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-adrenergic effects on insulin signaling and
action in 3-adrenoceptor-deficient brown
adipocytes
1 Department of Internal Medicine I, Medical University of Lübeck, 23538 Lübeck; 2 Department of Internal Medicine III, University of Leipzig, 04103 Leipzig, Germany; 3 Joslin Diabetes Center and Harvard Medical School, and 4 Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215; and 5 Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain
Cross talk
between adrenergic and insulin signaling systems may represent a
fundamental molecular basis of insulin resistance. We have
characterized a newly established
3-adrenoceptor-deficient (3-KO) brown
adipocyte cell line and have used it to selectively investigate the
potential role of novel-state and typical -adrenoceptors (-AR) on
insulin signaling and action. The novel-state 1-AR agonist CGP-12177 strongly induced uncoupling protein-1 in
3-KO brown adipocytes as opposed to the
3-selective agonist CL-316,243. Furthermore, CGP-12177
potently reduced insulin-induced glucose uptake and glycogen synthesis.
Neither the selective 1- and
2-antagonists metoprolol and ICI-118,551 nor the
nonselective antagonist propranolol blocked these effects. The
classical 1-AR agonist dobutamine and the
2-AR agonist clenbuterol also considerably diminished insulin-induced glucose uptake. In contrast to CGP-12177 treatment, these negative effects were completely abrogated by metoprolol and
ICI-118,551. Stimulation with CGP-12177 did not impair insulin receptor
kinase activity but decreased insulin receptor substrate-1 binding to
phosphatidylinositol (PI) 3-kinase and activation of protein kinase B. Thus the present study characterizes a novel cell system to selectively
analyze molecular and functional interactions between novel and
classical -adrenoceptor types with insulin action. Furthermore, it
indicates insulin receptor-independent, but PI 3-kinase-dependent,
potent negative effects of the novel 1-adrenoceptor
state on diverse biological end points of insulin action.
-adrenoceptor; adipose tissue; insulin resistance; CGP-12177
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