Oxidized neutral lipid lipolysis regulates insulin signaling during acute stress

Acute hyperglycemia and systemic insulin resistance (IR) often develop after injury or surgery. This stress response, appropriately known as critical illness diabetes, leads to increased post-operative complications and mortality. Insulin administration reduces this hyperglycemia in some patients but has a risk of dangerous hypoglycemia. The underlying mechanisms driving IR are unknown, which limits the development of alternative therapies and emphasizes the need to elucidate the pathophysiology. It is, however, known that surgical animal models rapidly develop adipose IR, and impaired insulin action in adipose alone can result in whole-body IR. Therefore, we focused on how adipose contributes to stress-induced IR. We have previously demonstrated using a mouse model of surgery that the development of IR and hyperglycemia are dependent on adipose lipolysis. Furthermore, β-adrenergic stimulation of adipocytes causes inhibition and dissociation of mTORC1 and mTORC2, key steps in the insulin cascade, in a lipolysis-dependent manner. Therefore, we hypothesized that a product of adipose lipolysis was responsible for the development of IR. We found that lipid extracts isolated from forskolin-stimulated 3T3-L1 adipocytes inhibited the activity of mTORC in vitro, however “traditional” lipolytic products (DAG, MAG, fatty acids) had no effect. Interestingly, stimulating peroxidation of fatty acids further exacerbated mTORC inhibition, while antioxidants reversed this effect. This suggests that the active species is an oxidized fatty acid. In fact, incubation of mTORC with in vitro auto-oxidized fatty acids is sufficient to inhibit kinase activity. Therefore, we propose that lipolysis breaks down oxidized TAGs into oxidized fatty acids, which cause mTORC dissociation and attenuation of insulin signaling during the stress response. Our work will elucidate a novel role for oxidized TAGs and their lipolytic products in the regulation of insulin signaling. Defining the mechanism by which catecholamine-stimulated lipolysis attenuates insulin signaling will provide novel therapeutic targets for improved post-operative glucose homeostasis.