Dataset Information

Multiplatform Metabolomics Investigation of Antiadipogenic Effects on 3T3-L1 Adipocytes by a Potent Diarylheptanoid.

ABSTRACT: Obesity is fast becoming a serious health problem worldwide. Of the many possible antiobesity strategies, one interesting approach focuses on blocking adipocyte differentiation and lipid accumulation to counteract the rise in fat storage. However, there is currently no drug available for the treatment of obesity that works by inhibiting adipocyte differentiation. Here we use a broad-based metabolomics approach to interrogate and better understand metabolic changes that occur during adipocyte differentiation. In particular, we focus on changes induced by the antiadipogenic diarylheptanoid, which was isolated from a traditional Chinese medicine Dioscorea zingiberensis and identified as (3 R,5 R)-3,5-dihydroxy-1-(3,4-dihydroxyphenyl)-7-(4-hydroxyphenyl)-heptane (1). Targeted aqueous metabolic profiling indicated that a total of 14 metabolites involved in the TCA cycle, glycolysis, amino acid metabolism, and purine catabolism participate in regulating energy metabolism, lipogenesis, and lipolysis in adipocyte differentiation and can be modulated by diarylheptanoid 1. As indicated by lipidomics analysis, diarylheptanoid 1 restored the quantity and degree of unsaturation of long-chain free fatty acids and restored the levels of 171 lipids mainly from 10 lipid classes in adipocytes. In addition, carbohydrate metabolism in diarylheptanoid-1-treated adipocytes further demonstrated the delayed differentiation process by flux analysis. Our results provide valuable information for further understanding the metabolic adjustment in adipocytes subjected to diarylheptanoid 1 treatment. Moreover, this study offers new insight into developing antiadipogenic leading compounds based on metabolomics.

SUBMITTER: Du D

PROVIDER: S-EPMC6289581 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Multiplatform Metabolomics Investigation of Antiadipogenic Effects on 3T3-L1 Adipocytes by a Potent Diarylheptanoid.

Du Dan D Gu Haiwei H Djukovic Danijel D Bettcher Lisa L Gong Meng M Zheng Wen W Hu Liqiang L Zhang Xinyu X Zhang Renke R Wang Dongfang D Raftery Daniel D

Journal of proteome research 20180503 6

Obesity is fast becoming a serious health problem worldwide. Of the many possible antiobesity strategies, one interesting approach focuses on blocking adipocyte differentiation and lipid accumulation to counteract the rise in fat storage. However, there is currently no drug available for the treatment of obesity that works by inhibiting adipocyte differentiation. Here we use a broad-based metabolomics approach to interrogate and better understand metabolic changes that occur during adipocyte dif ...[more]

PMID: 29688022

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Project description:Since obesity causes at least 2.8 million death each year and is a major risk factor for many diseases, it is critical to evaluate alternative treatment approaches. In this context, studies on the research of natural product-based therapeutics in the fight against obesity are increasing. In this study, it was aimed to evaluate the antiadipogenic and antiobesogenic efficacy of pterostilbene a natural phenolic compound in 3T3-L1 cells. The mature 3T3-L1 adipocytes were exposed to pterostilbene at different concentrations and half-maximum inhibitory concentrations (IC50) were determined by MTT assay. Oil-Red-O staining was applied to determine lipid accumulation. Phase contrast microscopy, Giemsa, F-actin and DAPI staining were applied to examine the efficacy of pterostilbene on the morphology of 3T3-L1 adipocyte cells. Moreover, expressions of adinopectin and glucose transporter-4 (Glut-4) in relation to insulin resistance were evaluated using immunofluorescent staining and qRT-PCR. Pterostilbene caused no significant cytotoxicity towards preadipocytes at concentrations ≤7.5 -M and the percentage of viable cells remained above about 86% for 24 h, 48 h and 72 h (p > 0.05). Therefore, pterostilbene treatment at 5 and 7.5 -M was used in the subsequent experiments as safe dosages. In addition, it was observed that pterostilbene treatment reduced lipid accumulation in adipocyte differentiation. Adipocytes treated with a dose of 7.5 -M for 14 days showed less intense lipid deposition and a more spindle-like morphology compared to the adipocytes treated with a dose of 5 -M. Especially on the 14th day, actin filaments were filamentous in adipocytes treated with pterostilbene 7.5 -M compared to the adipocytes treated with a dose of 5 -M; the filaments were similarly oriented as in preadipocytes, and chromatin condensation was observed to be quite high. Our data suggests that the pterostilbene supplementation may help weight control and the antiadipogenic and that antiobesogenic activity is mediated in part by reduction of lipid accumulation and induction of Glut-4 and Adiponectin levels.

Project description:The differentiation of precursor cells into mature adipocytes (adipogenesis) has been an area of increased focus, spurred by a rise in obesity rates. Though our understanding of adipogenesis and its regulation at the cellular level is growing, many questions remain, especially regarding the regulation of the metabolome. The 3T3-L1 cell line is the most well characterized cellular model of adipogenesis. Using a time course metabolomics approach, we show that the 3T3-L1 preadipocyte metabolome is greatly altered during the first 48 hours of differentiation, where cells go through about two rounds of cell division, a process known as mitotic clonal expansion. Short-chain peptides were among several small molecules that were increased during mitotic clonal expansion. Additional indicators of protein turnover were also increased, including bilirubin, a degradation product of heme-containing proteins, and 3-methylhistidine, a post-translationally modified amino acid that is not reutilized for protein synthesis. To study the origin of the peptides, we treated differentiating preadipocytes with 18O labeled water and found that 18O was incorporated into the short chain peptides, confirming them, at least in part, as products of hydrolysis. Inhibitors of the proteasome or matrix metalloproteinases affected the peptide levels during differentiation, but inhibitors of autophagy or peptidases did not. 18O was also incorporated into several choline metabolites including cytidine 5'-diphosphocholine (CDP-choline), glycerophosphocholine, and several phosphatidylcholine species, indicative of phosphatidylcholine synthesis/degradation and of flux through the CDP-choline cycle, a hallmark of proliferating cells. 18O-Tracer metabolomics further showed metabolic labeling of glutamate, suggestive of glutaminolysis, also characteristic of proliferating cells. Together, these results highlight the utility of 18O isotope labeling in combination with metabolomics to uncover changes in cellular metabolism that are not detectable by time-resolved metabolomics.

Dataset Information

Multiplatform Metabolomics Investigation of Antiadipogenic Effects on 3T3-L1 Adipocytes by a Potent Diarylheptanoid.

Publications

Multiplatform Metabolomics Investigation of Antiadipogenic Effects on 3T3-L1 Adipocytes by a Potent Diarylheptanoid.

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