title: NOD1 activation induces proinflammatory gene expression and insulin resistance in 3T3-L1 adipocytes.
abstract: 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 IRS-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.
authors.affiliation: Department of Nutrition, The University of Tennessee, Knoxville, USA. ling.zhao@utk.edu
authors.forename: Ling
authors.initials: L
authors.lastname: Zhao
authors.forename: Pan
authors.initials: P
authors.lastname: Hu
authors.forename: Yijun
authors.initials: Y
authors.lastname: Zhou
authors.forename: Jaanki
authors.initials: J
authors.lastname: Purohit
authors.forename: Daniel
authors.initials: D
authors.lastname: Hwang
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism*; D000818:Animals; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D005947:Glucose / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology*; D051379:Mice; D008820:Mice, Obese; D053474:Nod1 Signaling Adaptor Protein / Q000235:genetics / Q000378:metabolism*; D009765:Obesity / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
chemical_list: D018925:Chemokines; D016207:Cytokines; D018836:Inflammation Mediators; D053474:Nod1 Signaling Adaptor Protein; C507873:Nod1 protein, mouse; D012333:RNA, Messenger; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose