Inflammation and Insulin Resistance

Current evidence indicates that chronic activation of the proinflammatory state may be an underlying mechanism for insulin resistance. Together, these findings suggest that increased macrophage activation can be an important contributor to the pathogenesis of cellular insulin resistance. To assess this concept, we have used genetic deletion of key molecules controlling the inflammatory pathway, in mouse KO studies. Macrophage specific deletion of IKKβ or JNK1 disables the cytokine stimulated NFκB or JNK1/AP2 proinflammatory pathways leading to decreased tissue inflammatory markers, enhanced insulin sensitivity, and protection from the effects of high fat diet to cause insulin resistance. The enhanced insulin sensitivity and protection against insulin resistance were manifested in liver, muscle, and adipose tissue, indicating that inhibition of the inflammatory pathway within macrophages leads to a global state of heightened insulin sensitivity. Taking another approach to this issue, omega‐3 fatty acids (ω‐3 FAs), DHA and EPA, exert anti‐inflammatory effects, but the mechanisms are poorly understood. We found show that the G protein‐coupled receptor 120 (GPR120) functions as an ω‐3 FA receptor/sensor. Stimulation of GPR120 with ω‐3 FAs or a chemical agonist causes broad anti‐inflammatory effects in monocytic RAW 264.7 cells and in primary intraperitoneal macrophages. All of these effects are abrogated by GPR120 knockdown. Since chronic macrophage‐mediated tissue inflammation is a key mechanism for insulin resistance in obesity, we fed obese WT and GPR120 knockout mice a high fat diet with or without ω‐3 FA supplementation. The ω‐3 FA treatment inhibited inflammation and enhanced systemic insulin sensitivity in WT mice, but was without effect in GPR120 knockout mice. Thus, GPR120 is a functional ω‐3 FA receptor/sensor and mediates potent insulin sensitizing and anti‐diabetic effects in vivo by repressing macrophage‐induced tissue inflammation.