Hypothalamic phosphatidylinositol 3-kinase-phosphodiesterase 3B-cyclic AMP pathway of leptin signalling is impaired following chronic central leptin infusion.
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.
Sahu
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Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA. asahu@pitt.edu
Metlakunta
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AS
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
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