2011 Grant Award - Brigitte I. Frohnert, M.D., Ph.D.

Oxidative Stress and Development of Insulin Resistance

Brigitte I. Frohnert, M.D., Ph.D.
Department of Pediatrics, University of Minnesota

It is well known that the prevalence of obesity in western countries has been increasing, along with the incidence of obesity-related diseases such as type 2 diabetes mellitus and cardiovascular disease. There is now substantial evidence that obesity-related inflammation in fat tissue plays a causative role in the development of insulin resistance; however, the mechanism for this is poorly understood. While tissue inflammation is associated with adipocyte oxidative stress, previous research has primarily focused on the role of the macrophage in inducing oxidative stress in adipocytes. This study takes a new perspective in proposing that oxidative stress in adipocytes leads to increased inflammation in macrophages. Oxidative stress in adipocytes is associated with increased production of reactive lipids, a process termed lipid peroxidation. Recently, we have measured two products of lipid peroxidation, glutathione-4-hydroxy-trans-2-nonenal (GS-HNE) and glutathione-4-hydroxy-trans-2-nonenoic acid (GS-DHN) in human fat and shown in vitro that they are able to stimulate production of TNF−α in macrophages. We hypothesize that in humans, these products of lipid peroxidation will be positively associated with increased body mass index (BMI), fasting insulin, serum free fatty acids and dyslipidemia. Further, expression of key enzymes in the production of GS-HNE and GS-DHN are expected to be positively associated with their levels in adipose. Finally, we propose to study the interaction of adipocytes and macrophages in vitro using two well-characterized cell culture lines. The studies described in this proposal, if successful, will support a novel mechanism for induction of adipose inflammation and provide evidence that this is present in obese humans. Insight into this process may lead to new interventions for prevention or treatment of obesity-related insulin resistance.