| Summary: | 博士 === 國立陽明大學 === 生理學研究所 === 98 === As compared with Paleolithic ancestors or highly active humans, modern people living within advanced settings are prone to develop obesity and obesity-associated comorbidities. In addition to the effect of physical activity, insulin actions for different nutrients should be of high importance. Insulin resistance (IR) was initially defined as the presence of resistance to insulin-stimulated glucose uptake. A cluster of abnormalities resulted from IR were termed IR syndrome, including obesity, glucose intolerance, dyslipidemia, and even severe cardiovascular complications. Notably, hyperinsulinemia is the common root of several IR-associated comorbidities such as obesity. The precise pathogenesis of obesity remains controversial. Our findings demonstrated that long-chain fatty acid (LCFA) influx is responsive at much lower insulin concentrations in adipocytes, highlighting its importance in adipose energy homeostasis. In obesity, diminished adipose glucose utilization suggests that some other substrates may be responsible for the adipose triglyceride (TG) overaccumulation. Here we attempted to evaluate if LCFA flux was modulated by a physiologically relevant condition of hyperinsulinemia in 3T3-L1 adipocytes, and that the altered LCFA influx might eventually contribute to the TG overaccumulation in obesity. The effects of prolonged insulin exposure to adipocytes on basal, insulin-stimulated LCFA uptake, as well as intracellular LCFA metabolism were measured. Prolonged insulin exposure was found to induce IR yet enhance basal and insulin-stimulated LCFA uptake in normoglycemic condition, and the addition of high glucose exacerbated these abnormalities of both glucose and LCFA influx. Along with the enhanced LCFA uptake was an increase in the rates of intracellular LCFA deposition and incorporation into TG, but a decrease was found in basal and insulin-suppressive LCFA oxidation, as well as in isoproterenol-induced fatty acid efflux. Inhibition of either phosphatidylinositol 3-kinase (PI3K) or mitogen-activated protein kinase (MAPK) pathway showed no effect on the IR induction. Only inhibition of MAPK pathway could specifically prevent the enhanced LCFA influx in both basal and insulin-stimulated states. In hyperinsulinemic insulin-resistant 3T3-L1 adipocytes, basal and insulin-stimulated LCFA uptake tends to increase via a MAPK-dependent mechanism. The increment of LCFA influx predominantly accounts for TG overaccumulation, but not for mitochondrial oxidation, and is prone to retain within adipocytes. These findings may interpret the plausible mechanism of pathogenesis for obesity in hyperinsulinemia-associated IR. The present study demonstrated that, in the presence of hyperinsulinemia, LCFA serves as the substrate for TG storage during the development of IR-associated obesity. Targeting the MAPK branch of adipose insulin signaling may be considered as a therapeutic approach against hyperinsulinemia-associated obesity.
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