Molecular Mechanisms of Obesity and Insulin Resistance

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DESCRIPTION (provided by applicant): Obesity is associated with insulin resistance and type II diabetes, but the molecular events linking increased adiposity to these pathological conditions remains unclear. We intend to utilize a novel mammalian model of obesity and insulin resistance, the pre-hibernating marmot, to characterize the molecular defects underlying the development of these abnormal conditions. During the autumn, marmots undergo a doubling of body mass in the form of fat. This weight gain is associated with a profound hyperinsulinemia, and marmots display all of the characteristics of peripheral insulin resistance. Before this insulin resistance develops into frank diabetes, however, the animals begin hibernation, where they have suppressed appetite and rely almost exclusively on fat stores for energy. During this period, insulin resistance is apparently reversed, as the circulating insulin levels return to normal. None of the insulin signal transduction pathways have been evaluated during the astonishing period of weight gain, nor have they been investigated during the animal's subsequent conversion into this lipolytic state. In the studies described herein, we will characterize the effect of this rapid weight gain on insulin's ability to activate known signaling intermediates. We will obtain blood samples and tissue biopsies from these animals throughout the course of this pre-hibernation period, as well as following entry into hibernation. These studies could uncover important information about the molecular events associated with the development of insulin resistance. Moreover, by correlating the concentration of fat-derived circulating factors (e.g. free fatty acids, tumor necrosis factor-alpha, and resistin) with the degree of insulin resistance, we might uncover novel information about the contribution of these factors to the pathogenesis of type II diabetes mellitus. Ultimately, the exaggerated characteristics of hibernators could assist us in the identification of abnormalities relevant to the human condition.