Rapid inhibition of leptin signaling by glucocorticoids in vitro and in vivo
| Autor: | Ryoko Ishida-Takahashi, Naruhiro Fujita, Tetsuya Fukushima, Mikako Degawa-Yamauchi, Takahiro Abe, Yoshihiko Yamaguchi, Katsumi Eguchi, Hironori Yamasaki, Hiroyuki Sakamaki, Shigeo Uotani |
|---|---|
| Rok vydání: | 2004 |
| Předmět: |
Leptin
Male STAT3 Transcription Factor endocrine system medicine.medical_specialty Time Factors MAP Kinase Signaling System Blotting Western In Vitro Techniques Transfection Biochemistry stat Dexamethasone Rats Sprague-Dawley chemistry.chemical_compound Mice In vivo Internal medicine Cell Line Tumor polycyclic compounds medicine Animals Humans Enzyme Inhibitors Phosphorylation STAT3 Molecular Biology Glucocorticoids Flavonoids Leptin receptor biology Dose-Response Relationship Drug digestive oral and skin physiology JAK-STAT signaling pathway Tyrosine phosphorylation Cell Biology Rats DNA-Binding Proteins Endocrinology chemistry biology.protein Trans-Activators Tyrosine sense organs hormones hormone substitutes and hormone antagonists Signal Transduction |
| Zdroj: | The Journal of biological chemistry. 279(19) |
| ISSN: | 0021-9258 |
| Popis: | Elevated secretion of glucocorticoids (GCs) or hypersensitivity to GCs has a permissive effect on the development of obesity and leads to abnormalities of body fat distribution. Recent studies demonstrated GCs act as antagonists of leptin in rodents. However, little is known about the interaction between GCs and leptin signaling. In the present study, we investigated the effects of GCs on leptin action in vitro and in vivo. GCs rapidly inhibited the leptin-induced STAT3 phosphorylation in a dose- and time-dependent manner, as assayed by Western blotting using anti-phosphospecific-STAT3 in human hepatoma cell lines (Huh7) transiently expressing long form leptin receptor. GCs also inhibited the leptin-induced JAK2 tyrosine phosphorylation but unaltered the specific binding of (125)I-leptin to the cells. Parallel experiments, however, demonstrated that the inhibitory effects of GCs were not observed in either IL-6- or LIF-induced STAT3 phosphorylation. Furthermore, we examined the feeding behavior and hypothalamic leptin signaling following intracerebroventricular (icv) infusion of GCs prior to icv leptin infusion in Sprague-Dawley rats. The food intake after 24 h of icv leptin injection increased 3-fold in GCs-treated animals. In addition, central infusion of GCs resulted in a marked reduction of hypothalamic STAT3 phosphorylation in response to icv infusion of leptin. To clarify the molecular mechanism by which GCs rapidly reduce leptin-induced JAK/STAT signaling, we examined the intracellular signal transduction pathway potentially mediated by GCs. PD98059, a specific MEK inhibitor, blocked the inhibitory effects of GCs on leptin-induced JAK/STAT activation in Huh7 cells. These results suggest GCs antagonize leptin action by a rapid inhibition of the leptin-induced JAK/STAT pathway partly via MAPK cascade. |
| Databáze: | OpenAIRE |
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