Caffeine-Stimulated Intestinal Epithelial Cells Suppress Lipid Accumulation in Adipocytes

Abstract

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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