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Articles in PresS, published online ahead of print March 5, 2002
Am J Physiol Endocrinol Metab, 10.1152/ajpendo.00531.2001
Submitted on November 27, 2001
Accepted on February 27, 2002
1 Department of Internal Medicine I, Medical University of Lubeck, Lubeck, Germany
2 Department of Internal Medicine III, University of Leipzig, Leipzig, Germany
3 Joslin Diabetes Center and Harvard Medical School, Boston, MA, USA
4 Facultad de Farmacia, Universidad Complutense, Madrid, Spain
5 Department of Medicine, Harvard Medical School, Boston, MA, USA
* To whom correspondence should be addressed. E-mail: johannes.klein{at}medinf.mu-luebeck.de.
Crosstalk between adrenergic and insulin signaling systems may represent a fundamental molecular basis of insulin resistance. We have characterized a newly established ß3-adrenoceptor-deficient (ß3-KO) brown adipocyte cell line and have used it to selectively investigate the potential role of novel state and typical ß-adrenoceptors (ß-AR) on insulin signaling and action. The novel state ß1-AR agonist CGP 12177 strongly induced uncoupling protein-1 in ß3-KO brown adipocytes as opposed to the ß3-selective agonist CL 316,243. Furthermore, CGP 12177 potently reduced insulin-induced glucose uptake and glycogen synthesis. Neither the selective ß1- and ß2-antagonists metoprolol and ICI 118,551, nor the non-selective antagonist propranolol blocked these effects. The classical ß1-AR agonist dobutamine and the ß2-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 IRS-1 binding to phosphatidylinositol 3-kinase (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 ß-adrenoceptor types with insulin action. Furthermore, it indicates insulin receptor-independent but PI 3-kinase-dependent, potent negative effects of the novel ß1-adrenoceptor state on diverse biological endpoints of insulin action.
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