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 hyperglycemia in some patients, but has a risk of hypoglycemia. The underlying mechanism of post-operative IR is largely unknown, which limits alternative therapies and emphasizes the need to elucidate the pathophysiology. It is, however, known that surgical animal models rapidly develop adipose IR. Impaired insulin action in adipose alone can result in whole body IR and hyperglycemia. Therefore, this proposal will focus on how adipocyte lipolysis contributes to stress-induced IR. Inhibition of mTOR complexes 1 and 2, kinase complexes integral to insulin signaling, is associated with the onset of IR. Our previous work demonstrates that catecholamine-induced attenuation of insulin signaling requires lipolysis of the neutral lipids triacylglycerols (TAGs) and causes mTOR complex dissociation. We recently observed that the presence of lipolytic products of oxidized neutral lipids (oxNL) induces mTOR complex dissociation. We hypothesize that lipolysis breaks down oxidized TAGs into oxidized fatty acids (oxFAs), which cause mTOR complex dissociation and attenuation of insulin signaling within adipocytes during stress response. To this purpose, we propose the following aims.
In Aim 1, we will define the oxFAs responsible by examining in vitro whether oxidation of known polyunsaturated FAs generates products that cause mTOR complex dissociation. Additionally, we will elucidate the type responsible by class-specific chemical derivitization of oxFAs.
In Aim 2, we will determine the role of adipose lipolysis and oxFA-mediated mTOR complex inhibition during the acute stress response by treating wild-type and adipose-specific adipose triglyceride lipase null mice with ? receptor agonists. We will also stimulate the onset of the stress response by subjecting mice to a hypovolemic model of acute trauma. The potential effect of oxFA production on mTOR complex dissociation and the development of IR within adipose will be determined. Our work will elucidate a novel role for oxNLs 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. The research project proposed will be carried out in conjunction with a rigorous training plan composed of the following: integrative coursework and interactive training, participation in research meetings and seminars, participation in scientific conferences, and professional development. The combination of the proposed research along with an active training plan will yield meaningful contributions to the field and the training required to excel as a successful independent researcher.
The acute stress response is activated by injury or surgery and results in systemic insulin resistance and hyperglycemia, leading to increased post-operative complications and mortality. The proposed study will test the hypothesis that during acute stress lipolysis breaks down oxidized triacylglycerols into oxidized fatty acids, which cause mTOR complex dissociation and thus attenuation of insulin signaling. By defining the mechanism by which acute stress-stimulated lipolysis attenuates insulin signaling, this work will provide novel therapeutic targets for improved post-operative glucose homeostasis.
