Mild mitochondrial uncoupling induces 3T3-L1 adipocyte de-differenciation by a PPAEγ-independent mechanism, whereas TNFα-induced de-differentiation is PPARγ dependent

Silvia Veronica Tejerina Vargas, Aurélia De Pauw, Sebastien Vankoningsloo, Andrée Houbion, Patricia Renard, Françoise De Longueville, Martine Raes, Thierry Arnould

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Abstract

Impairment of mitochondrial activity affects lipid-metabolizing tissues and mild mitochondrial uncoupling has been proposed as a possible strategy to fight obesity and associated diseases. In this report, we characterized the 3T3-L1-adipocyte 'de-differentiation' induced by carbonyl cyanide (p-trifluoromethoxy)-phenylhydrazone (FCCP), a mitochondrial uncoupler. We found a decrease in triglyceride (TG) content in adipocytes incubated with this molecule. We next analyzed the expression of genes encoding adipogenic markers and effectors and compared the differentially expressed genes in adipocytes treated with FCCP or TNF{alpha} (a cytokine known to induce adipocyte de-differentiation). Furthermore, a significant decrease in the transcriptional activity of PPAR{gamma} and C/EBP{alpha} transcription factors was found in adipocytes with impaired mitochondrial activity. However, although these modifications were also found in TNF{alpha}-treated adipocytes, rosiglitazone and 9-cis retinoic acid (PPAR{gamma} and RXR ligands) were unable to prevent triglyceride loss in FCCP-treated cells. Metabolic assays also revealed that TG reduction could be mediated by a downregulation of lipid synthesis rather than an upregulation of fatty acid oxidation. Finally, lipolysis stimulated by the uncoupler also seems to contribute to the TG reduction, a process associated with perilipin A downregulation. These results highlight some new mechanisms that might potentially be involved in adipocyte de-differentiation initiated by a mitochondrial uncoupling.
Original languageEnglish
Pages (from-to)145-155
Number of pages11
JournalJournal of Cell Science
Volume122
Publication statusPublished - 2009

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Peroxisome Proliferator-Activated Receptors
Adipocytes
Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone
Triglycerides
rosiglitazone
PPAR gamma
Down-Regulation
Tumor Necrosis Factor-alpha
CCAAT-Enhancer-Binding Protein-alpha
Lipids
Lipolysis
Transcription Factors
Up-Regulation
Fatty Acids
Obesity
Cytokines
Ligands
Gene Expression
Genes

Keywords

  • Adipocyte de-diffenciation
  • Mitochondrial dysfunction
  • Gene expression

Cite this

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title = "Mild mitochondrial uncoupling induces 3T3-L1 adipocyte de-differenciation by a PPAEγ-independent mechanism, whereas TNFα-induced de-differentiation is PPARγ dependent",
abstract = "Impairment of mitochondrial activity affects lipid-metabolizing tissues and mild mitochondrial uncoupling has been proposed as a possible strategy to fight obesity and associated diseases. In this report, we characterized the 3T3-L1-adipocyte 'de-differentiation' induced by carbonyl cyanide (p-trifluoromethoxy)-phenylhydrazone (FCCP), a mitochondrial uncoupler. We found a decrease in triglyceride (TG) content in adipocytes incubated with this molecule. We next analyzed the expression of genes encoding adipogenic markers and effectors and compared the differentially expressed genes in adipocytes treated with FCCP or TNF{alpha} (a cytokine known to induce adipocyte de-differentiation). Furthermore, a significant decrease in the transcriptional activity of PPAR{gamma} and C/EBP{alpha} transcription factors was found in adipocytes with impaired mitochondrial activity. However, although these modifications were also found in TNF{alpha}-treated adipocytes, rosiglitazone and 9-cis retinoic acid (PPAR{gamma} and RXR ligands) were unable to prevent triglyceride loss in FCCP-treated cells. Metabolic assays also revealed that TG reduction could be mediated by a downregulation of lipid synthesis rather than an upregulation of fatty acid oxidation. Finally, lipolysis stimulated by the uncoupler also seems to contribute to the TG reduction, a process associated with perilipin A downregulation. These results highlight some new mechanisms that might potentially be involved in adipocyte de-differentiation initiated by a mitochondrial uncoupling.",
keywords = "Adipocyte de-diffenciation, Mitochondrial dysfunction, Gene expression",
author = "{Tejerina Vargas}, {Silvia Veronica} and {De Pauw}, Aur{\'e}lia and Sebastien Vankoningsloo and Andr{\'e}e Houbion and Patricia Renard and {De Longueville}, Fran{\cc}oise and Martine Raes and Thierry Arnould",
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T1 - Mild mitochondrial uncoupling induces 3T3-L1 adipocyte de-differenciation by a PPAEγ-independent mechanism, whereas TNFα-induced de-differentiation is PPARγ dependent

AU - Tejerina Vargas, Silvia Veronica

AU - De Pauw, Aurélia

AU - Vankoningsloo, Sebastien

AU - Houbion, Andrée

AU - Renard, Patricia

AU - De Longueville, Françoise

AU - Raes, Martine

AU - Arnould, Thierry

N1 - Publication code : RES. ACAD.

PY - 2009

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N2 - Impairment of mitochondrial activity affects lipid-metabolizing tissues and mild mitochondrial uncoupling has been proposed as a possible strategy to fight obesity and associated diseases. In this report, we characterized the 3T3-L1-adipocyte 'de-differentiation' induced by carbonyl cyanide (p-trifluoromethoxy)-phenylhydrazone (FCCP), a mitochondrial uncoupler. We found a decrease in triglyceride (TG) content in adipocytes incubated with this molecule. We next analyzed the expression of genes encoding adipogenic markers and effectors and compared the differentially expressed genes in adipocytes treated with FCCP or TNF{alpha} (a cytokine known to induce adipocyte de-differentiation). Furthermore, a significant decrease in the transcriptional activity of PPAR{gamma} and C/EBP{alpha} transcription factors was found in adipocytes with impaired mitochondrial activity. However, although these modifications were also found in TNF{alpha}-treated adipocytes, rosiglitazone and 9-cis retinoic acid (PPAR{gamma} and RXR ligands) were unable to prevent triglyceride loss in FCCP-treated cells. Metabolic assays also revealed that TG reduction could be mediated by a downregulation of lipid synthesis rather than an upregulation of fatty acid oxidation. Finally, lipolysis stimulated by the uncoupler also seems to contribute to the TG reduction, a process associated with perilipin A downregulation. These results highlight some new mechanisms that might potentially be involved in adipocyte de-differentiation initiated by a mitochondrial uncoupling.

AB - Impairment of mitochondrial activity affects lipid-metabolizing tissues and mild mitochondrial uncoupling has been proposed as a possible strategy to fight obesity and associated diseases. In this report, we characterized the 3T3-L1-adipocyte 'de-differentiation' induced by carbonyl cyanide (p-trifluoromethoxy)-phenylhydrazone (FCCP), a mitochondrial uncoupler. We found a decrease in triglyceride (TG) content in adipocytes incubated with this molecule. We next analyzed the expression of genes encoding adipogenic markers and effectors and compared the differentially expressed genes in adipocytes treated with FCCP or TNF{alpha} (a cytokine known to induce adipocyte de-differentiation). Furthermore, a significant decrease in the transcriptional activity of PPAR{gamma} and C/EBP{alpha} transcription factors was found in adipocytes with impaired mitochondrial activity. However, although these modifications were also found in TNF{alpha}-treated adipocytes, rosiglitazone and 9-cis retinoic acid (PPAR{gamma} and RXR ligands) were unable to prevent triglyceride loss in FCCP-treated cells. Metabolic assays also revealed that TG reduction could be mediated by a downregulation of lipid synthesis rather than an upregulation of fatty acid oxidation. Finally, lipolysis stimulated by the uncoupler also seems to contribute to the TG reduction, a process associated with perilipin A downregulation. These results highlight some new mechanisms that might potentially be involved in adipocyte de-differentiation initiated by a mitochondrial uncoupling.

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