Linked Life Data

20587749

Source:http://linkedlifedata.com/resource/pubmed/id/20587749

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
3
pubmed:dateCreated
2011-3-1
pubmed:abstractText
Obesity has been shown to create stress in the endoplasmic reticulum (ER), and that initiates the activation of the unfolded protein response (UPR). This has been reported to cause insulin resistance in selective tissues through activation of the inositol-requiring enzyme 1? (IRE1?)-c-Jun NH(2)-terminal kinase (JNK) pathway, which results in the phosphorylation of the insulin receptor substrate-1 (IRS-1) at an inhibitory site and blocks insulin receptor signaling. In this study, we report that the Src homology domain-containing adaptor protein Nck1, previously shown to modulate the UPR, is of functional importance in obesity-induced ER stress signaling and inhibition of insulin actions. We have examined obese Nck1(-/-) and Nck1(+/+) mice for glucose tolerance, insulin sensitivity, and signaling as well as for ER stress markers and IRS-1 phosphorylation at Ser(307). Our findings show that obese Nck1-deficient mice display improved glucose disposal accompanied by enhanced insulin signaling in liver. This correlates with attenuated IRE1? and JNK activation and IRS-1 phosphorylation at Ser(307) compared with obese wild-type mice. Consistent with our in vivo data, we report that downregulation of Nck1 using siRNA in HepG2 cells results in decreased thapsigargin-induced IRE1? activation and signaling and IRS-1 phosphorylation at Ser(307), whereas it markedly enhances insulin signaling. Overall, in liver and in cultured cells, we show that depletion of Nck1 attenuates the UPR signal and its inhibitory action on insulin signaling. Taken all together, our findings implicate Nck1 in regulating the UPR, which secondary to obesity impairs glucose homeostasis and insulin actions.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Mar
pubmed:issn
1522-1555
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
300
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
E423-34
pubmed:dateRevised
2011-11-17
pubmed:meshHeading
pubmed-meshheading:20587749-Adaptor Proteins, Signal Transducing, pubmed-meshheading:20587749-Animals, pubmed-meshheading:20587749-Blood Glucose, pubmed-meshheading:20587749-Blotting, Western, pubmed-meshheading:20587749-Endoplasmic Reticulum, pubmed-meshheading:20587749-Glucose Intolerance, pubmed-meshheading:20587749-Glycogen, pubmed-meshheading:20587749-HEK293 Cells, pubmed-meshheading:20587749-Homeostasis, pubmed-meshheading:20587749-Humans, pubmed-meshheading:20587749-Insulin, pubmed-meshheading:20587749-Insulin Resistance, pubmed-meshheading:20587749-JNK Mitogen-Activated Protein Kinases, pubmed-meshheading:20587749-Liver, pubmed-meshheading:20587749-Membrane Proteins, pubmed-meshheading:20587749-Mice, pubmed-meshheading:20587749-Mice, Knockout, pubmed-meshheading:20587749-Mice, Obese, pubmed-meshheading:20587749-Oncogene Proteins, pubmed-meshheading:20587749-Phosphorylation, pubmed-meshheading:20587749-Protein-Serine-Threonine Kinases, pubmed-meshheading:20587749-Reverse Transcriptase Polymerase Chain Reaction, pubmed-meshheading:20587749-Signal Transduction, pubmed-meshheading:20587749-Unfolded Protein Response
pubmed:year
2011
pubmed:articleTitle
Deletion of Nck1 attenuates hepatic ER stress signaling and improves glucose tolerance and insulin signaling in liver of obese mice.
pubmed:affiliation
Polypeptide Hormone Laboratory, Department of Experimental Medicine, Research Institute of the McGill University Health Centre, McGill University, 3640 University Street, Montreal, QC, Canada.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't