Abstract
Overcrowded adipocytes secrete excess adipokines and cytokines under stress, which results in a deregulated metabolism. This negative response to stress increases the possibility of obesity and several of its associated diseases, such as cancer and atherosclerosis. Therefore, a reduction in the number of adipocytes may be a rational strategy to relieve the undesired expansion of adipose tissue. A newly synthesized xanthene analog, MI-401, was found to have two distinct effects on the regulation of the adipocyte's life cycle. MI-401 efficiently down regulated the expression of transcription factors, PPARγ and C/EBPα, and lipogenesis proteins, FAS and FABP4. This down regulation resulted in the inhibition of adipogenesis. Without newly differentiated adipocytes, the total number of adipocytes will not increase. In addition to this inhibitory effect, MI-401 was able to actively kill mature adipocytes. It specifically triggered apoptosis in adipocytes at low micro molar concentration and spared preadipocytes and fibroblasts. These dual functionalities make MI-401 an effective agent in the regulation of the birth and death of adipocytes.
MeSH terms
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3T3-L1 Cells
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Adipocytes / cytology
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Adipocytes / drug effects*
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Adipocytes / metabolism
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Adipogenesis / drug effects*
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Animals
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Apoptosis / drug effects
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Benzamides / chemical synthesis
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Benzamides / pharmacology*
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CCAAT-Enhancer-Binding Proteins / antagonists & inhibitors
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CCAAT-Enhancer-Binding Proteins / genetics
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CCAAT-Enhancer-Binding Proteins / metabolism
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Cell Count
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Cell Differentiation
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Fatty Acid-Binding Proteins / antagonists & inhibitors
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Fatty Acid-Binding Proteins / genetics
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Fatty Acid-Binding Proteins / metabolism
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Gene Expression Regulation
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Hypolipidemic Agents / chemical synthesis
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Hypolipidemic Agents / pharmacology*
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Lipogenesis / drug effects*
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Mice
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NIH 3T3 Cells
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Organ Specificity
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PPAR gamma / antagonists & inhibitors
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PPAR gamma / genetics
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PPAR gamma / metabolism
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Signal Transduction
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Xanthenes / chemical synthesis
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Xanthenes / pharmacology*
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fas Receptor / antagonists & inhibitors
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fas Receptor / genetics
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fas Receptor / metabolism
Substances
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Benzamides
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CCAAT-Enhancer-Binding Proteins
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CEBPA protein, mouse
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Fabp4 protein, mouse
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Fas protein, mouse
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Fatty Acid-Binding Proteins
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Hypolipidemic Agents
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MI-401
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PPAR gamma
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Xanthenes
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fas Receptor
Grants and funding
This research was supported in part by NIH GM094880. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.