Document Detail


Neuronal suppressor of cytokine signaling-3 deficiency enhances hypothalamic leptin-dependent phosphatidylinositol 3-kinase signaling.
MedLine Citation:
PMID:  21325649     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Suppressor of cytokine signaling-3 (SOCS3) is thought to be involved in the development of central leptin resistance and obesity by inhibiting STAT3 pathway. Because phosphatidylinositol 3-kinase (PI3K) pathway plays an important role in transducing leptin action in the hypothalamus, we examined whether SOCS3 exerted an inhibition on this pathway. We first determined whether leptin sensitivity in the hypothalamic PI3K pathway was increased in brain-specific Socs3-deficient (NesKO) mice. In NesKO mice, hypothalamic insulin receptor substrate-1 (IRS1)-associated PI3K activity was significantly increased at 30 min and remained elevated up to 2 h after leptin intraperitoneal injection, but in wild-type (WT) littermates, the significant increase was only at 30 min. Hypothalamic p-STAT3 levels were increased up to 5 h in NesKO as opposed to 2 h in WT mice. In food-restricted WT mice with reduced body weight, leptin increased hypothalamic PI3K activity only at 30 min, and p-STAT3 levels at 30-120 min postinjection. These results suggest increased leptin sensitivity in both PI3K and STAT3 pathways in the hypothalamus of NesKO mice, which was not due to a lean phenotype. In the next experiment with a clonal hypothalamic neuronal cell line expressing proopiomelanocortin, we observed that whereas leptin significantly increased IRS1-associated PI3K activity and p-JAK2 levels in cells transfected with control vector, it failed to do so in SOCS3-overexpressed cells. Altogether, these results imply a SOCS3 inhibition of the PI3K pathway of leptin signaling in the hypothalamus, which may be one of the mechanisms behind the development of central leptin resistance and obesity.
Authors:
Anantha S Metlakunta; Maitrayee Sahu; Hideo Yasukawa; Sandeep S Dhillon; Denise D Belsham; Akihiko Yoshimura; Abhiram Sahu
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-02-16
Journal Detail:
Title:  American journal of physiology. Regulatory, integrative and comparative physiology     Volume:  300     ISSN:  1522-1490     ISO Abbreviation:  Am. J. Physiol. Regul. Integr. Comp. Physiol.     Publication Date:  2011 May 
Date Detail:
Created Date:  2011-05-04     Completed Date:  2011-06-30     Revised Date:  2013-06-30    
Medline Journal Info:
Nlm Unique ID:  100901230     Medline TA:  Am J Physiol Regul Integr Comp Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  R1185-93     Citation Subset:  IM    
Affiliation:
Dept. of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Magee-Womens Research Institute, 204 Craft Avenue, Pittsburgh, PA 15213, USA.
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MeSH Terms
Descriptor/Qualifier:
Adiposity
Animals
Caloric Restriction
Cell Line
Eating
Genotype
Hypothalamus / enzymology*
Insulin Receptor Substrate Proteins / metabolism
Janus Kinase 2 / metabolism
Leptin / metabolism*
Mice
Mice, 129 Strain
Mice, Knockout
Neurons / enzymology*
Obesity / enzymology*,  genetics
Phenotype
Phosphatidylinositol 3-Kinase / metabolism*
Phosphorylation
Pro-Opiomelanocortin / metabolism
STAT3 Transcription Factor / metabolism
Signal Transduction*
Suppressor of Cytokine Signaling Proteins / deficiency*,  genetics
Time Factors
Transfection
Weight Loss
Grant Support
ID/Acronym/Agency:
DK78068/DK/NIDDK NIH HHS; R01 DK61499/DK/NIDDK NIH HHS; //Canadian Institutes of Health Research
Chemical
Reg. No./Substance:
0/Insulin Receptor Substrate Proteins; 0/Irs1 protein, mouse; 0/Leptin; 0/STAT3 Transcription Factor; 0/Socs3 protein, mouse; 0/Stat3 protein, mouse; 0/Suppressor of Cytokine Signaling Proteins; 66796-54-1/Pro-Opiomelanocortin; EC 2.7.1.137/Phosphatidylinositol 3-Kinase; EC 2.7.10.2/Jak2 protein, mouse; EC 2.7.10.2/Janus Kinase 2
Comments/Corrections

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


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