Document Detail


Leptin-induced nitric oxide production in white adipocytes is mediated through PKA and MAP kinase activation.
MedLine Citation:
PMID:  15772123     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Leptin injection increases plasma levels of nitrites and/or nitrates, an index of nitric oxide (NO) production. Because plasma levels of NO are correlated with fat mass and because adipose tissue is the main source of leptin, it seems that adipose tissue plays a major role in NO release induced by leptin. Adipocytes express both leptin receptors and nitric oxide synthase (NOS; including the endothelial isoform, NOS III, and the inducible isoform, NOS II). In this study, we have demonstrated that physiological concentrations of leptin stimulate NOS activity in adipocytes. This effect of leptin is abolished by 1) AG490, an inhibitor of Janus tyrosine kinase 2/signal transducer and activator of transcription 3; 2) U0126, an inhibitor of mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (p42/p44 MAPK); and 3) N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide (H-89) or Rp diastereomer of adenosine 3',5'-cyclic phosphorothioate, two inhibitors of protein kinase A, but not by wortmannin, an inhibitor of phosphatidylinositol 3-kinase. Immunoblotting studies have shown that leptin fails to activate Akt but increases p42/p44 MAPK phosphorylation, an effect that is prevented by U0126 but not by H-89. Furthermore, leptin induces NOS III phosphorylation at Ser(1179) and Thr(497), but not when adipocytes are pretreated with H-89 or U0126. Finally, stimulation of adipocyte NOS activity by leptin is either unaltered when protein phosphatase 2A is inhibited by 1 nM okadaic acid or completely abolished when protein phosphatase 1 (PP1) activity is inhibited by 3 nM tautomycin, which supports a crucial role for PP1 in mediating this effect of leptin. On the whole, these experiments demonstrate that NOS activity is a novel target for leptin in adipocytes and that the leptin-induced NOS activity is at least in part the result of NOS III phosphorylations via both protein kinase A and p42/p44 MAPK activation. More generally, this study also leads to the hypothesis of NO as a potentially important factor for leptin signaling in adipocytes.
Authors:
Nadia Mehebik; Anne-Marie Jaubert; Dominique Sabourault; Yves Giudicelli; Catherine Ribière
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2005-03-16
Journal Detail:
Title:  American journal of physiology. Cell physiology     Volume:  289     ISSN:  0363-6143     ISO Abbreviation:  Am. J. Physiol., Cell Physiol.     Publication Date:  2005 Aug 
Date Detail:
Created Date:  2005-07-08     Completed Date:  2005-08-11     Revised Date:  2012-06-05    
Medline Journal Info:
Nlm Unique ID:  100901225     Medline TA:  Am J Physiol Cell Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  C379-87     Citation Subset:  IM    
Affiliation:
Department of Biochemistry and Molecular Biology (UPRES EA-2493), Faculty of Médecine Paris-Ile de France-Ouest, University of Versailles Saint-Quentin en Yvelines, Paris, France.
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MeSH Terms
Descriptor/Qualifier:
Adipose Tissue / drug effects,  metabolism*
Animals
Blotting, Western
Cyclic AMP-Dependent Protein Kinases / drug effects,  metabolism*
Electrophoresis, Polyacrylamide Gel
Enzyme Activation / drug effects,  physiology
Intracellular Signaling Peptides and Proteins / pharmacology
Isoenzymes / drug effects,  metabolism
Janus Kinase 2
Leptin / metabolism*
Mice
Mitogen-Activated Protein Kinases / metabolism*
Nitric Oxide / metabolism*
Protein-Tyrosine Kinases / drug effects,  metabolism
Proto-Oncogene Proteins / drug effects,  metabolism
Chemical
Reg. No./Substance:
0/Intracellular Signaling Peptides and Proteins; 0/Isoenzymes; 0/Leptin; 0/Proto-Oncogene Proteins; 0/protein kinase modulator; 10102-43-9/Nitric Oxide; EC 2.7.10.1/Janus Kinase 2; EC 2.7.10.1/Protein-Tyrosine Kinases; EC 2.7.10.2/Jak2 protein, mouse; EC 2.7.11.11/Cyclic AMP-Dependent Protein Kinases; EC 2.7.11.24/Mitogen-Activated Protein Kinases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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