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Insulin Signalling in Human Adipocytes and its Interplay with beta-Adrenergic Control of Lipolysis
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten.
2018 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [sv]

The prevalence of obesity has over the last 40 years nearly tripled and obesity is one of the major risk factors of developing type 2 diabetes. Type 2 diabetes was formerly called adultonset diabetes but today, probably due to the rise in childhood obesity, it is also seen in children and adolescents. Type 2 diabetes is diagnosed when the body no longer can control the glucose levels in the blood. This is due to an insulin resistant state in the insulin responding tissues, liver, adipose and muscle and insufficient production of insulin in the pancreas. However, in spite of extensive research the mechanisms behind insulin resistance is still not known.

The adipose tissue is believed to play a major role in the development of whole body insulin resistance. Adipocytes are the most important sites for storage of the high energy containing triacylglycerols. Insulin stimulation causes the adipocyte to increase the uptake of glucose and to reduce lipolysis: the hydrolysis of triacylglycerol and release of glycerol and fatty acids. The insulin signalling network is complex with numerous proteins involved. These signaling proteins not only transmit the insulin signal but also create negative and positive feedbackloops and induce cross talk between different parts of the network and with the signalling of other hormones. One important positive feedback in insulin signalling is the mTORC1 mediated feedback to phosphorylation of IRS1 at serine 307. In paper I we found that in human adipocytes this feedback is not likely catalysed by the assumed kinase S6K1. However we find an immunoprecipitate of mTOR to contain a ser307 phosphorylating kinase.

Scaffolding proteins serve as docking sites for several proteins to promote protein-protein interactions that facilitate signal transduction. In paper II we demonstrate the existence of the scaffolding protein IQGAP1 in human adipocytes and that the expression of IQGAP1 is downregulated in type 2 diabetes. We reveal that IQGAP1 co-localises with caveolae, invaginations of the plasma membrane where the insulin receptor is situated, and that this interaction is increased upon insulin stimulation.

In paper III we focus on the control of lipolysis, and sought to understand the interplay between insulin and beta-adrenergic stimulation. We demonstrated that the re-esterification of fatty acids is downregulated in type 2 diabetes causing an increased release of fatty acids from the cells. We showed that beta-adrenergic stimulation with isoproterenol induced a negative feedback via PKA/Epac1 -> PI3K -> PKB -> PDE3B that reduced the cAMP levels and thereby also reduced lipolysis. We also showed that insulin, in addition to its well-known anti-lipolytic effect, at high concentrations had a positive effect on lipolysis. In conclusion we reveal an intricate control of the stimulation as well as the inhibition of lipolysis induced by both isoproterenol and insulin.

sted, utgiver, år, opplag, sider
Linköping: Linköping University Electronic Press, 2018. , s. 49
Serie
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1624
HSV kategori
Identifikatorer
URN: urn:nbn:se:liu:diva-147618DOI: 10.3384/diss.diva-147618ISBN: 9789176852859 (tryckt)OAI: oai:DiVA.org:liu-147618DiVA, id: diva2:1202335
Disputas
2018-06-05, Berzeliussalen, Campus US, Linköping, 09:00 (svensk)
Opponent
Veileder
Tilgjengelig fra: 2018-04-27 Laget: 2018-04-27 Sist oppdatert: 2019-09-30bibliografisk kontrollert
Delarbeid
1. Phosphorylation of IRS1 at Serine 307 in Response to Insulin in Human Adipocytes Is Not Likely to be Catalyzed by p70 Ribosomal S6 Kinase
Åpne denne publikasjonen i ny fane eller vindu >>Phosphorylation of IRS1 at Serine 307 in Response to Insulin in Human Adipocytes Is Not Likely to be Catalyzed by p70 Ribosomal S6 Kinase
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2013 (engelsk)Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 4Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

The insulin receptor substrate-1 (IRS1) is phosphorylated on serine 307 (human sequence, corresponding to murine serine 302) in response to insulin as part of a feedback loop that controls IRS1 phosphorylation on tyrosine residues by the insulin receptor. This in turn directly affects downstream signaling and is in human adipocytes implicated in the pathogenesis of insulin resistance and type 2 diabetes. The phosphorylation is inhibited by rapamycin, a specific inhibitor of mammalian target of rapamycin (mTOR) in complex with raptor (mTORC1). The mTORC1-downstream p70 ribosomal protein S6 kinase (S6K1), which is activated by insulin, can phosphorylate IRS1 at serine 307 in vitro and is considered the physiological protein kinase. Because the IRS1 serine 307-kinase catalyzes a critical step in the control of insulin signaling and constitutes a potential target for treatment of insulin resistance, it is important to know whether S6K1 is the physiological serine 307-kinase or not. We report that, by several criteria, S6K1 does not phosphorylate IRS1 at serine 307 in response to insulin in intact human primary adipocytes: (i) The time-courses for phosphorylation of S6K1 and its phosphorylation of S6 are not compatible with the phosphorylation of IRS1 at serine 307; (ii) A dominant-negative construct of S6K1 inhibits the phosphorylation of S6, without effect on the phosphorylation of IRS1 at serine 307; (iii) The specific inhibitor of S6K1 PF-4708671 inhibits the phosphorylation of S6, without effect on phosphorylation of IRS1 at serine 307. mTOR-immunoprecipitates from insulin-stimulated adipocytes contains an unidentified protein kinase specific for phosphorylation of IRS1 at serine 307, but it is not mTOR or S6K1.

sted, utgiver, år, opplag, sider
Public Library of Science, 2013
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-93257 (URN)10.1371/journal.pone.0059725 (DOI)000317717300032 ()
Merknad

Funding Agencies|Swedish Diabetes Fund||Novo Nordic Foundation||University of Linkoping||Swedish Research Council||

Tilgjengelig fra: 2013-05-28 Laget: 2013-05-28 Sist oppdatert: 2019-06-28
2. Scaffolding protein IQGAP1: an insulin-dependent link between caveolae and the cytoskeleton in primary human adipocytes?
Åpne denne publikasjonen i ny fane eller vindu >>Scaffolding protein IQGAP1: an insulin-dependent link between caveolae and the cytoskeleton in primary human adipocytes?
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2016 (engelsk)Inngår i: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 473, nr 19, s. 3177-3188Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

The ubiquitously expressed IQ motif-containing GTPase activating protein-1 (IQGAP1) is a scaffolding protein implicated in an array of cellular functions, in particular by binding to cytoskeletal elements and signaling proteins. A role of IQGAP1 in adipocytes has not been reported. We therefore investigated the cellular IQGAP1 interactome in primary human adipocytes. Immunoprecipitation and quantitative mass spectrometry identified caveolae and caveolae-associated proteins as the major IQGAP1 interactors alongside cytoskeletal proteins. We confirmed co-localization of IQGAP1 with the defining caveolar marker protein caveolin-1 by confocal microscopy and proximity ligation assay. Most interestingly, insulin enhanced the number of IQGAP1 interactions with caveolin-1 by five-fold. Moreover, we found a significantly reduced abundance of IQGAP1 in adipocytes from patients with type 2 diabetes compared with cells from nondiabetic control subjects. Both the abundance of IQGAP1 protein and mRNA were reduced, indicating a transcriptional defect in diabetes. Our findings suggest a novel role of IQGAP1 in insulin-regulated interaction between caveolae and cytoskeletal elements of the adipocyte, and that this is quelled in the diabetic state.

sted, utgiver, år, opplag, sider
Portland Press, 2016
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-131958 (URN)10.1042/BCJ20160581 (DOI)000393755500017 ()27458251 (PubMedID)
Merknad

Funding agencies: University of Linkoping; 3-year program at the Swedish Diabetes Fund; 5-year program at the Swedish Research Council

Tilgjengelig fra: 2016-10-12 Laget: 2016-10-12 Sist oppdatert: 2018-04-27bibliografisk kontrollert

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