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Insulin and the ß3-Adrenoceptor Differentially Regulate Uncoupling Protein-1 Expression

Research Division Joslin Diabetes Center (J.K., M.F., C.R.K.) Harvard Medical School Boston, Massachusetts 02215
Department of Internal Medicine I (J.K.) Medical University of Lübeck 23538 Lübeck, Germany
Facultad de Farmacia (M.B.) Universidad Complutense 28040 Madrid, Spain

Cross-talk between insulin and the adrenergic system is important in the regulation of energy homeostasis. In cultured, differentiated mouse brown adipocytes, ß3-adrenergic stimulation induced a 4.5-fold increase in uncoupling protein-1 (UCP-1) expression, which was diminished by 25% in the presence of insulin. ß3-Adrenergic stimulation also activated mitogen-activated protein (MAP) kinase by 3.5-fold and caused a decrease in basal phosphoinositide (PI) 3-kinase activity detected in p110- and Gß-subunit-immunoprecipitates in a time-dependent manner, whereas insulin stimulated p110- and phosphotyrosine-associated PI 3-kinase activity. Inhibition of MAP kinase or PI 3-kinase potentiated the ß3-adrenergic effect on UCP-1 expression, both alone and in the presence of insulin. Thus, insulin inhibits ß3-adrenergic stimulation of UCP-1, and both MAP kinase and PI 3-kinase are negative regulatory elements in the ß3-adrenergic control of UCP-1 expression. Cross-talk between the adrenergic and insulin signaling systems and impaired regulation of UCP-1 might contribute to the development of a reduced energy balance, resulting in obesity and insulin resistance.

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