Glutathionylated products of lipid peroxidation: A novel mechanism of adipocyte to macrophage signaling

Obesity-associated insulin resistance has long been linked to both increased adipocyte oxidative stress as well as the presence of inflammatory changes in adipose tissue, including the infiltration and activation of tissue-resident macrophages. In order to investigate the connections between obesity-associated oxidative stress in adipocytes and increased inflammation in adipose tissue associated with the development of insulin resistance, our laboratory recently demonstrated that adipocytes form glutathionylated products of oxidative stress including glutathionyl-4-hydroxy-2-nonenal (GS-HNE) and glutathionyl-1,4-dihydroxynonene (GS-DHN). The abundance of both GS-HNE and GS-DHN were increased in the visceral adipose tissue of ob/ob mice and diet-induced obese, insulin-resistant mice. Further, these products of lipid peroxidation were shown to induce inflammatory changes in macrophages. Finally, in a mouse model, overproduction of GS-HNE was associated with increased fasting glucose levels and moderately impaired glucose tolerance. Together, these findings suggest a novel mechanism by which obesity-induced oxidative stress in adipocytes may lead to activation of tissue-resident macrophages. As adipose tissue inflammation has been shown to play an important role in the development of insulin resistance, further study of this pathway may lead to potential interventions to attenuate the metabolic consequences of obesity.