Correlation of β3-adrenoceptor-induced activation of cyclic amp-dependent protein kinase with activation of lipolysis in rat white adipocytes

Previous studies using L6 myotubes have suggested that glycogen synthase kinase-3 (GSK-3) is phosphorylated and inactivated in response to insulin by protein kinase B (PKB, also known as Akt or RAC) (Cross, D. A. E., Alessi, D. R., Cohen, P., Andjelkovic, M., and Hemmings, B. A. (1995) Nature 378, 785-789). In the present study, marked increases in the activity of PKB have been shown to occur in insulin-treated rat epididymal fat cells with a time course compatible with the observed decrease in GSK-3 activity. Isoproterenol, acting primarily through ␤ 3 -adrenoreceptors, was found to decrease GSK-3 activity to a similar extent (approximately 50%) to insulin. However, unlike the effect of insulin, the inhibition of GSK by isoproterenol was not found to be sensitive to inhibition by the phosphatidylinositol 3-kinase inhibitors, wortmannin or LY 294002. The change in GSK-3 activity brought about by isoproterenol could not be mimicked by the addition of permeant cyclic AMP analogues or forskolin to the cells, although at the concentrations used, these agents were able to stimulate lipolysis. Isoproterenol, but again not the cyclic AMP analogues, was found to increase the activity of PKB, although to a lesser extent than insulin. While wortmannin abolished the stimulation of PKB activity by insulin, it was without effect on the activation seen in response to isoproterenol. The activation of PKB by isoproterenol was not accompanied by any detectable change in the electrophoretic mobility of the protein on SDS-polyacrylamide gel electrophoresis. It would therefore appear that distinct mechanisms exist for the stimulation of PKB by insulin and isoproterenol in rat fat cells.

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“…2B). This is consistent with reported EC 50 values for the actions of BRL 37344 on the stimulation of lipolysis in this cell type (32)(33)(34).…”

Section: Inactivation Of Gsk-3 In Fat Cells In Response Tosupporting

confidence: 82%

Regulation of Protein Kinase B and Glycogen Synthase Kinase-3 by Insulin and β-Adrenergic Agonists in Rat Epididymal Fat Cells

Moule

Welsh

Edgell

et al. 1997

Journal of Biological Chemistry

229

168

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“…Nevertheless, quantitative differences in the CAMP-lipolysis relationships have been reported when comparing the effects of various lipolytic agents. The existence of CAMP-independent lipolytic responses and of cAMP compartmentalization have been proposed to explain such discrepancies (Allen & Quesenberry, 1988;Hollenga et al 1991;Murphy et al 1993). The validity of the concept of different pools of intracellular cAMP is still questioned.…”

Section: Contribution O F Adenylylcyclase ( E C 4611)-coupled Membmentioning

confidence: 99%

Cellular aspects of fuel mobilization and selection in white adipocytes

Lafontan

Langin

1995

Proc. Nutr. Soc.

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“…It also is known that animals lacking functional BAT, because of ablation of UCP1, gain more weight than their wild-type counterparts under thermo-neutral conditions (Feldmann et al, 2009). In rodent models of obesity, administration of b 3 -adrenoceptor agonists not only leads to enhanced lipolysis in white adipocytes (Murphy et al, 1993), but also enhanced insulin sensitivity, glucose use, and triglyceride clearance (Yoshida et al, 1994;Liu et al, 1998;Bartelt et al, 2011). These latter effects are partially mediated by an increase in thermogenesis, whereby circulating fatty acids mobilized from white fat stores are converted into heat by activated brown fat (Weyer et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

PDE3 and PDE4 Isozyme-Selective Inhibitors Are Both Required for Synergistic Activation of Brown Adipose Tissue

Kraynik

Miyaoka

Beavo

2013

Molecular Pharmacology

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Brown adipose tissue (BAT) is a highly thermogenic organ that converts lipids and glucose into heat. Many of the metabolic and gene transcriptional hallmarks of BAT activation, namely increased lipolysis, uncoupling protein-1 (UCP1) mRNA, and glucose uptake, are regulated by the adrenergic second messenger, cAMP. Cyclic nucleotide phosphodiesterases (PDEs) catalyze the breakdown of cAMP, thereby regulating the magnitude and duration of this signaling molecule. In the absence of adrenergic stimulus, we found that it required a combination of a PDE3 and a PDE4 inhibitor to fully induce UCP1 mRNA and lipolysis in brown adipocytes, whereas neither PDE inhibitor alone had any substantial effect under basal conditions. Under submaximal b-adrenoceptor stimulation of brown adipocytes, a PDE3 inhibitor alone could potentiate induction of UCP1 mRNA, whereas a PDE4 inhibitor alone could augment lipolysis, indicating differential roles for each of these two PDEs. Neither induction of UCP1 nor lipolysis was altered by inhibition of PDE1, PDE2, or PDE8A. Finally, when injected into mice, the combination of PDE3 and PDE4 inhibitors stimulated glucose uptake in BAT under thermoneutral and fasted conditions, a response that was further potentiated by the global ablation of PDE8A. Taken together, these data reveal that multiple PDEs work in concert to regulate three of the important pathways leading to BAT activation, a finding that may provide an improved conceptual basis for the development of therapies for obesity-related diseases.

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Correlation of β3-adrenoceptor-induced activation of cyclic amp-dependent protein kinase with activation of lipolysis in rat white adipocytes

Cited by 41 publications

References 29 publications

Regulation of Protein Kinase B and Glycogen Synthase Kinase-3 by Insulin and β-Adrenergic Agonists in Rat Epididymal Fat Cells

Regulation of Protein Kinase B and Glycogen Synthase Kinase-3 by Insulin and β-Adrenergic Agonists in Rat Epididymal Fat Cells

Cellular aspects of fuel mobilization and selection in white adipocytes

PDE3 and PDE4 Isozyme-Selective Inhibitors Are Both Required for Synergistic Activation of Brown Adipose Tissue

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