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.
RESEARCH DESIGN AND 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.