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Insulin and beta-adrenergic receptors mediate lipolytic and anti-lipolytic signalling that is not altered by type 2 diabetes in human adipocytes
Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.ORCID iD: 0000-0001-5702-4116
Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
2019 (English)In: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 476, p. 2883-2908Article in journal (Refereed) Published
Abstract [en]

Control of fatty acid storage and release in adipose tissue is fundamental in energy homeostasis and the development of obesity and type 2 diabetes. We here take the whole signalling network into account to identify how insulin and beta-adrenergic stimulation in concert controls lipolysis in mature subcutaneous adipocytes obtained from non-diabetic and, in parallel, type 2 diabetic women. We report that, and show how, the anti-lipolytic effect of insulin can be fully explained by protein kinase B (PKB/Akt)-dependent activation of the phosphodiesterase PDE3B. Through the same PKB-dependent pathway beta-adrenergic receptor signalling, via cAMP and PI3K alpha, is anti-lipolytic and inhibits its own stimulation of lipolysis by 50%. Through this pathway both insulin and beta-adrenergic signalling control phosphorylation of FOXO1. The dose-response of lipolysis is bell-shaped, such that insulin is anti-lipolytic at low concentrations, but at higher concentrations of insulin lipolysis was increasingly restored due to inhibition of PDE3B. The control of lipolysis was not altered in adipocytes from diabetic individuals. However, the release of fatty acids was increased by 50% in diabetes due to reduced reesterification of lipolytically liberated fatty acids. In conclusion, our results reveal mechanisms of control by insulin and beta-adrenergic stimulation - in human adipocytes - that define a network of checks and balances ensuring robust control to secure uninterrupted supply of fatty acids without reaching concentrations that put cellular integrity at risk. Moreover, our results define how selective insulin resistance leave lipolytic control by insulin unaltered in diabetes, while the fatty acid release is substantially increased.

Place, publisher, year, edition, pages
PORTLAND PRESS LTD , 2019. Vol. 476, p. 2883-2908
National Category
Endocrinology and Diabetes
Identifiers
URN: urn:nbn:se:liu:diva-161387DOI: 10.1042/BCJ20190594ISI: 000489732900012PubMedID: 31519735OAI: oai:DiVA.org:liu-161387DiVA, id: diva2:1367478
Note

Funding Agencies|University of Linkoping; Swedish Diabetes Fund; Swedish Research CouncilSwedish Research Council

Available from: 2019-11-04 Created: 2019-11-04 Last updated: 2019-11-04

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Jönsson, CeciliaCastor Batista, Ana PaulaKjölhede, PrebenStrålfors, Peter
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Divison of NeurobiologyFaculty of Medicine and Health SciencesDivision of Children's and Women's healthDepartment of Gynaecology and Obstetrics in Linköping
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Biochemical Journal
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