title: NOD1 activation induces innate immune responses and insulin resistance in human adipocytes.
abstract: OBJECTIVE
  The innate immune-receptor nucleotide oligomerization domain (NOD) protein recognizes intracellular bacterial peptidoglycan. Activation of the innate immune system contributes to the development and progression of insulin resistance. The present study aimed to determine the presence of NOD1 and NOD2 in human adipose cells as well as to assess their functionality.
  
  
  METHODS
  Subcutaneous abdominal fat from obese subjects was biopsied and characterized for NOD expression using quantitative real-time PCR (qPCR). Human adipocytes were stimulated with iE-DAP (NOD1-specific ligand), and NOD1, proinflammatory cytokine production and nuclear factor (NF)-κB activation were quantified using qPCR, enzyme-linked immunosorbent assay (Elisa) and luciferase assay. Insulin-stimulated glucose uptake was determined by measuring 2-deoxy-D-[(3)H] glucose uptake. Expression and phosphorylation of IRS-1, Akt and JNK were evaluated using Western blotting.
  
  
  RESULTS
  NOD1/NOD2 mRNA expression was induced during adipocyte differentiation and enhanced in human adipose depots. Stimulation of isolated human adipocytes with iE-DAP induced NF-κB p65 nuclear translocation and a marked increase in proinflammatory cytokine production, including MCP-1, IL-6 and IL-8. NOD1 activation weakened insulin signal transduction as revealed by increased JNK and IRS-1 Ser307 phosphorylation, inhibited IRS-1 tyrosine phosphorylation, and reduced insulin-induced phosphorylation of Akt on Ser473 and Thr308 in human adipocytes. Moreover, NOD1 activation reduced insulin-induced glucose uptake, leading to insulin resistance.
  
  
  CONCLUSIONS
  These results suggest that NOD1 signaling could be one of the links between innate immunity and insulin resistance in human adipocytes. This study provides supporting evidence for NOD1 protein as a component of innate immunity involved in insulin resistance.
authors.affiliation: Department of Endocrinology and Metabolism, Fourth Affiliated Hospital, China Medical University, 110032 Shenyang, PR China. zhou-yijun@hotmail.com
authors.forename: Y-J
authors.initials: YJ
authors.lastname: Zhou
authors.forename: H
authors.initials: H
authors.lastname: Zhou
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.forename: Y-L
authors.initials: YL
authors.lastname: Song
mesh_terms: D052438:Adipocytes, White / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003960:Diaminopimelic Acid / Q000031:analogs & derivatives; D005260:Female; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D007333:Insulin Resistance / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism; D053474:Nod1 Signaling Adaptor Protein / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D016207:Cytokines; D016328:NF-kappa B; C119067:NOD1 protein, human; C429018:NOD2 protein, human; D053474:Nod1 Signaling Adaptor Protein; D053473:Nod2 Signaling Adaptor Protein; D012333:RNA, Messenger; D003960:Diaminopimelic Acid; C034331:N(2)-(gamma-D-glutamyl)-meso-2,2'-diaminopimelic acid; D005947:Glucose