| NOD2 activation induces muscle cell-autonomous innate immune responses and insulin resistance. | |
| | |
MedLine Citation:
|
PMID: 20926588 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
Insulin resistance is associated with chronic low-grade inflammation in vivo, largely mediated by activated innate immune cells. Cytokines and pathogen-derived ligands of surface toll-like receptors can directly cause insulin resistance in muscle cells. However, it is not known if intracellular pathogen sensors can, on their own, provoke insulin resistance. Here, we show that the cytosolic pattern recognition receptors nucleotide-binding oligomerization domain-containing protein (NOD)1 and NOD2 are expressed in immune and metabolic tissues and hypothesize that their activation in muscle cells would result in cell-autonomous responses leading to insulin resistance. Bacterial peptidoglycan motifs that selectively activate NOD2 were directly administered to L6- GLUT4myc myotubes in culture. Within 3 h, insulin resistance arose, characterized by reductions in each insulin-stimulated glucose uptake, GLUT4 translocation, Akt Ser(473) phosphorylation, and insulin receptor substrate 1 tyrosine phosphorylation. Muscle cell-autonomous responses to NOD2 ligand included activation of the stress/inflammation markers c-Jun N-terminal kinase, ERK1/2, p38 MAPK, degradation of inhibitor of κBα, and production of proinflammatory cytokines. These results show that NOD2 alone is capable of acutely inducing insulin resistance within muscle cells, possibly by activating endogenous inflammatory signals and/or through cytokine production, curbing upstream insulin signals. NOD2 is hence a new inflammation target connected to insulin resistance, and this link occurs without the need of additional contributing cell types. This study provides supporting evidence for the integration of innate immune and metabolic responses through the involvement of NOD proteins and suggests the possible participation of cell autonomous immune responses in the development of insulin resistance in skeletal muscle, the major depot for postprandial glucose utilization. |
| | |
Authors:
|
Akhilesh K Tamrakar; Jonathan D Schertzer; Tim T Chiu; Kevin P Foley; Philip J Bilan; Dana J Philpott; Amira Klip |
Related Documents
:
|
14704748 - Modulators of insulin action and their role in insulin resistance. 11796688 - Exercise training improves muscle insulin resistance but not insulin receptor signaling... 19013138 - Coexistences of insulin signaling-related proteins and choline acetyltransferase in neu... 7685118 - Insulin receptor substrate 1 mediates insulin and insulin-like growth factor i-stimulat... 18334488 - Fat-specific protein 27 regulates storage of triacylglycerol. 9481088 - New concepts and insights on pathogenesis and treatment of diabetic complications: poly... |
Publication Detail:
|
Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-10-06 |
Journal Detail:
|
Title: Endocrinology Volume: 151 ISSN: 1945-7170 ISO Abbreviation: Endocrinology Publication Date: 2010 Dec |
Date Detail:
|
Created Date: 2010-11-24 Completed Date: 2011-01-04 Revised Date: - |
Medline Journal Info:
|
Nlm Unique ID: 0375040 Medline TA: Endocrinology Country: United States |
Other Details:
|
Languages: eng Pagination: 5624-37 Citation Subset: AIM; IM |
Affiliation:
|
Program in Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
Adipose Tissue
/
metabolism Animals Cell Line Cytokines / metabolism Dose-Response Relationship, Drug Gene Expression Regulation / physiology* Glucose / metabolism HIV Protease Inhibitors / pharmacology Immunity, Innate / physiology* Indinavir / pharmacology Insulin / administration & dosage, pharmacology Insulin Resistance / physiology* Intracellular Signaling Peptides and Proteins / genetics, metabolism* Liver / metabolism Lung / metabolism Muscle Cells / metabolism* Myocardium / metabolism Nod1 Signaling Adaptor Protein / genetics, metabolism RNA, Small Interfering Rats |
| Grant Support | |
ID/Acronym/Agency:
|
//Canadian Institutes of Health Research |
| Chemical | |
Reg. No./Substance:
|
0/Cytokines; 0/HIV Protease Inhibitors; 0/Intracellular Signaling Peptides and Proteins; 0/NOD2 protein, rat; 0/Nod1 Signaling Adaptor Protein; 0/RNA, Small Interfering; 11061-68-0/Insulin; 150378-17-9/Indinavir; 50-99-7/Glucose |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Inhibition of the type 2 iodothyronine deiodinase underlies the elevated plasma TSH associated with ...
Next Document: Molecular cloning, characterization, and chromosome mapping of reptilian estrogen receptors.