Circulating NOD1 Activators and Hematopoietic NOD1 Contribute to Metabolic Inflammation and Insulin Resistance

Kenny L. Chan, Theresa H. Tam, Parastoo Boroumand, David Prescott, Sheila R. Costford, Nichole K. Escalante, Noah Fine, Yu Shan Tu, Susan J. Robertson, Dilshaayee Prabaharan, Zhi Liu, Philip J. Bilan, Michael W. Salter, Michael Glogauer, Stephen E. Girardin, Dana J. Philpott, Amira Klip

Research output: Contribution to journalArticlepeer-review

49 Scopus citations

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.

Original languageEnglish
Pages (from-to)2415-2426
Number of pages12
JournalCell Reports
Volume18
Issue number10
DOIs
StatePublished - 7 Mar 2017
Externally publishedYes

Keywords

  • NOD1
  • gut microbiome
  • inflammation
  • insulin resistance
  • macrophage
  • neutrophil
  • obesity

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