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β-adrenergic regulation of glucose transporters
Stockholm University, Faculty of Science, The Wenner-Gren Institute .
Responsible organisation
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The transport of glucose across the plasma membrane is a fundamental mechanism to provide cells with its basic requirements for energy yielding processes. It is also vital for clearing glucose from blood into tissues, a process normally stimulated by the hormone insulin in mammals. The sympathetic nervous system, normally activated during stress, also regulates glucose transport. The sympathetic neurotransmitter noradrenaline, acts on the family of adrenergic receptors (ARs). An important subtype of the AR family is the β-AR, which is subdivided into the β1, β2, and β3-AR. Glucose is transported across the plasma membrane by the family of glucose transporters (GLUT1-12, and HMIT). In this thesis, I have investigated the β-AR regulation of GLUT1 and 4, and glucose uptake, in skeletal muscle cells and brown adipocytes in culture, model systems which correspond to metabolically active, sympathetically innervated and insulin-sensitive tissues.

In brown adipocytes, activation of the β3-ARs induced the expression of GLUT1, resulting in a large increase of glucose uptake. In skeletal myotubes, we postulate there is a possible mechanism where β2-ARs can regulate the intrinsic activity of GLUT1.

We found that insulin signaling, but not β-adrenergic signaling, mediated glucose uptake through class I phosphatidylinositol 3-kinase (PI3K). The β-adrenergic signaling to glucose uptake appeared to involve a PI3K related kinase (PIKK), in both skeletal myotubes and brown adipocytes. Furthermore, the increase of glucose uptake by β-ARs in brown adipocytes is partially mediated by AMP-activated protein kinase (AMPK).

However, in an artificially constructed system, with cells expressing GLUT4 and β2-ARs, both insulin and β-adrenergic activation translocated GLUT4 and increased glucose uptake.

These results show that β-adrenergic signaling increase glucose uptake by regulating glucose transporters through distinct pathways, in skeletal myotubes and brown adipocytes.

Place, publisher, year, edition, pages
Wenner-Grens institut för experimentell biologi , 2008. , 61 p.
Keyword [en]
adrenergic receptors, glucose transporters
National Category
Physiology
Research subject
Physiology
Identifiers
URN: urn:nbn:se:su:diva-8273ISBN: 978-91-7155-766-7 (print)OAI: oai:DiVA.org:su-8273DiVA: diva2:199952
Public defence
2008-11-17, hörsalen, Frescati backe, Svante Arrhenius väg 21 A, Stockholm, 10:00
Opponent
Supervisors
Available from: 2008-10-27 Created: 2008-10-21 Last updated: 2011-02-23Bibliographically approved
List of papers
1. β1- and β3-adrenergic receptor stimulated glucose uptake is dependent on a PI3K related kinase in brown adipocytes
Open this publication in new window or tab >>β1- and β3-adrenergic receptor stimulated glucose uptake is dependent on a PI3K related kinase in brown adipocytes
Manuscript (Other academic)
Identifiers
urn:nbn:se:su:diva-25547 (URN)
Note
Part of urn:nbn:se:su:diva-8273Available from: 2008-10-27 Created: 2008-10-21 Last updated: 2010-01-13Bibliographically approved
2. β-adrenoceptors, but not α-adrenoceptors, stimulate AMP-activated protein kinase in brown adipocytes independently of uncoupling protein-1
Open this publication in new window or tab >>β-adrenoceptors, but not α-adrenoceptors, stimulate AMP-activated protein kinase in brown adipocytes independently of uncoupling protein-1
Show others...
2005 In: Diabetologia, ISSN 0012-186X, Vol. 48, no 11, 2386-95 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:su:diva-25548 (URN)
Note
Part of urn:nbn:se:su:diva-8273Available from: 2008-10-27 Created: 2008-10-21Bibliographically approved
3. Involvement of a PI3K related kinase in β2-adrenergic receptor stimulated glucose uptake in L6 myotubes
Open this publication in new window or tab >>Involvement of a PI3K related kinase in β2-adrenergic receptor stimulated glucose uptake in L6 myotubes
Manuscript (Other academic)
Identifiers
urn:nbn:se:su:diva-25549 (URN)
Note
Part of urn:nbn:se:su:diva-8273Available from: 2008-10-27 Created: 2008-10-21 Last updated: 2010-01-13Bibliographically approved
4. Stimulation of β2-adrenergic receptors leads to translocation of GLUT4 and glucose uptake in CHO-GLUT4myc cells
Open this publication in new window or tab >>Stimulation of β2-adrenergic receptors leads to translocation of GLUT4 and glucose uptake in CHO-GLUT4myc cells
Show others...
Manuscript (Other academic)
Identifiers
urn:nbn:se:su:diva-25550 (URN)
Note
Part of urn:nbn:se:su:diva-8273Available from: 2008-10-27 Created: 2008-10-21 Last updated: 2010-01-13Bibliographically approved
5. β-adrenergic modulation of glucose uptake through GLUT1
Open this publication in new window or tab >>β-adrenergic modulation of glucose uptake through GLUT1
Show others...
(English)Manuscript (Other academic)
Identifiers
urn:nbn:se:su:diva-25551 (URN)
Note
Part of urn:nbn:se:su:diva-8273Available from: 2008-10-27 Created: 2008-10-21 Last updated: 2010-02-19Bibliographically approved
6. β3-adrenergic receptors stimulate glucose uptake in brown adipocytes by two mechanisms independently of GLUT4 translocation
Open this publication in new window or tab >>β3-adrenergic receptors stimulate glucose uptake in brown adipocytes by two mechanisms independently of GLUT4 translocation
2006 (English)In: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 147, no 12, 5730-5739 p.Article in journal (Refereed) Published
Abstract [en]

To identify the mechanisms whereby norepinephrine induces glucose uptake in brown adipose tissue, we used mouse brown adipocytes in culture. Proliferating brown adipocytes had high levels of glucose transporter (GLUT) 1 mRNA and low levels of GLUT4 mRNA. The ratio of GLUT4/GLUT1 mRNA expression increased during differentiation, and mature brown adipocytes had high levels of GLUT4 mRNA. The endogenous adrenergic neurotransmitter norepinephrine induced a potent increase in GLUT1 mRNA and a decrease of GLUT4 mRNA in mature brown adipocytes. The norepinephrine effect was mimicked by isoprenaline and CL 316243 and was thus mediated by beta(3)-adrenergic receptors. The cAMP analog 8-bromoadenosine-cAMP partly mimicked the response on GLUT1 mRNA increase and fully mimicked the GLUT4 mRNA decrease. We found no involvement of alpha(1) or alpha(2)-adrenergic receptors on GLUT1 or GLUT4 mRNA transcription. Norepinephrine treatment led to a large increase of GLUT1 protein amount in brown adipocytes as visualized with immunocytochemical staining and subcellular fractionation. A large part of the newly synthesized GLUT1 was found in the plasma membrane (PM). The potent transcriptional inhibitor actinomycin D fully abolished this increase of GLUT1 protein at all time points examined. Norepinephrine treatment shifted GLUT4 from the PM to an intracellular vesicular compartment. Norepinephrine increased 2-deoxy-D-glucose uptake 2-fold at an early time point ( 1 h) and 4-fold at later time point ( 5 h). Addition of actinomycin D did not block the early phase but blocked a large part of the later phase of 2-deoxy-D-glucose uptake. These results imply that adrenergic stimulation through beta(3)-adrenergic receptors induces glucose uptake in brown adipocytes via two mechanisms: 1) a mechanism not dependent on GLUT1 and GLUT4 translocation, 2) a mechanism that is dependent on de novo synthesis of GLUT1 protein and increase of GLUT1 protein at the PM.

National Category
Natural Sciences
Identifiers
urn:nbn:se:su:diva-25709 (URN)10.1210/en.2006-0242 (DOI)
Available from: 2009-02-05 Created: 2009-01-28 Last updated: 2017-12-13Bibliographically approved

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