Chronic inflammation is associated with obesity and insulin resistance. However, the underlying mechanisms are not fully understood. Pattern recognition receptors Toll-like receptors and Nucleotide-oligomerization domain containing proteins play critical roles in innate immune response. Here we report that activation of nucleotide binding oligomerization domain containing protein 1 (NOD1) in adipocytes induces proinflammatory response and impairs insulin signaling and insulin-induced glucose uptake. NOD1 and NOD2 mRNA are markedly increased in differentiated murine 3T3-L1 adipocytes and human primary adipocyte culture upon adipocyte conversion. Moreover, NOD1 mRNA is markedly increased only in the fat tissues in diet-induced obese mice, but not in genetically obese ob/ob mice. Stimulation of NOD1 with a synthetic ligand Tri-DAP induces proinflammatory chemokine MCP-1, RANTES and cytokine TNF-α and MIP-2 (human IL-8 homolog) and IL-6 mRNA expression in 3T3-L1 adipocytes in a time and dose dependent manner. Similar proinflammatory profiles are observed in human primary adipocyte culture stimulated with Tri-DAP. Furthermore, NOD1 activation suppresses insulin signaling as revealed by attenuated tyrosine phosphorylation, and increased inhibitory serine phosphorylation, of insulin receptor substrate-1 and attenuated phosphorylation of Akt and downstream target GSK3α/3β, resulting in decreased insulin-induced glucose uptake in 3T3-L1 adipocytes. Together, our results suggest that NOD1 may play an important role in adipose inflammation and insulin resistance in diet-induced obesity.
- insulin resistance
- Copyright © 2011, American Journal of Physiology - Endocrinology and Metabolism