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

Publication date: 7 March 2017
Source:Cell Reports, Volume 18, Issue 10
Author(s): Kenny L. Chan, Theresa H. Tam, Parastoo Boroumand, David Prescott, Sheila R. Costford, Nichole K. Escalante, Noah Fine, YuShan Tu, Susan J. Robertson, Dilshaayee Prabaharan, Zhi Liu, Philip J. Bilan, Michael W. Salter, Michael Glogauer, Stephen E. Girardin, Dana J. Philpott, Amira Klip
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.

Graphical abstract

Teaser

Chan et al. identify that activators of NOD1, a receptor for bacterial cell wall peptidoglycan, increase in the bloodstream during high fat feeding. Moreover, depleting NOD1 from the immune system prevents pro-inflammatory macrophage activation and neutrophil infiltration in adipose tissue during a high fat diet, to improve whole-body insulin sensitivity.


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