Abdominal obesity is more strongly associated with an increased risk of myocardial infarction, angina pectoris, stroke, and non-insulin dependent diabetes mellitus than is gluteofemoral obesity. The reasons for this are unknown. It is well established that the turnover of triglycerides and the metabolism of glucose are all increased in abdominal compared with gluteofemoral fat cells. However, adipocytes from obese patients exhibit decreased insulin sensitivity for glucose transport and metabolism. The extent to which this """"""""insulin resistance"""""""" is reflected in the adipose tissue itself is unclear. This proposal is based on the hypothesis that alterations in insulin and counter-regulatory hormone signalling characterize adipocytes isolated from abdominal adipose tissue of patients exhibiting abdominal obesity. According to the model, a defect in insulin signalling would not be associated with adipocytes isolated from the abdominal or gluteofemoral region of patients exhibiting gluteofemoral obesity. To test this hypothesis, adipocytes isolated from the abdominal and gluteofemoral regions of obese patients exhibiting either abdominal or gluteofemoral obesity, will be used to ask the following questions: 1) Are there differences in the maximal rates or the half-maximal concentrations of agonist required to stimulate lipogenesis or lipolysis between different adipocyte stores or among subjects with different forms of obesity? The kinetics of lipogenesis and lipolysis will be characterized by measuring the concentration-dependency of insulin-stimulated glucose transport, metabolism and conversion to lipid, and norepinephrine and glucagon mediated lipolysis. 2) Are there differences in metabolic activity and in the ability to metabolize fatty acids between different adipocyte stores or among patients with different forms of obesity? Parameters which characterize the metabolic state of the cell, such as oxygen consumption and the ATP/ADP ratio, will be measured, and the ability of the cells to oxidize fatty acids and secrete lipoprotein lipase in response to insulin will be determined. 3) Are there differences in the early signal transduction pathway between different adipocyte stores or among patients with different forms of obesity? The concentration dependence for insulin and the counter-regulatory hormones to modulate: insulin receptor autophosphorylation, tyrosine phosphorylation of the insulin receptor substrate, IRS-1, activation of phosphatidylinositol 3-kinase, intracellular cAMP, free Ca2+ and pH will be compared. These parameters represent rapid signalling events that are independent of glucose uptake and metabolism that could be impaired in adipocytes from specific sites of obesity. The results of these studies should provide novel mechanistic information about insulin signalling in obesity and the differences between obese and non-obese adipose tissue sites.
Showing the most recent 10 out of 876 publications
