Suppression of insulin‐stimulated phosphatidylinositol 3‐kinase activity by the β<sub>3</sub>‐adrenoceptor agonist CL316243 in rat adipocytes

Ohsaka, Yasuhito; Tokumitsu, Yukiko; Nomura, Yasuyuki

doi:10.1016/s0014-5793(97)00007-0

Cited by 14 publications

(15 citation statements)

References 33 publications

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“…This suggests insulin receptor-independent and receptor-dependent cross-talking mechanisms. In agreement with this work, Ohsaka et al (28) have demonstrated that insulin-stimulated PI 3-kinase activity is suppressed by ␤ 3 -adrenergic stimulation in rat adipocytes via a direct cAMP-dependent mechanism. Furthermore, this decrease in PI 3-kinase activity is associated with a reduction in insulin-induced activation of Akt.…”

Section: Discussionsupporting

confidence: 85%

β3-Adrenergic Stimulation Differentially Inhibits Insulin Signaling and Decreases Insulin-induced Glucose Uptake in Brown Adipocytes

Klein¹,

Faßhauer²,

Ito³

et al. 1999

Journal of Biological Chemistry

227

220

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Activity of the sympathetic nervous system is an important factor involved in the pathogenesis of insulin resistance and associated metabolic and vascular abnormalities. In this study, we investigate the molecular basis of cross-talk between ␤ 3 -adrenergic and insulin signaling systems in mouse brown adipocytes immortalized by SV40 T infection. Insulin-induced tyrosine phosphorylation of the insulin receptor, insulin receptor substrate 1 (IRS-1), and IRS-2 was reduced by prestimulation of ␤ 3 -adrenergic receptors (CL316243). Similarly, insulin-induced IRS-1-associated and phosphotyrosineassociated phosphatidylinositol 3-kinase (PI 3-kinase) activity, but not IRS-2-associated PI 3-kinase activity, was reduced by ␤ 3 -adrenergic prestimulation. Furthermore, insulin-stimulated activation of Akt, but not mitogen-activated protein kinase, was diminished. Insulininduced glucose uptake was completely inhibited by ␤ 3 -adrenergic prestimulation. These effects appear to be protein kinase A-dependent. Furthermore inhibition of protein kinase C restored the ␤ 3 -receptor-mediated reductions in insulin-induced IRS-1 tyrosine phosphorylation and IRS-1-associated PI 3-kinase activity. Together, these findings indicate cross-talk between adrenergic and insulin signaling pathways. This interaction is protein kinase A-dependent and, at least in part, protein kinase C-dependent, and could play an important role in the pathogenesis of insulin resistance associated with sympathetic overactivity and regulation of brown fat metabolism.The sympathetic nervous system has long been recognized to play an important role in the pathogenesis of insulin resistance and associated metabolic and vascular abnormalities, such as type 2 diabetes, obesity, dyslipidemia, and hypertension (for a recent review see Ref. 1). At a molecular level, insulin has been shown to phosphorylate tyrosyl residues in the C terminus of the ␤ 2 -adrenergic receptor (2), whereas ␤-adrenergic stimulation can inhibit the activation of the insulin receptor in some tissues (3-7). However, the potential molecular mechanisms downstream of these interactions and their effects remain poorly elucidated.To investigate the cross-talk between the insulin and adrenergic signaling systems, we have utilized brown adipocytes. These provide an attractive cell model for several reasons. Brown adipose tissue (BAT) 1 is highly regulated by the sympathetic nervous system and expresses different subtypes of adrenergic receptors (8 -10), including the ␤ 3 -adrenergic receptor, a potential target for anti-obesity and anti-diabetic drug therapy (11,12). BAT is important in controlling energy balance in rodents by its capacity to uncouple mitochondrial respiration, a process mediated by the expression of the uncoupling protein-1 (UCP-1) (for recent review see Ref. 13 and references therein). And finally, BAT is an insulin-sensitive tissue and contains the main elements of the insulin signaling system (14 -17). Thus, in the cells binding of insulin to its receptor leads to activation of the r...

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Section: Discussionsupporting

confidence: 85%

β3-Adrenergic Stimulation Differentially Inhibits Insulin Signaling and Decreases Insulin-induced Glucose Uptake in Brown Adipocytes

Klein¹,

Faßhauer²,

Ito³

et al. 1999

Journal of Biological Chemistry

227

220

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“…Although previous studies have reported only inhibitory effects of cAMP-elevating agents on lipid kinase activity, these studies were conducted in differentiated cells (1,48) or in cells where cAMP fails to stimulate mitogenesis (9,45,61). Our data indicating that both PI3K and Rac1 are required for cAMP-stimulated proliferation, together with the stimulatory effects of cAMP on Akt and membrane ruffling, strongly support the idea that cAMP stimulates PI3K activity.…”

Section: Discussionsupporting

confidence: 79%

“…For most growth factors shown to require PI3K activity, growth factor treatment stimulates lipid kinase activity. Although only inhibitory effects of cAMP on PI3K lipid kinase activity have been reported, these studies were performed in differentiated cells, i.e., adipocytes (48) and neutrophils (1), or in cells where cAMP fails to stimulate proliferation, such as bovine airway smooth muscle cells (61), B16 melanoma cells (9), and lymphoid cells (45). Whether cAMP requires PI3K activity in cells where it is a mitogen was examined here.…”

mentioning

confidence: 99%

Protein Kinase A-Dependent and -Independent Signaling Pathways Contribute to Cyclic AMP-Stimulated Proliferation

Cass

Summers

Prendergast

et al. 1999

Molecular and Cellular Biology

176

152

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The effects of cyclic AMP (cAMP) on cell proliferation are cell type specific. Although the growth-inhibitory effects of cAMP have been well studied, much less is known regarding how cAMP stimulates proliferation. We report that cAMP stimulates proliferation through both protein kinase A (PKA)-dependent and PKA-independent signaling pathways and that phosphatidylinositol 3-kinase (PI3K) is required for cAMP-stimulated mitogenesis. In cells where cAMP is a mitogen, cAMP-elevating agents stimulate membrane ruffling, Akt phosphorylation, and p70 ribosomal S6 protein kinase (p70s6k) activity. cAMP effects on ruffle formation and Akt were PKA independent but sensitive to wortmannin. In contrast, cAMP-stimulated p70s6k activity was repressed by PKA inhibitors but not by wortmannin or microinjection of the N-terminal SH2 domain of the p85 regulatory subunit of PI3K, indicating that p70s6k and Akt can be regulated independently. Microinjection of highly specific inhibitors of PI3K or Rac1, or treatment with the p70s6k inhibitor rapamycin, impaired cAMP-stimulated DNA synthesis, demonstrating that PKA-dependent and -independent pathways contribute to cAMP-mediated mitogenesis. Direct elevation of PI3K activity through microinjection of an antibody that stimulates PI3K activity or stable expression of membrane-localized p110 was sufficient to confer hormoneindependent DNA synthesis when accompanied by elevations in p70s6k activity. These findings indicate that multiple pathways contribute to cAMP-stimulated mitogenesis, only some of which are PKA dependent. Furthermore, they demonstrate that the ability of cAMP to stimulate both p70s6k-and PI3K-dependent pathways is an important facet of cAMP-regulated cell cycle progression.Cyclic AMP (cAMP) exerts differential effects on cell proliferation. In many cells, including CHO cells, aortic smooth muscle cells, and Rat-1 fibroblasts, cAMP inhibits the mitogenic response to growth factors (8). Growth-inhibitory effects of cAMP are mediated partly through activation of cAMPdependent protein kinase A (PKA), which interferes with Raf activation and signaling (23). Less is known regarding how cAMP stimulates growth, although accumulating evidence has dissociated the mitogenic effects of cAMP from effects on mitogen-activated protein kinase (MAPK) (37,42,76). In contrast, the effects of cAMP on p70s6k correlate with effects on proliferation, and inhibition of p70s6k activation abolishes cAMP-stimulated DNA synthesis (10). These results prompted us to examine the role of phosphatidylinositol 3-kinase (PI3K)-dependent signaling pathways in cAMP-stimulated proliferation.Multiple isoforms of PI3K that vary in lipid substrate specificity and subunit structure have been identified (reviewed in reference 71). Typically, mitogens that activate receptor tyrosine kinases stimulate PI3K␣/␤ whereas those that activate G-protein-coupled receptors stimulate PI3K␥, although exceptions have been noted (36,52,66,67). PI3K is required for the mitogenic activity of many growth factors, including platel...

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“…It is not clear whether increased sympathetic nervous system activity, commonly found in insulin resistance syndrome (122), contributes to decreased insulin signaling. However, in brown adipocytes (Klein, J., and Kahn, C.R., unpublished data) and white adipocytes (123), stimulation of the β-adrenergic receptor decreases insulin-stimulated PI3-kinase activity. Desensitization of β-adrenergic receptors by isoproterenol increases insulin-stimulated glucose uptake in white adipocytes (124).…”

Section: Acquired Factorsmentioning

confidence: 96%

Protein–protein interaction in insulin signaling and the molecular mechanisms of insulin resistance

Virkamäki

Ueki²,

Kahn³

1999

J. Clin. Invest.

770

527

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Insulin is an anabolic hormone with powerful metabolic effects. The events after insulin binds to its receptor are highly regulated and specific. Defining the key steps that lead to the specificity in insulin signaling presents a major challenge to biochemical research, but the outcome should offer new therapeutic approaches for treatment of patients suffering from insulin-resistant states, including type 2 diabetes.The insulin receptor belongs to the large family of growth factor receptors with intrinsic tyrosine kinase activity. Following insulin binding, the receptor undergoes autophosphorylation on multiple tyrosine residues. This results in activation of the receptor kinase and tyrosine phosphorylation of a family of insulin receptor substrate (IRS) proteins. These substrates are commonly referred to as docking proteins, since several other intracellular proteins bind to the phosphorylated substrates, thereby transmitting the signal downstream. Like other growth factors, insulin uses phosphorylation and the resultant protein-protein interactions as essential tools to transmit and compartmentalize its signal. These intracellular protein-protein interactions are pivotal in transmitting the signal from the receptor to the final cellular effect, such as translocation of vesicles containing GLUT4 glucose transporters from the intracellular pool to the plasma membrane, activation of glycogen or protein synthesis, and initiation of specific gene transcription ( Figure 1). In this article, we review some of our current understanding about early insulin signal transduction through the network of IRS interacting proteins and the mechanisms that may modify insulin signal transduction in insulinresistant states, especially obesity and type 2 diabetes. Protein-protein interactionsSome of the best-characterized protein interaction domains involved in insulin signaling are the PH (pleckstrin homology), PTB (phosphotyrosine binding), SH2, and SH3 domains (1) ( Table 1). Other, less-characterized domains (e.g., LIM, PDZ, NOTCH, and WW) may also prove to be relevant (2).These interaction domains exist in the natural tertiary structure of proteins. In other cases, the domains for interaction are created by posttranslational covalent modification of the protein. The most common examples of the latter are the effects of phosphorylation of proteins on tyrosine or serine/threonine residues and the lipid modification by prenylation or fatty acid acylation Figure 2 illustrates how signal transduction is transmitted from the receptor downstream using different types of domains. PH domains, which are found in most of the proteins that interact with the insulin receptor, bind to charged headgroups of specific phosphatidylinositides and are thereby targeted preferentially to membrane structures. PH domains in the IRS proteins target the proteins to the membrane adjacent to the insulin receptor (3). PTB domains, also found in IRS proteins, recognize the phosphotyrosine in the amino acid sequence asparagine-proline-any amino acid-phospho...

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Suppression of insulin‐stimulated phosphatidylinositol 3‐kinase activity by the β₃‐adrenoceptor agonist CL316243 in rat adipocytes

Cited by 14 publications

References 33 publications

β3-Adrenergic Stimulation Differentially Inhibits Insulin Signaling and Decreases Insulin-induced Glucose Uptake in Brown Adipocytes

β3-Adrenergic Stimulation Differentially Inhibits Insulin Signaling and Decreases Insulin-induced Glucose Uptake in Brown Adipocytes

Protein Kinase A-Dependent and -Independent Signaling Pathways Contribute to Cyclic AMP-Stimulated Proliferation

Protein–protein interaction in insulin signaling and the molecular mechanisms of insulin resistance

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Suppression of insulin‐stimulated phosphatidylinositol 3‐kinase activity by the β3‐adrenoceptor agonist CL316243 in rat adipocytes

Cited by 14 publications

References 33 publications

β3-Adrenergic Stimulation Differentially Inhibits Insulin Signaling and Decreases Insulin-induced Glucose Uptake in Brown Adipocytes

β3-Adrenergic Stimulation Differentially Inhibits Insulin Signaling and Decreases Insulin-induced Glucose Uptake in Brown Adipocytes

Protein Kinase A-Dependent and -Independent Signaling Pathways Contribute to Cyclic AMP-Stimulated Proliferation

Protein–protein interaction in insulin signaling and the molecular mechanisms of insulin resistance

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Product

Resources

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Suppression of insulin‐stimulated phosphatidylinositol 3‐kinase activity by the β₃‐adrenoceptor agonist CL316243 in rat adipocytes