Integrating the Metabolic and Genetic Faces of Obesity

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DESCRIPTION (provided by applicant): The rapid increase in the prevalence of obesity in the US represents a major health problem. Obesity-associated risks of cardiovascular disease and diabetes mellitus are likely related to the fact that obese individuals tend to be insulin resistant and hyperinsulinemic. Not all obese individuals are insulin resistant, however, and insulin-mediated glucose uptake (IMGU) rates vary more than six-fold in healthy individuals whose body mass index (BMI) is equal to or more than 25.0 kg/m2. Furthermore, it is not uncommon for individuals of the same gender and BMI to have widely divergent values for IMGU. Given that inherited factors are likely to account for approximately 50% of the variability in IMGU in the population at large, and that insulin sensitivity tends to decrease as body weight increases, it seems evident that differential gene expression influences the manner in which adipocytes respond to caloric excess/obesity, leading to different metabolic consequences. We have assembled a unique group of clinical and basic scientists to test the hypothesis that differential gene expression related to adipocyte differentiation and function underlies the variability in IMGU associated with obesity. Specifically, individuals who, in the setting of caloric excess, are able to increase adipogenesis, increase FFA uptake and storage in adipose tissue, and increase anti-inflammatory and decrease inflammatory adipocytokine secretion, will not be insulin resistant, while those who are not able to respond in this manner will be insulin-resistant. Furthermore, we hypothesize that the insulin-resistant subgroup of obese individuals will demonstrate abnormalities in adipocyte differentiation and terminal function that improve in association with insulin sensitization via interventions targeting adipose tissue, but that these changes will not be seen in insulin-sensitive controls that lack change in insulin sensitivity with the same interventions. Thus, Drs. Reaven and McLaughlin will identify and recruit age-, sex- and BMI-matched individuals who differ in their IMGU. Adipose tissue biopsies will be harvested and, in collaboration with Drs. Tsao, Cushman and Sherman, markers of adipocyte differentiation/function will be compared including cell size distribution, gene expression, and insulin-suppression of lipolysis. In addition, adipocytokine production will be measured from isolated plasma. Finally, we will evaluate changes in these markers to two insulin-sensitizing interventions that target adipose tissue: weight loss and thiazolidenedione (TZD) treatment. We believe that this work will add substantially to the current gap in knowledge regarding the link between obesity and insulin-resistance, and ultimately aid in the development of novel therapeutic targets.