Abstract
Using male Sprague-Dawley rats implanted with third intracerebroventricular (ICV) cannulae, we found that cilostamide, a phosphodiesterase 3 (PDE3) inhibitor, (i) reversed the established effects of leptin on food intake and body weight, (ii) blocked, at the hypothalamic level, the leptin-induced tyrosine phosphorylation of signal transducer and activator of transcription 3 (Stat3) and (iii) blocked the DNA binding of p-Stat3. Additionally, ICV administration of leptin increased hypothalamic phosphatidylinositol 3-kinase (PI3K) and PDE3B activities and decreased cyclic AMP (cAMP) concentration. These results indicate that a PI3K-PDE3B-cAMP pathway interacting with the Janus kinase 2 (Jak2)-Stat3 pathway constitutes a critical component of leptin signaling in the hypothalamus.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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3',5'-Cyclic-AMP Phosphodiesterases / antagonists & inhibitors
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3',5'-Cyclic-AMP Phosphodiesterases / metabolism*
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Animals
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Body Weight / drug effects
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Cyclic AMP / metabolism*
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Cyclic Nucleotide Phosphodiesterases, Type 3
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DNA / metabolism
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DNA-Binding Proteins / metabolism
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Electrodes, Implanted
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Enzyme Activation / drug effects
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Enzyme Inhibitors / administration & dosage
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Feeding Behavior / drug effects*
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Hypothalamus / drug effects*
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Hypothalamus / physiology
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Injections, Intraventricular
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Janus Kinase 2
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Leptin / administration & dosage*
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Male
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Phosphatidylinositol 3-Kinases / metabolism*
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Phosphorylation / drug effects
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Protein Binding / drug effects
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Protein-Tyrosine Kinases / metabolism
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Proto-Oncogene Proteins*
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Quinolones / administration & dosage
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Rats
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Rats, Sprague-Dawley
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STAT3 Transcription Factor
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Signal Transduction / drug effects
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Signal Transduction / physiology
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Trans-Activators / metabolism
Substances
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DNA-Binding Proteins
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Enzyme Inhibitors
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Leptin
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Proto-Oncogene Proteins
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Quinolones
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STAT3 Transcription Factor
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Stat3 protein, rat
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Trans-Activators
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cilostamide
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DNA
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Cyclic AMP
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Phosphatidylinositol 3-Kinases
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Protein-Tyrosine Kinases
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Jak2 protein, rat
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Janus Kinase 2
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3',5'-Cyclic-AMP Phosphodiesterases
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Cyclic Nucleotide Phosphodiesterases, Type 3
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Pde3b protein, rat