Visceral Adiposity: Role of Inflammation in Potentiating Insulin Resistance

Stanford University, Stanford CA

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Abstract

DESCRIPTION (provided by applicant): The epidemic of obesity in the United States is a major public health dilemma. Obesity-related morbidities such as type 2 diabetes and cardiovascular disease have been shown to be strongly associated with insulin resistance. Since not all obese individuals are insulin resistant, it is important to identify those who are and therefore at greatest risk for these complications. Visceral adiposity has recently been identified as a potential independent risk factor for insulin resistance. Increased lipolytic activity and its anatomic location providing direct delivery of free fatty acids to the liver may contribute to insulin resistance. Nonetheless, a growing body of evidence suggests that inflammation may also play a role in mediating insulin resistance, and that both adipocytes and macrophage infiltration in adipose tissue may be sources of cytokine secretion. We hypothesize that visceral adipose tissue (VAT) contributes to insulin resistance via increased inflammatory activity. This study has the following aims: 1.To determine whether visceral adipose tissue and/or cells express higher levels of pro-inflammatory genes in insulin resistant subjects than in equally obese, non-insulin resistant subjects. We hypothesize that VAT of insulin resistant subjects will demonstrate higher expression of pro-inflammatory cytokines and macrophage markers than in non-insulin resistant subjects/Conversely, we hypothesize that insulin resistant subjects will have decreased gene expression of adiponectin, which has anti-inflammatory properties, when compared with VAT of non-insulin resistant subjects. 2. To determine whether subcutaneous adipose tissue and/or cells express higher levels of pro- inflammatory genes in insulin resistant subjects than in equally obese, non-insulin resistant subjects. 3. To determine whether inflammatory gene expression is greater in visceral adipose tissue and/or cells than in subcutaneous adipose tissue and/or cells in both insulin resistant and non-insulin resistant subjects. We will perform quantitative real time Polymerase Chain Reaction (rtPCR) for gene expression analysis and use direct measurement of insulin-mediated glucose disposal by the insulin suppression test to quantify insulin resistance. This study will provide important information as to whether inflammatory properties distinctive to VAT may contribute to pathogenesis of insulin resistance. As the economic, social, and public health burden of obesity in the United States continues to rise, understanding the mechanistic link between obesity and insulin resistance becomes of critical importance. Targeting activation of inflammatory pathways in obesity may eventually play a role in our repertoire of interventions.