title: NOD1 activators link innate immunity to insulin resistance.
abstract: OBJECTIVE
  Insulin resistance associates with chronic inflammation, and participatory elements of the immune system are emerging. We hypothesized that bacterial elements acting on distinct intracellular pattern recognition receptors of the innate immune system, such as bacterial peptidoglycan (PGN) acting on nucleotide oligomerization domain (NOD) proteins, contribute to insulin resistance.
  
  
  METHODS
  Metabolic and inflammatory properties were assessed in wild-type (WT) and NOD1/2(-/-) double knockout mice fed a high-fat diet (HFD) for 16 weeks. Insulin resistance was measured by hyperinsulinemic euglycemic clamps in mice injected with mimetics of meso-diaminopimelic acid-containing PGN or the minimal bioactive PGN motif, which activate NOD1 and NOD2, respectively. Systemic and tissue-specific inflammation was assessed using enzyme-linked immunosorbent assays in NOD ligand-injected mice. Cytokine secretion, glucose uptake, and insulin signaling were assessed in adipocytes and primary hepatocytes exposed to NOD ligands in vitro.
  
  
  RESULTS
  NOD1/2(-/-) mice were protected from HFD-induced inflammation, lipid accumulation, and peripheral insulin intolerance. Conversely, direct activation of NOD1 protein caused insulin resistance. NOD1 ligands induced peripheral and hepatic insulin resistance within 6 h in WT, but not NOD1(-/-), mice. NOD2 ligands only modestly reduced peripheral glucose disposal. NOD1 ligand elicited minor changes in circulating proinflammatory mediators, yet caused adipose tissue inflammation and insulin resistance of muscle AS160 and liver FOXO1. Ex vivo, NOD1 ligand caused proinflammatory cytokine secretion and impaired insulin-stimulated glucose uptake directly in adipocytes. NOD1 ligand also caused inflammation and insulin resistance directly in primary hepatocytes from WT, but not NOD1(-/-), mice.
  
  
  CONCLUSIONS
  We identify NOD proteins as innate immune components that are involved in diet-induced inflammation and insulin intolerance. Acute activation of NOD proteins by mimetics of bacterial PGNs causes whole-body insulin resistance, bolstering the concept that innate immune responses to distinctive bacterial cues directly lead to insulin resistance. Hence, NOD1 is a plausible, new link between innate immunity and metabolism.
authors.affiliation: Program in Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Schertzer
authors.forename: Akhilesh K
authors.initials: AK
authors.lastname: Tamrakar
authors.forename: Joao G
authors.initials: JG
authors.lastname: Magalhães
authors.forename: Sandra
authors.initials: S
authors.lastname: Pereira
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Bilan
authors.forename: Morgan D
authors.initials: MD
authors.lastname: Fullerton
authors.forename: Zhi
authors.initials: Z
authors.lastname: Liu
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Steinberg
authors.forename: Adria
authors.initials: A
authors.lastname: Giacca
authors.forename: Dana J
authors.initials: DJ
authors.lastname: Philpott
authors.forename: Amira
authors.initials: A
authors.lastname: Klip
mesh_terms: D000273:Adipose Tissue / Q000276:immunology / Q000378:metabolism; D000818:Animals; D030161:Avian Proteins / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004041:Dietary Fats / Q000378:metabolism*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D015309:Glucose Clamp Technique; D007113:Immunity, Innate / Q000502:physiology*; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D007333:Insulin Resistance / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D053474:Nod1 Signaling Adaptor Protein / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction / Q000276:immunology
chemical_list: D030161:Avian Proteins; D016207:Cytokines; D004041:Dietary Fats; C071280:EMF-1 protein, Gallus gallus; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D053474:Nod1 Signaling Adaptor Protein; C507873:Nod1 protein, mouse; D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse