AMP-activated protein kinase complexes containing the β2 regulatory subunit are upregulated during and contribute to adipogenesis

Katwan, O. J., Alghamdi, F., Almabrouk, T. A. , Mancini, S. J., Kennedy, S. , Oakhill, J. S., Scott, J. W. and Salt, I. P. (2019) AMP-activated protein kinase complexes containing the β2 regulatory subunit are upregulated during and contribute to adipogenesis. Biochemical Journal, 476(12), pp. 1725-1740. (doi:10.1042/BCJ20180714) (PMID:31189568) (PMCID:PMC6595317)

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Abstract

AMP-activated protein kinase (AMPK) is a heterotrimer of α catalytic and β and γ regulatory subunits that acts to regulate cellular and whole-body nutrient metabolism. The key role of AMPK in sensing energy status has led to significant interest in AMPK as a therapeutic target for dysfunctional metabolism in type 2 diabetes, insulin resistance and obesity. Despite the actions of AMPK in liver and skeletal muscle being extensively studied, the role of AMPK in adipose tissue and adipocytes remains less well characterised. Small molecules that selectively influence AMPK heterotrimers containing specific AMPKβ subunit isoforms have been developed, including MT47-100, which selectively inhibits complexes containing AMPKβ2. AMPKβ1 and AMPKβ2 are the principal AMPKβ subunit isoforms in rodent liver and skeletal muscle respectively, yet the contribution of specific AMPKβ isoforms to adipose tissue function, however, remains largely unknown. This study therefore sought to determine the contribution of AMPKβ subunit isoforms to adipocyte biology, focussing on adipogenesis. AMPKβ2 was the principal AMPKβ isoform in 3T3-L1 adipocytes, isolated rodent adipocytes and human subcutaneous adipose tissue, as assessed by the contribution to total cellular AMPK activity. Downregulation of AMPKβ2 with siRNA inhibited lipid accumulation, cellular adiponectin levels and adiponectin secretion during 3T3-L1 adipogenesis, whereas downregulation of AMPKβ1 had no effect. Incubation of 3T3-L1 cells with MT47-100 selectively inhibited AMPK complexes containing AMPKβ2 whilst simultaneously inhibiting cellular lipid accumulation as well as cellular levels and secretion of adiponectin. Taken together, these data indicate that increased expression of AMPKβ2 is an important feature of efficient adipogenesis.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Mancini, Dr Sarah and Alghamdi, Fatmah and Salt, Dr Ian and ALMABROUK, Tarek Ali Mohamed and Katwan, Omar Jassim and Kennedy, Dr Simon
Authors: Katwan, O. J., Alghamdi, F., Almabrouk, T. A., Mancini, S. J., Kennedy, S., Oakhill, J. S., Scott, J. W., and Salt, I. P.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
College of Medical Veterinary and Life Sciences > School of Life Sciences
Journal Name:Biochemical Journal
Publisher:Portland Press
ISSN:0264-6021
ISSN (Online):1470-8728
Published Online:26 June 2019
Copyright Holders:Copyright © 2019 The Authors
First Published:First published in Biochemical Journal 476(12): 1725-1740
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
641891Inhibition of endothelial mitogen-activated protein kinases by amp-activated protein kinaseIan SaltBritish Heart Foundation (BHF)PG/13/82/30483RI CARDIOVASCULAR & MEDICAL SCIENCES
580311The sensitive assessment of the activity of cellular signalling pathways regulating insulin action and the cardiovascular complications of diabetesIan SaltDiabetes UK (DIABETUK)11/0004309RI CARDIOVASCULAR & MEDICAL SCIENCES