealed plant species that exert different lipid metabolism regulatory effects in adipocytes. There are plants that reduce lipid accumulation and enhance lipolysis, B. javanica, Melaleuca leucadendra, Zingiber purpureum, and Clerodendrum serratum. There are some plants that enhance lipolysis but not reduce lipid accumulation, Leucas lavandulifolia, Mentha arvensis, Pimpinella anisum, E. longifolia, Piper crocatum, Guazuma ulmifolia, and Sapindus rarak. There is also a plant that reduces lipid accumulation but not enhance lipoysis, Momordica charantia. Taken together, the findings of this study provide significant contributions to the body of knowledge in anti-obesity research from Indonesian medicinal plants. Not only has this study provided scientific basis and rationale for the use of those potential plants for medicinal purposes, but it has also provided information on different mode of anti-obesity effects to address this global health problem.
Conffering University: 北海道大学
Degree Report Number: 甲第13325号
Degree Level: 博士
Degree Discipline: 農学
Examination Committee Members: (主査) 准教授 園山 慶, 特任教授 原 博, 教授 松浦 英幸, 講師 加藤 英介
Degree Affiliation: 農学院(応用生物科学専攻)
Type: theses (doctoral)
Appears in Collections:課程博士 (Doctorate by way of Advanced Course) > 農学院(Graduate School of Agriculture)
学位論文 (Theses) > 博士 (農学)

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