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In human adipocytes the insulin receptor and IRS1 are localized in caveolae, and caveolae destruction makes cells resistant to insulin signaling for metabolic and mitogenic control
Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Caveolae are plasma membrane invaginations with several functions, one of which appears to be to organize receptor mediated sigoaling. Here we show that in human adipocytes the iosulin receptor is localized in caveolae: by electron microscopy and immunogold detection and by isolating caveolae from plasma membranes. We similarly demonstrate that significant part of the immediate downstream signal mediator IRS1 is localized at the plasma membrane and caveolae. A detailed image shows the caveola as a bulb, protroding into the cell interior, with a neck attaching it to the plasma membrane. The caveolar structural protein caveolin is localized in the neck aod not in the bulb of the caveola. The receptor is active in caveolae since insulin stimulation caused tyrosine specific phosphorylation of the receptor recovered in isolated caveolae. Caveolae contain a major part of the free cholesterol in the plasma membrane and cholesterol is a stroctural component of caveolae. Depletion of cholesterol from the cells using B-cyclodextrio blocks insulin stimulation of glucose uptake, insulin inhibition of perilipin phosphorylation in response to isoproterenol, and insulio stimulation of protein kinase B and Map-kinases ERK1/2 phosphorylation- in effect making the human adipocytes insulin resistant. The insulin-stimulated phosphorylation of the insulin receptor and IRS1 are, however, not affected, indicating that caveolae integrity is required downstream of IRS1, consistent with its colocalization with the insulin receptor io caveolae in human adipocytes.

National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-84462OAI: oai:DiVA.org:liu-84462DiVA: diva2:559405
Available from: 2012-10-09 Created: 2012-10-09 Last updated: 2013-09-10Bibliographically approved
In thesis
1. Caveolae in insulin signalling in human and rat adipocytes
Open this publication in new window or tab >>Caveolae in insulin signalling in human and rat adipocytes
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The pancreatic hormone insulin is a key hormone in maintenance of metabolic homeostasis but it also exerts control on gene expression and cell growth. This thesis presents results on fhe role of caveolae in insulin signalling in human and rat adipocytes. Caveolae are invaginations of the plasma membrane, characterised by the structural protein caveolin. Caveolae and caveolin have been implicated in a variety of functions, like uptake of molecular cargo into the cell, cholesterol transport and signal transduction. After isolation of caveolae and using electron microscopy on cell membranes, the insulin receptor was demonstrated to be localised in caveolae of human adipocytes. We also used biochemical and morphological methods to show that the glucose transporter GLUT4 was translocated to caveolae in response to insulin in rat adipocytes, indicating fhat the caveola is the locale for glucose uptake in adipocytes.

Adipocytes fhat were depleted of cholesterol using ß-cyclodextrin lacked caveolae invaginations. In cells fhus depleted of cholesterol and caveolae, fhe insulin receptor itself was not affected, but insulin signalling to metabolic control was inhibited. In rat adipocytes, insulin signalling to mitogenic control was not affected. In human fat cells, however, insulin's mitogenic signalling was dependent on caveolae/cholesterol. In contrast to other cells studied, including rat adipocytes, where the insulin receptor substrate (IRS-1) is mainly cytosolic, in human adipocytes IRS-1 was found in the plasma membrane and in caveolae. These results show the importance of choosing the relevant system to work with, since there are clear species differences.

We performed an analysis of the lipid composition of purified caveolae from rat adipocytes. As expected, cholesterol constitutes a major part of caveolae, but there is also an enrichment of sphingomyelin and the gangliosides GM1, GM3, GD3 and GD1a, while there is less protein, compared to the surrounding plasma membrane.

Taken together, caveolae appear as hnbs for insulin signalling. Caveolae seem necessary for fhe maintenance of metabolic signalling, like glucose uptake, and defects in caveolae may thus be the cause of insulin resistance.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet, 2003. 54 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 782
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-25673 (URN)10049 (Local ID)91-7373-539-6 (ISBN)10049 (Archive number)10049 (OAI)
Public defence
2003-04-11, Berzeliussalen, Hälsouniversitet, Linköping, 13:00 (Swedish)
Opponent
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2012-10-09Bibliographically approved

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Karlsson, MargaretaThorn, HansDanielsson, AnnaKarin G., StenkulaGustavsson, JohannaNyström, Fredrik H.Strålfors, Peter

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Karlsson, MargaretaThorn, HansDanielsson, AnnaKarin G., StenkulaGustavsson, JohannaNyström, Fredrik H.Strålfors, Peter
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