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Non-transactivational, dual pathways for LPA-induced Erk1/2 activation in primary cultures of brown pre-adipocytes
Stockholm University, Faculty of Science, The Wenner-Gren Institute.
Stockholm University, Faculty of Science, The Wenner-Gren Institute.
Stockholm University, Faculty of Science, The Wenner-Gren Institute.
Stockholm University, Faculty of Science, The Wenner-Gren Institute.
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2010 (English)In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 316, no 16, 2664-75 p.Article in journal (Refereed) Published
Abstract [en]

In many cell types, G-protein-coupled receptor (GPCR)-induced Erk1/2 MAP kinase activation is mediated via receptor tyrosine kinase (RTK) transactivation, in particular via the epidermal growth factor (EGF) receptor. Lysophosphatidic acid (LPA), acting via GPCRs, is a mitogen and MAP kinase activator in many systems, and LPA can regulate adipocyte proliferation. The mechanism by which LPA activates the Erk1/2 MAP kinase is generally accepted to be via EGF receptor transactivation. In primary cultures of brown pre-adipocytes, EGF can induce Erk1/2 activation, which is obligatory and determinant for EGF-induced proliferation of these cells. Therefore, we have here examined whether LPA, via EGF transactivation, can activate Erk1/2 in brown pre-adipocytes. We found that LPA could induce Erk1/2 activation. However, the LPA-induced Erk1/2 activation was independent of transactivation of EGF receptors (or PDGF receptors) in these cells (whereas in transformed HIB-1B brown adipocytes, the LPA-induced Erk1/2 activation indeed proceeded via EGF receptor transactivation). In the brown pre-adipocytes, LPA instead induced Erk1/2 activation via two distinct non-transactivational pathways, one G(i)-protein dependent, involving PKC and Src activation, the other, a PTX-insensitive pathway, involving PI3K (but not Akt) activation. Earlier studies showing LPA-induced Erk1/2 activation being fully dependent on RTK transactivation have all been performed in cell lines and transfected cells. The present study implies that in non-transformed systems, RTK transactivation may not be involved in the mediation of GPCR-induced Erk1/2 MAP kinase activation

Place, publisher, year, edition, pages
2010. Vol. 316, no 16, 2664-75 p.
Keyword [en]
Lysophosphatidic acid, Transactivation, Brown adipocytes, Erk1/2, EGF receptor, PI3K
National Category
Other Biological Topics
Research subject
Physiology
Identifiers
URN: urn:nbn:se:su:diva-37122DOI: 10.1016/j.yexcr.2010.05.029ISI: 000281305800013PubMedID: 20576526OAI: oai:DiVA.org:su-37122DiVA: diva2:293034
Available from: 2010-02-10 Created: 2010-02-10 Last updated: 2017-12-12Bibliographically approved
In thesis
1. Role of caveolin-1 in brown adipose tissue
Open this publication in new window or tab >>Role of caveolin-1 in brown adipose tissue
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Caveolae are 50-100 nm invaginations in the plasma membrane. Caveolae and the protein caveolin-1 (Cav1) have been shown to be important in many signaling pathways in different cell types; however, in some cell types caveolae and Cav1 do not seem to affect the investigated signaling pathways. In my thesis, I have investigated the role of caveolin-1 (Cav1) in metabolism and b3-adrenergic, LPA-, EGF- and PDGF-receptor signaling in brown adipocytes.

Brown adipose tissue is responsible for nonshivering thermogenesis. Recent studies have shown that not only infants but also adult man can have brown adipose tissue and that the presence is negatively correlated with both obesity and age. By understanding how signaling for proliferation and differentiation in brown adipocytes is regulated, it could be possible in the future to activate brown adipose tissue to combat obesity and the metabolic syndrome.

In brown adipocytes, both epidermal growth factor (EGF) and platelet-derived growth factor (PDGF) were able to induce proliferation, which was dependent on Erk1/2 activation. However, EGF and PDGF utilized different pathways to activate Erk1/2, with EGF signaling partially occurring via a Src-pathway (not involving PI3K/PKC) and PDGF via a PI3K/PKC/Src-pathway. Furthermore, LPA receptors were able to activate Erk1/2 via two pathways, one Gi/PKC/Src-pathway and one PI3K-pathway. For these receptors, Cav1-ablation did not affect the agonist-induced Erk1/2 activation. Cav1 was, however, required for proper b3-adrenergic receptor (b3-AR) signaling to cAMP and for adenylyl cyclase activity.

In Cav1-ablated mice, the adrenergic receptors are desensitized. However, this desensitization could be overcome physiologically, and the Cav1-ablated mice were therefore able to survive in prolonged cold by nonshivering thermogenesis.

In conclusion, ablation of Cav1 affected certain signaling pathways in brown adipocytes, while other pathways were not affected or could be physiologically rescued.

Place, publisher, year, edition, pages
Stockholm: The Wenner-Gren Institute, Stockholm University, 2010. 110 p.
Keyword
caveolin, brown adipose tissue, metabolism, signaling
National Category
Physiology
Research subject
Physiology
Identifiers
urn:nbn:se:su:diva-37125 (URN)978-91-7447-005-5 (ISBN)
Public defence
2010-03-12, Hörsal 107, Frescati Backe, Svante Arrhenius väg 21 A, Stockholm, 10:00 (English)
Opponent
Supervisors
Note
At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 1: Manuscript. Paper 3: Manuscript. Paper 4: Manuscript.Available from: 2010-02-18 Created: 2010-02-10 Last updated: 2010-02-16Bibliographically approved
2. cAMP-Regulated Cell Proliferation in Brown Preadipocytes
Open this publication in new window or tab >>cAMP-Regulated Cell Proliferation in Brown Preadipocytes
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

As a prototypical second messenger, cAMP is involved in the regulation of multiple cell functions. cAMP has a well established inhibitory effect on cell proliferation in smooth muscle and epithelial cell types. However, there is accumulating evidence also for stimulatory effect on proliferation, mainly in endocrine cell types.

Mechanisms mediating the cAMP stimulatory effect are not well studied. cAMP, produced via β1-adrenoceptor activation, promotes cell proliferation in brown preadipocytes. Due to the importance of brown adipose tissue in energy metabolism and its implication in the treatment of obesity and type II diabetes, understanding the mechanisms of tissue recruitment has clinical implication for the treatment of these metabolic syndromes.

We found that the Erk1/2 family of MAPK, often involved in regulation of cell proliferation, can be activated in response to the stimulation of G protein-coupled receptors, including adrenergic receptors (α1-, α2-, β1- and β3-Adrenoceptors) and mitogenic lysophosphatidic acid (LPA) in primary cultured brown adipocytes. In contrast to the case e.g. in many immortalized cell lines and various primary cultured cells, EGF receptor transactivation is not employed in Erk1/2 activation by any G protein-coupled receptor tested in brown adipocytes. This suggests that EGF receptor transactivation is not an universal mediation process for GPCR activation of MAPK.

cAMP-activated cell proliferation in brown preadipocytes is mediated through PKA rather than Epac under serum-free conditions. This effect is independent of PI3K/Akt, mTOR or Erk1/2 MAPK pathways. Differential responses to two different MEK inhibitors PD98059 and U0126 suggested the involvement of a pathway sensitive to PD98059, but independent of the Erk1/2 family of MAPK. At the transcriptional level, by combining microarray and RT-qPCR, we have identified eight genes, under the regulation of cAMP, that may be involved in the further mediation of the cAMP effect on cell proliferation.

An understanding of cAMP-induced cell proliferation may be of importance both in metabolic and cancer research.

Place, publisher, year, edition, pages
Stockholm: Department of Molecular Biosciences, Stockholm University, 2013. 78 p.
National Category
Other Biological Topics
Research subject
Physiology
Identifiers
urn:nbn:se:su:diva-88393 (URN)978-91-7447-664-4 (ISBN)
Public defence
2013-04-12, Nordenskiöldsalen, Geovetenskapens hus, Svante Arrhenius väg 8, Stockholm, 10:00 (English)
Opponent
Supervisors
Note

At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Submitted. Paper 3: Manuscript. Paper 4: Manuscript.

Available from: 2013-03-21 Created: 2013-03-13 Last updated: 2013-03-22Bibliographically approved

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