title: Circulating NOD1 Activators and Hematopoietic NOD1 Contribute to Metabolic Inflammation and Insulin Resistance.
abstract: Insulin resistance is a chronic inflammatory condition accompanying obesity or high fat diets that leads to type 2 diabetes. It is hypothesized that lipids and gut bacterial compounds in particular contribute to metabolic inflammation by activating the immune system; however, the receptors detecting these "instigators" of inflammation remain largely undefined. Here, we show that circulating activators of NOD1, a receptor for bacterial peptidoglycan, increase with high fat feeding in mice, suggesting that NOD1 could be a critical sensor leading to metabolic inflammation. Hematopoietic depletion of NOD1 did not prevent weight gain but protected chimeric mice against diet-induced glucose and insulin intolerance. Mechanistically, while macrophage infiltration of adipose tissue persisted, notably these cells were less pro-inflammatory, had lower CXCL1 production, and consequently, lower neutrophil chemoattraction into the tissue. These findings reveal macrophage NOD1 as a cell-specific target to combat diet-induced inflammation past the step of macrophage infiltration, leading to insulin resistance.
authors.affiliation: Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada; Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Kenny L
authors.initials: KL
authors.lastname: Chan
authors.affiliation: Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.
authors.forename: Theresa H
authors.initials: TH
authors.lastname: Tam
authors.affiliation: Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada; Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Parastoo
authors.initials: P
authors.lastname: Boroumand
authors.affiliation: Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Prescott
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Sheila R
authors.initials: SR
authors.lastname: Costford
authors.affiliation: Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Nichole K
authors.initials: NK
authors.lastname: Escalante
authors.affiliation: Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Toronto, Ontario M5S 3E2, Canada.
authors.forename: Noah
authors.initials: N
authors.lastname: Fine
authors.affiliation: Neurosciences and Mental Health Program, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.
authors.forename: YuShan
authors.initials: Y
authors.lastname: Tu
authors.affiliation: Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Robertson
authors.affiliation: Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.
authors.forename: Dilshaayee
authors.initials: D
authors.lastname: Prabaharan
authors.affiliation: Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Bilan
authors.affiliation: Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada; Neurosciences and Mental Health Program, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Salter
authors.affiliation: Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Toronto, Ontario M5S 3E2, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Glogauer
authors.affiliation: Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Girardin
authors.affiliation: Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Dana J
authors.initials: DJ
authors.lastname: Philpott
authors.affiliation: Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada; Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada; Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada. Electronic address: amira@sickkids.ca.
authors.forename: Amira
authors.initials: A
authors.lastname: Klip
mesh_terms: D000273:Adipose Tissue / Q000473:pathology; D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D016764:Cell Polarity / Q000187:drug effects; D054360:Chemokine CXCL1 / Q000378:metabolism; D002630:Chemotactic Factors / Q000494:pharmacology; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D017353:Gene Deletion; D005947:Glucose / Q000378:metabolism; D006410:Hematopoiesis / Q000187:drug effects; D007249:Inflammation / Q000150:complications / Q000378:metabolism* / Q000473:pathology*; D007333:Insulin Resistance; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000187:drug effects; D053474:Nod1 Signaling Adaptor Protein / Q000378:metabolism*; D009765:Obesity / Q000097:blood / Q000150:complications / Q000473:pathology
chemical_list: D054360:Chemokine CXCL1; D002630:Chemotactic Factors; D053474:Nod1 Signaling Adaptor Protein; C507873:Nod1 protein, mouse; D005947:Glucose
keywords: NOD1; gut microbiome; inflammation; insulin resistance; macrophage; neutrophil; obesity