Blockade of adipocyte differentiation by cordycepin.

Abstract

BACKGROUND AND PURPOSE:

Cordyceps militaris has the potential to suppress differentiation of pre-adipocytes. However, the active entities in the extract and the underlying mechanisms of its action are not known. Hence, we investigated whether and how cordycepin (3'-deoxyadenosine), a constituent of C. militaris, inhibits adipogenesis.

EXPERIMENTAL APPROACH:

Differentiation of 3T3-L1 pre-adipocytes and pre-adipocytes in primary cultures was induced by Insulin, dexamethasone and IBMX, and these were used as in vitro models of adipogenesis. The effects of cordycepin on adipogenesis were examined with particular focus on the regulation of CCAAT/enhancer-binding protein β (C/EBPβ) and PPARγ.

KEY RESULTS:

Cordycepin suppressed the lipid accumulation and induction of adipogenic markers that occurred on differentiation of pre-adipocytes and also blocked the down-regulation of a pre-adipocyte marker. This anti-adipogenic effect was reversible and mediated by an adenosine transporter, but not A₁, A₂ or A₃ adenosine receptors. This effect of cordycepin was not reproduced by other adenosine-related substances, including ATP, ADP and adenosine. Early induction of the adipogenic C/EBPβ-PPARγ pathway was suppressed by cordycepin. Blockade of mTORC1 via inhibition of PKB (Akt) and activation of AMP kinase was identified as the crucial upstream event targeted by cordycepin. In addition to its negative effect on adipogenesis, cordycepin suppressed lipid accumulation in mature adipocytes.

CONCLUSIONS AND IMPLICATIONS:

These results suggest that the anti-adipogenic effects of cordycepin occur through its intervention in the mTORC1-C/EBPβ-PPARγ pathway. Cordycepin, by blocking both adipogenesis and lipid accumulation, may have potential as a therapeutic agent for effective treatment of obesity and obesity-related disorders.

• Authors: Shuhei Takahashi, Minori Tamai, Shotaro Nakajima, Hironori Kato, Hisashi Johno, Tomoyuki Nakamura, Masanori Kitamura
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 167 Issue 3 Pg. 561-75 (Oct 2012) ISSN: 1476-5381 [Electronic] England
• PMID: 22537056 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.

Chemical References

• CCAAT-Enhancer-Binding Protein-beta
• Deoxyadenosines
• Insulin
• Multiprotein Complexes
• PPAR gamma
• Dexamethasone
• Mechanistic Target of Rapamycin Complex 1
• TOR Serine-Threonine Kinases
• cordycepin
• 1-Methyl-3-isobutylxanthine

Topics

• 1-Methyl-3-isobutylxanthine (pharmacology)
• 3T3-L1 Cells
• Adipocytes (drug effects, metabolism)
• Adipogenesis (drug effects)
• Animals
• CCAAT-Enhancer-Binding Protein-beta (metabolism)
• Cell Differentiation (drug effects)
• Cordyceps (chemistry)
• Deoxyadenosines (isolation & purification, pharmacology)
• Dexamethasone (pharmacology)
• Down-Regulation (drug effects)
• Insulin (pharmacology)
• Lipid Metabolism (drug effects)
• Mechanistic Target of Rapamycin Complex 1
• Mice
• Multiprotein Complexes (metabolism)
• PPAR gamma (metabolism)
• TOR Serine-Threonine Kinases (metabolism)