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The adipose Nod-like receptor protein 3 (NLRP3) inflammasome initiates insulin resistance; however, the mechanism of inflammasome activation in adipose tissue remains elusive. In this study, homocysteine (Hcy) was found to participate in insulin resistance via a NLRP3 inflammasome-related process. Hcy-induced activation of NLRP3 inflammasomes were observed in adipose tissue during the generation of insulin resistance in vivo. This animal model suggests that diets high in omega-3 fatty acids alter serum and adipose lipid profiles, and in this way, omega-3 fatty acids may reduce adipose tissue inflammation and attenuate insulin resistance.