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Cytokines induce catabolic effects in cultured adipocytes by multiple mechanisms
W Doerrler1, K R Feingold, C Grunfeld
1Department of Medicine, University of California, San Francisco.
Abstract:
Previous studies have demonstrated that some cytokines induce a coordinate catabolic response in adipose cells which leads to decreased fat storage. The mechanisms by which cytokines cause these effects are unknown. The primary purpose of the present study was to determine the effects of TNF, IL-1, IFN-alpha and IFN-alpha on the mRNA levels of the key enzymes involved in fat metabolism in 3T3-F442A adipocytes. TNF, IL-1, IFN-alpha and IFN-gamma decreased lipoprotein lipase activity and increased lipolysis in adipocytes. TNF, IFN-alpha and IFN-gamma decreased fatty acid synthesis while IL-1 increased fatty acid synthesis. However, the cytokine effects on mRNA levels were not always consistent with the observed changes in activity and were unique for each cytokine. Specifically, while all cytokines decreased LPL activity, only TNF and IFN-gamma decreased LPL mRNA levels. In addition, while TNF, IFN-alpha and IFN-gamma decreased fatty acid synthesis, only TNF significantly decreased the mRNA levels of both acetyl CoA carboxylase and fatty acid synthase, the key enzymes in fatty acid synthesis. IFN-alpha and IFN-gamma decreased fatty acid synthase mRNA levels without significantly altering acetyl CoA carboxylase mRNA. IL-1 caused a slight increase in fatty acid synthesis and increased acetyl CoA carboxylase mRNA levels. Finally, while all cytokines increased lipolysis, hormone sensitive lipase mRNA levels were decreased by TNF, IFN-alpha and IFN-gamma treatment. These results indicate that the regulation of adipocyte lipid metabolism by cytokines is complex and that coordinate changes in mRNA levels cannot account for the observed metabolic changes.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
Cytokines impact fat metabolism by altering enzyme activity and mRNA levels in adipocytes. These complex interactions show that changes in gene expression alone do not fully explain the metabolic effects of cytokines on fat storage.
Area of Science:
- Biochemistry
- Cell Biology
- Molecular Biology
Background:
- Cytokines are known to induce catabolic responses in adipose cells, reducing fat storage.
- The precise molecular mechanisms underlying cytokine-induced changes in fat metabolism remain largely unknown.
Purpose of the Study:
- To investigate the effects of tumor necrosis factor (TNF), interleukin-1 (IL-1), interferon-alpha (IFN-alpha), and interferon-gamma (IFN-gamma) on the mRNA levels of key enzymes in adipocyte fat metabolism.
- To correlate these mRNA level changes with observed alterations in enzyme activity and lipolysis.
Main Methods:
- Utilized 3T3-F442A adipocytes as a model system.
- Assessed the mRNA levels of enzymes involved in lipoprotein lipase (LPL) activity, fatty acid synthesis, and lipolysis following cytokine treatment.
- Measured enzyme activities and lipolysis rates in response to the same cytokine treatments.
Main Results:
- All tested cytokines (TNF, IL-1, IFN-alpha, IFN-gamma) decreased lipoprotein lipase activity and increased lipolysis.
- TNF, IFN-alpha, and IFN-gamma reduced fatty acid synthesis, whereas IL-1 increased it.
- Cytokine effects on mRNA levels were not always consistent with activity changes; for example, only TNF and IFN-gamma decreased LPL mRNA, despite all cytokines reducing LPL activity.
Conclusions:
- Cytokine regulation of adipocyte lipid metabolism is intricate and involves complex post-transcriptional or post-translational modifications.
- Observed metabolic changes cannot be solely explained by coordinate alterations in the mRNA levels of key metabolic enzymes.
- Different cytokines exert unique and sometimes opposing effects on specific pathways within adipocyte lipid metabolism.