2-Aminopurine inhibits leptin receptor signal transduction

Hosoi Toru

Matsunami Naomi

Nagahama Tomoko

Okuma Yasunobu

Ozawa Koichiro

Takizawa Tsuyoshi

Nomura Yasuyuki

European Journal of Pharmacology

Leptin is an important circulating signal for regulation of food intake and body weight. In the present study, we investigated the effect of 2-aminopurine (2-AP), an inhibitor of double-strand RNA-activated protein kinase (PKR), on leptin signal transduction. 2-AP dose-dependently inhibited leptin-induced phosporylation of signal transducer and activator of transcription 3 (STAT3), extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) in HEK293 cells stably transfected with the Ob-Rb leptin receptor. On the other hand, we observed only slight inhibition of leptin-induced STAT3 activation by purine treatment, indicating that the inhibitory effect will be dramatically enhanced in the presence of an amino group. 2-AP did not inhibit PMA-induced ERK activation, indicating that the effect may be leptin-signal specific. The inhibitory effect of 2-AP was not mediated by newly synthesized protein because the inhibitory effect of 2-AP on leptin-induced STAT3 activation was not abrogated in the presence of the protein synthesis inhibitor cycloheximide. Interestingly, leptin did not induce PKR activation, suggesting that the effect of 2-AP on leptin signal may be independent of PKR. Finally, 2-AP inhibited leptin-induced phosphorylation of the Ob-Rb leptin receptor. These results provide evidence of a novel action of 2-AP, i.e., inhibition of activation of leptin signal transduction at the level of the Ob-Rb leptin receptor.

leptin

2-aminopurine

signal transducer and activator of transcription 3 (STAT3)

extracellular signal-regulated kinase (ERK)

double-strand RNA-activated protein kinase (PKR)

Ob-Rb leptin receptor

Medical sciences [ 490 ]

eng

Elsevier

Copyright (c) 2006 Elsevier Ltd.

[ISSN] 0014-2999

[DOI] 10.1016/j.ejphar.2006.09.044

[NCID] AA00639687

[PMID] 17070518

[DOI] http://dx.doi.org/10.1016/j.ejphar.2006.09.044 isVersionOf