Obesity and high-fat diet activate IKKβ/NF-κB and JNK pathways in adipocytes, hepatocytes, and associated macrophages. Stimuli that have been shown to activate these pathways during metabolic dysregulation include ligands for TNF-α, IL-1, Toll, or AGE receptors (TNFR, IL-1R, TLR, or RAGE, respectively), intracellular stresses including ROS and ER stress, ceramide, and various PKC isoforms. Obesity-induced IKKβ activation leads to NF-κB translocation and the increased expression of numerous markers and potential mediators of inflammation that can cause insulin resistance. Obesity-induced JNK activation promotes the phosphorylation of IRS-1 at serine sites that negatively regulate normal signaling through the insulin receptor/IRS-1 axis. Examples include serine-302 (pS302) and serine-307 (pS307). By contrast, evidence has not been reported for obesity-induced effects on transcription factors such as AP-1 that are regulated by JNK. IKKβ and/or NF-κB are inhibited or repressed by the actions of salicylates, TZDs, and statins.

Dietary excess and obesity cause lipid accumulation in adipocytes, initiating a state of cellular stress and activation of JNK and NF-κB. These inflammatory signaling pathways regulate protein phosphorylation and cellular transcriptional events, thereby leading to increased adipocyte production of proinflammatory cytokines, including TNF-α, IL-6, leptin, and resistin, chemokines such as MCP-1, and other proatherogenic mediators, for example PAI-1. Endothelial adhesion molecules (e.g., ICAM-1 and VCAM-1) and chemoattractant molecules (designated CCX) bind integrins and chemokine receptors (CCR), respectively, on the monocyte surface to recruit them to the adipose tissues. The monocytes that differentiate into macrophages produce many of the same inflammatory cytokines and chemokines as those listed above, and additional ones, to further promote local inflammation and propagate the inflammatory diathesis systemically. pS, phosphoserine.

Healthy liver contains a broad repertoire of cells that participate in inflammatory and immune responses, including resident hepatic macrophages (Kupffer cells), B and T cells, NK and NKT cells, DCs, liver sinusoidal endothelial cells, hepatic stellate cells, and hepatocytes. Hepatic steatosis and obesity are accompanied by the activation of inflammatory signaling pathways in liver. Proinflammatory cytokines and FFAs, produced either by hepatocytes in response to steatosis or by abdominal fat tissue, may activate Kupffer cells. Numbers of regulatory NKT cells decrease in parallel with the Kupffer cell activation.

Increasing adiposity activates inflammatory responses in fat and liver, with associated increases in the production of cytokines and chemokines. Immune cells including monocytes and macrophages are recruited and/or activated, and together these cause local insulin resistance. Portal delivery of abdominal fat–derived cytokines and lipids contributes to hepatic inflammation and insulin resistance. Proinflammatory and proatherogenic mediators are produced in the adipose tissue and liver and associated immune cells. This creates a systemic inflammatory diathesis that promotes insulin resistance in skeletal muscle and other tissues and atherogenesis in the vasculature.