Low-grade systemic inflammation is often associated with metabolic syndrome, which plays a critical role in the development of the obesity-associated inflammatory diseases, including insulin resistance and atherosclerosis. Here, we investigate how Toll-like receptor–MyD88 signaling in myeloid and adipocytes coordinately participates in the initiation and progression of high fat diet–induced systemic inflammation and metabolic inflammatory diseases. MyD88 deficiency in myeloid cells inhibits macrophage recruitment to adipose tissue and their switch to an M1-like phenotype. This is accompanied by substantially reduced diet-induced systemic inflammation, insulin resistance, and atherosclerosis. MyD88 deficiency in adipocytes ameliorated diet-induced infiltration of M1 macrophages in the adipose tissue and insulin resistance. Mechanistically, we have identified a novel pathway in which LPS/TLR4 engagement promotes nuclear localization of IRAK2 to facilitate export of a specific subset of inflammation related mRNAs to the cytoplasm for translation. IRAK2 kinase activity is required for LPS-induced IRAK2 nuclear translocation. IRAK2 kinase inactivation attenuated high fat diet–induced systemic inflammation and metabolic inflammatory diseases. Collectively, these results implicate a critical MyD88/IRAK2-dependent interplay between myeloid cells and adipocytes in the initiation and progression of obesity-associated inflammatory diseases.