Model of overlapping metabolic and inflammatory signaling and sensing pathways in adipocytes or macrophages. Inflammatory pathways can be initiated by extracellular mediators such as cytokines and lipids or by intracellular stresses such as ER stress or excess ROS production by mitochondria. Signals from all of these mediators converge on inflammatory signaling pathways, including the kinases JNK and IKK. These pathways lead to the production of additional inflammatory mediators through transcriptional regulation as well as to the direct inhibition of insulin signaling. Other pathways such as those mediated through the SOCS proteins and iNOS are also involved in inflammation-mediated inhibition of insulin action. Opposing the inflammatory pathways are transcription factors from the PPAR and LXR families, which promote nutrient transport and metabolism and antagonize inflammatory activity. More proximal regulation is provided by FABPs, which likely sequester ligands of these transcription factors, thus promoting a more inflammatory environment. The absence of FABPs is antiinflammatory. The cell must strike a balance between metabolism and inflammation. In conditions of overnutrition, this becomes a particular challenge, as the very processes required for response to nutrients and nutrient utilization, such as mitochondrial oxidative metabolism and increasing protein synthesis in the ER, can induce the inflammatory response. IR, insulin receptor.