A Phosphatidylinositol 3-kinase Phosphodiesterase 3B-cyclic AMP Pathway in Hypothalamic Action of Leptin on Feeding

Nat Neurosci. 2002 Aug;5(8):727-8. doi: 10.1038/nn885.

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

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 3',5'-Cyclic-AMP Phosphodiesterases / antagonists & inhibitors
  • 3',5'-Cyclic-AMP Phosphodiesterases / metabolism*
  • Animals
  • Body Weight / drug effects
  • Cyclic AMP / metabolism*
  • Cyclic Nucleotide Phosphodiesterases, Type 3
  • DNA / metabolism
  • DNA-Binding Proteins / metabolism
  • Electrodes, Implanted
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / administration & dosage
  • Feeding Behavior / drug effects*
  • Hypothalamus / drug effects*
  • Hypothalamus / physiology
  • Injections, Intraventricular
  • Janus Kinase 2
  • Leptin / administration & dosage*
  • Male
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphorylation / drug effects
  • Protein Binding / drug effects
  • Protein-Tyrosine Kinases / metabolism
  • Proto-Oncogene Proteins*
  • Quinolones / administration & dosage
  • Rats
  • Rats, Sprague-Dawley
  • STAT3 Transcription Factor
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Trans-Activators / metabolism

Substances

  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Leptin
  • Proto-Oncogene Proteins
  • Quinolones
  • STAT3 Transcription Factor
  • Stat3 protein, rat
  • Trans-Activators
  • cilostamide
  • DNA
  • Cyclic AMP
  • Phosphatidylinositol 3-Kinases
  • Protein-Tyrosine Kinases
  • Jak2 protein, rat
  • Janus Kinase 2
  • 3',5'-Cyclic-AMP Phosphodiesterases
  • Cyclic Nucleotide Phosphodiesterases, Type 3
  • Pde3b protein, rat