This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The increasing prevalence of obesity, especially during the 1990's, has become a national epidemic with enormous public health implications. All subjects who become obese become more insulin resistant, and this insulin resistance, coupled with an insulin secretory defect, leads to type 2 diabetes in susceptible subjects. Yet the mechanisms interrelating obesity, insulin resistance, and type 2 diabetes are not well understood. Among subjects with the same BMI, there is a wide spectrum of insulin sensitivity: many lean subjects are insulin resistant, and many obese subjects are remarkably insulin sensitive. The insulin resistance phenotype encompasses many different tissues. Muscle is the primary tissue that controls glucose disposal, and there are numerous defects in the muscle of insulin resistant subjects, including an increase in intramuscular triglyceride (IMTG) and a decrease in muscle fiber lipid oxidative capacity. The link between insulin resistance and obesity suggest that adipocytes either directly or indirectly affect glucose disposal. However, not all fat is the same, and the expansion of abdominal fat is more important in the insulin resistance syndrome than is total fat. One explanation for obesity-related insulin resistance is the production of factors by adipose tissue, in particular visceral adipose tissue, that render some subjects more insulin resistant than others. Our recent data demonstrate for the first time that adipose tumor necrosis factor and IL-6 expression is related to insulin resistance independent of obesity. Thus, this proposal examines TNF and IL-6 expression in relation to the insulin resistance syndrome. Our overall goal is to determine whether the adipose tissue expression of these cytokines play a role in insulin resistance in humans, and to examine possible mechanisms for their actions. Hypothesis. High expression of IL-6 and TNF is associated with insulin resistance. Common polymorphisms for IL-6 and TNF result in increased adipose tissue expression of these cytokines.
Aim 1. Adipose tissue cytokine expression, along with features of the insulin resistance syndrome, will be measured in subjects with common polymorphisms in TNF (G-308A) and IL-6 (G-174C). Hypothesis 2. Visceral adipose tissue expression of IL-6 and TNF is increased in subjects with insulin resistance, and common polymorphisms in TNF and IL-6 influence the visceral/SQ expression of these cytokines.
Aim 2. TNF and IL-6 expression will be measured in subcutaneous and visceral adipose tissue of patients undergoing elective surgery. The relationship between adipose cytokine expression and the insulin resistance syndrome will be assessed.
Aim 3. TNF and IL-6 expression will be examined in visceral and SQ adipose tissue of subjects with the TNF (G-308A) and IL-6 (G-174C) polymorphisms. Hypothesis 3. The expression of IL-6 in adipose tissue is responsible for insulin resistance in mice.
Aim 4. Insulin sensitivity will be measured in rodents that are deficient in IL-6.
Aim 5. We will create transgenic mice that express IL-6 in adipose tissue only, and determine whether these mice demonstrate insulin resistance compared to IL-6 knockout mi
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