Abstract
Cross talk between adrenergic and insulin signaling systems may represent a fundamental molecular basis of insulin resistance. We have characterized a newly established beta(3)-adrenoceptor-deficient (beta(3)-KO) brown adipocyte cell line and have used it to selectively investigate the potential role of novel-state and typical beta-adrenoceptors (beta-AR) on insulin signaling and action. The novel-state beta(1)-AR agonist CGP-12177 strongly induced uncoupling protein-1 in beta(3)-KO brown adipocytes as opposed to the beta(3)-selective agonist CL-316,243. Furthermore, CGP-12177 potently reduced insulin-induced glucose uptake and glycogen synthesis. Neither the selective beta(1)- and beta(2)-antagonists metoprolol and ICI-118,551 nor the nonselective antagonist propranolol blocked these effects. The classical beta(1)-AR agonist dobutamine and the beta(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 beta-adrenoceptor types with insulin action. Furthermore, it indicates insulin receptor-independent, but PI 3-kinase-dependent, potent negative effects of the novel beta(1)-adrenoceptor state on diverse biological end points of insulin action.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adipocytes / cytology
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Adipocytes / drug effects
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Adipocytes / metabolism*
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Adipose Tissue, Brown / cytology
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Adipose Tissue, Brown / drug effects
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Adipose Tissue, Brown / metabolism
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Adrenergic beta-1 Receptor Agonists
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Adrenergic beta-1 Receptor Antagonists
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Adrenergic beta-2 Receptor Agonists
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Adrenergic beta-2 Receptor Antagonists
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Adrenergic beta-Agonists / pharmacology
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Adrenergic beta-Antagonists / pharmacology
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Animals
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Carrier Proteins / biosynthesis
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Cell Line
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Enzyme Activation / drug effects
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Glucose / pharmacokinetics
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Glycogen / biosynthesis
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Insulin / pharmacology*
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Insulin Receptor Substrate Proteins
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Insulin Resistance / physiology
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Intracellular Signaling Peptides and Proteins
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Ion Channels
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Membrane Proteins / biosynthesis
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Mice
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Mice, Knockout
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Mitochondrial Proteins
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoproteins / metabolism
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Protein Serine-Threonine Kinases*
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt
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Receptor Cross-Talk / drug effects
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Receptor Cross-Talk / physiology
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Receptor, Insulin / metabolism
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Receptors, Adrenergic, beta-1 / metabolism*
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Receptors, Adrenergic, beta-2 / metabolism*
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Receptors, Adrenergic, beta-3 / deficiency*
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Receptors, Adrenergic, beta-3 / genetics
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Signal Transduction / drug effects
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Signal Transduction / physiology
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Uncoupling Protein 1
Substances
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Adrenergic beta-1 Receptor Agonists
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Adrenergic beta-1 Receptor Antagonists
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Adrenergic beta-2 Receptor Agonists
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Adrenergic beta-2 Receptor Antagonists
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Adrenergic beta-Agonists
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Adrenergic beta-Antagonists
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Carrier Proteins
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Insulin
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Insulin Receptor Substrate Proteins
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Intracellular Signaling Peptides and Proteins
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Ion Channels
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Irs1 protein, mouse
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Irs2 protein, mouse
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Membrane Proteins
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Mitochondrial Proteins
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Phosphoproteins
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Proto-Oncogene Proteins
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Receptors, Adrenergic, beta-1
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Receptors, Adrenergic, beta-2
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Receptors, Adrenergic, beta-3
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Ucp1 protein, mouse
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Uncoupling Protein 1
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Glycogen
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Receptor, Insulin
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Glucose