title: Hypothalamic phosphatidylinositol 3-kinase-phosphodiesterase 3B-cyclic AMP pathway of leptin signalling is impaired following chronic central leptin infusion.
abstract: Leptin signalling in the hypothalamus is critical for the maintenance of normal body weight. Although hyperleptinaemia in obese people suggests a state of leptin resistance, and diet-induced obesity in rodents is associated with central leptin resistance, the underlying mechanisms remain unclear. Recent evidence suggests that, in addition to the signal transducer and activator of the transcription-3 (STAT3) pathway, leptin action is critical for energy homeostasis through an insulin-like signalling pathway involving an increase in phosphatidylinositol 3-kinase (PI3K) and phosphodiesterase 3B (PDE3B) activities and reduction in cyclic AMP (cAMP) levels in the hypothalamus. Here, we show that chronic central leptin (160 ng/h) infusion, which resulted in the development of resistance to the satiety action of leptin, impaired the PI3K-PDE3B-cAMP pathway of leptin signalling in the hypothalamus in that PI3K and PDE3B activities were increased and cAMP levels were decreased in the hypothalamus on day 2 of leptin infusion but remained unchanged on day 16. Additionally, induction of tyrosyl phosphorylation of insulin receptor substrate-1 observed on day 2 was not evident on day 16 of leptin infusion. By contrast, signalling through the STAT3-pathway remained activated in the hypothalamus throughout 16 days of leptin infusion. These findings show a differential response in PI3K-PDE3B-cAMP (impaired) and STAT3 (up-regulated) pathways to chronic central leptin infusion, and suggest a selective resistance in the PI3K-PDE3B-cAMP pathway of leptin signalling following a chronic increase in hypothalamic leptin tone attained by central infusion of this peptide hormone.
authors.affiliation: Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA. asahu@pitt.edu
authors.forename: A
authors.initials: A
authors.lastname: Sahu
authors.forename: A S
authors.initials: AS
authors.lastname: Metlakunta
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000502:physiology*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D000242:Cyclic AMP / Q000502:physiology*; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D007031:Hypothalamus / Q000187:drug effects*; D007276:Injections, Intraventricular; D007328:Insulin / Q000097:blood; D055504:Insulin Receptor Substrate Proteins; D020738:Leptin / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011863:Radioimmunoassay; D051381:Rats; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects*; D013238:Stereotaxic Techniques; D014443:Tyrosine / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; D020738:Leptin; D010750:Phosphoproteins; D050796:STAT3 Transcription Factor; D014443:Tyrosine; D000242:Cyclic AMP; D019869:Phosphatidylinositol 3-Kinases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; C517294:Pde3b protein, rat