Caffeine inhibits adipogenesis through modulation of mitotic clonal expansion and the AKT/GSK3 pathway in 3T3-L1 adipocytes

Kim, Hyo Jung; Yoon, Bo Kyung; Park, Hyounkyoung; Seok, Jo Woon; Choi, Hong-Seok; Yu, Jung Hwan; Choi, Youn Jeong; Song, Su Jin; Kim, Ara; Kim, Jae-Woo

doi:10.5483/bmbrep.2016.49.2.128

Cited by 63 publications

(50 citation statements)

References 34 publications

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“…Additional investigation into these genes may yield insights not only on the GxE role in specific traits but also on the underlying molecular mechanisms. For example, previous reports show that caffeine prevents and treats obesity presumably through mitotic clonal expansion effects (Li et al 2015;Kim et al 2016;Ohara et al 2016). Our work suggests that caffeine activates the GIPR pathway, which regulates insulin production.…”

Section: Wwwgenomeorgsupporting

confidence: 56%

High-throughput allele-specific expression across 250 environmental conditions

et al. 2016

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Gene-by-environment (GxE) interactions determine common disease risk factors and biomedically relevant complex traits. However, quantifying how the environment modulates genetic effects on human quantitative phenotypes presents unique challenges. Environmental covariates are complex and difficult to measure and control at the organismal level, as found in GWAS and epidemiological studies. An alternative approach focuses on the cellular environment using in vitro treatments as a proxy for the organismal environment. These cellular environments simplify the organism-level environmental exposures to provide a tractable influence on subcellular phenotypes, such as gene expression. Expression quantitative trait loci (eQTL) mapping studies identified GxE interactions in response to drug treatment and pathogen exposure. However, eQTL mapping approaches are infeasible for large-scale analysis of multiple cellular environments. Recently, allele-specific expression (ASE) analysis emerged as a powerful tool to identify GxE interactions in gene expression patterns by exploiting naturally occurring environmental exposures. Here we characterized genetic effects on the transcriptional response to 50 treatments in five cell types. We discovered 1455 genes with ASE (FDR < 10%) and 215 genes with GxE interactions. We demonstrated a major role for GxE interactions in complex traits. Genes with a transcriptional response to environmental perturbations showed sevenfold higher odds of being found in GWAS. Additionally, 105 genes that indicated GxE interactions (49%) were identified by GWAS as associated with complex traits. Examples include GIPR-caffeine interaction and obesity and include LAMP3-selenium interaction and Parkinson disease. Our results demonstrate that comprehensive catalogs of GxE interactions are indispensable to thoroughly annotate genes and bridge epidemiological and genomewide association studies.

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Section: Wwwgenomeorgsupporting

confidence: 56%

High-throughput allele-specific expression across 250 environmental conditions

et al. 2016

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“…This was supported by the previous report that caffeine has anti-obesity effects on suppressing the intracellular lipid accumulation after complete differentiation of 3T3-L1 adipocytes in a dose-dependent manner [14]. Moreover, Kim et al [15] reported that caffeine suppressed 3T3-L1 adipocyte differentiation and inhibited the expression of the CCAAT/enhancer binding protein (C/EBP)α and peroxisome proliferator-activated receptor (PPAR)γ two main adipogenic transcription factors.…”

Section: Lipid Accumulation Assaysupporting

confidence: 54%

Inhibition of Lipid Accumulation in 3t3-L1 Adipocytes by Morinda Citrifolia Linn. Leaf Extracts and Commercial Herbal Formulas for Weight Control

Saraphanchotiwitthaya

Sripalakit

2016

Int J Pharm Pharm Sci

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Objective: To determine the in vitro anti-obesity effects of Morinda citrifolia leaf extract and herbal formulas used for weight loss in Thailand on lipid accumulation in 3T3-L1 adipocytes.Methods: Differentiated 3T3-L1 adipocytes were treated with 0.1, 0.5 and 1 mg/ml M. citrifolia leaf extract, three herbal formulas (JL-RU, JL-TH, CD-H) and 1, 5 and 10 µg/ml rutin, gallic acid and caffeine. Lipid accumulation determined by measuring Oil Red O staining and triglyceride content measured by a colorimetric method in adipocytes were assayed compared to the control. The effect of test samples on the viability of preadipocytes and differentiated adipocytes were investigated.Results: Differentiated adipocytes treated with 1 mg/ml M. citrifolia extract moderately inhibited fat accumulation (45.12%) and highly reduced triglyceride content (85.09%). Among the three herbal formulas, JL-TH considerably inhibited fat accumulation (109.17%, 1 mg/ml) and decreased triglyceride content (95.00%, 1 mg/ml) in adipocytes; this was higher than that for CD-H and JL-RU, respectively. The viability of preadipocytes treated with CD-H at 1 mg/ml was slightly decreased while those treated with JL-TH at 0.05-1 mg/ml showed moderately decreased viability in a dose-response manner. For differentiated adipocytes, CD-H at 0.5-1 mg/ml moderately decreased cell viability while JL-TH at 0.05-1 mg/ml caused moderate to high reduction of cell viability in a dose-response relationship. Conclusion:M. citrifolia extract and three herbal formulas had anti-obesity effects in 3T3-L1 adipocytes, as indicated by a significant reduction in lipid accumulation, triglyceride content, and cell viability. These findings suggest a potential therapeutic approach for the prevention and treatment of obesity.

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“…Food factors suppress the gene expression of C/EBP␤ through regulation of mitotic clonal expansion in 3T3-L1 adipocytes and zebrafish (38,39). In addition, direct treatment with caffeine also suppresses mitotic clonal expansion in 3T3-L1 adipocytes (40). However, little is known about food factors which promote the degradation of C/EBP␤ protein.…”

Section: Discussionmentioning

confidence: 99%

Caffeine-Stimulated Intestinal Epithelial Cells Suppress Lipid Accumulation in Adipocytes

Mitani

Nagano

Harada

et al. 2017

J Nutr Sci Vitaminol

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Summary Caffeine is a methylxanthine derived from plant foods such as coffee beans and tea leaves, and has multiple biological activities against physiological response and several diseases. Although there are some reports about the direct effect of caffeine against anti-lipid accumulation in vitro, the effect of caffeine on lipid accumulation in adipocytes through stimulating intestinal epithelial cells is unknown. Since direct treatment with caffeine to 3T3-L1 cells did not affect lipid accumulation, we determined whether caffeinestimulated intestinal epithelial Caco-2 cells influence the lipid accumulation in 3T3-L1 adipocytes. Caco-2 cells were cultured on a transwell insert with or without caffeine for 24 h. Subsequently, the basolateral component of the Caco-2 cell culture on the transwell was collected and termed caffeine-conditioning medium (CCM). When 3T3-L1 adipocytes were incubated with CCM, CCM decreased lipid accumulation and suppressed gene expression of proliferator activated receptor (PPAR) ␥ and CCAAT/enhancer binding protein (C/EBP) ␣ in 3T3-L1 adipocytes. Furthermore, CCM decreased the expression of C/EBP␤ and C/EBP␦ at the protein level, but not at the mRNA level. We observed that a proteasome inhibitor, MG132, inhibited CCM-caused down-expression of C/EBP␤ and C/EBP␦ proteins, and that CCM promoted the ubiquitination level of C/EBP␤ and C/EBP␦ proteins. Protein microarray analysis showed caffeine suppresses the secretion of inflammatory cytokines, interleukin-8 and plasminogen activator inhibitor-1 from Caco-2 cells. These results suggest that caffeine indirectly suppresses lipid accumulation in 3T3-L1 adipocytes through decreasing secretion of inflammatory cytokines from Caco-2 cells. Key Words caffeine, adipogenesis, 3T3-L1 adipocytes, Caco-2 cells Obesity is a risk factor for multiple lifestyle diseases such as apoplexy, heart disease and diabetes (1, 2). Adipocytes play a critical role in regulating lipid metabolism and energy balance, which are associated with adiposity (3). An increase in the number of differentiated mature adipocytes and excess accumulation of body fat leads to adiposity. Adipocytes accumulate intracellular lipids during differentiation. As an in vitro model system for adipogenesis, murine 3T3-L1 cells, which were originally derived from mouse embryos, are often used. Differentiation of 3T3-L1 cells is induced by exposure to the inducers, such as 3-isobutyl-1-methylxanthine (IBMX), dexamethasone and insulin, and is responsible for the accumulation of a large amount of intracellular lipid droplets during adipocyte differentiation. Adipogenesis, the differentiation process for producing adipocytes, is a complex process that is regulated by various transcription factors and their related genes. The expression levels of CCAAT/enhancer binding protein (C/EBP) ␤ and C/EBP␦, as transcriptional factors, are increased in the early phase of adipocyte differentiation (4). Subsequently, these transcription factors up-regulate proliferator activated receptor (PPAR) ␥ and C/EBP␣, a...

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Caffeine inhibits adipogenesis through modulation of mitotic clonal expansion and the AKT/GSK3 pathway in 3T3-L1 adipocytes

Cited by 63 publications

References 34 publications

High-throughput allele-specific expression across 250 environmental conditions

High-throughput allele-specific expression across 250 environmental conditions

Inhibition of Lipid Accumulation in 3t3-L1 Adipocytes by Morinda Citrifolia Linn. Leaf Extracts and Commercial Herbal Formulas for Weight Control

Caffeine-Stimulated Intestinal Epithelial Cells Suppress Lipid Accumulation in Adipocytes

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