Downregulation of IRS-1 in adipose tissue of offspring of obese mice is programmed cell-autonomously through post-transcriptional mechanisms

Fernandez-Twinn, D. S., Alfaradhi, M. Z., Martin-Gronert, M. S., Duque-Guimaraes, D. E., Piekarz, A., Ferland-McCollough, D., Bushell, M. and Ozanne, S. E. (2014) Downregulation of IRS-1 in adipose tissue of offspring of obese mice is programmed cell-autonomously through post-transcriptional mechanisms. Molecular Metabolism, 3(3), pp. 325-333. (doi: 10.1016/j.molmet.2014.01.007) (PMID:24749062) (PMCID:PMC3986586)

Abstract

We determined the effects of maternal diet-induced obesity on offspring adipose tissue insulin signalling and miRNA expression in the aetiology of insulin resistance in later life. Although body composition and glucose tolerance of 8-week-old male offspring of obese dams were not dysregulated, serum insulin was significantly (p<0.05) elevated. Key insulin signalling proteins in adipose tissue were down-regulated, including the insulin receptor, catalytic (p110β) and regulatory (p85α) subunits of PI3K as well as AKT1 and 2 (all p<0.05). The largest reduction observed was in IRS-1 protein (p<0.001), which was regulated post-transcriptionally. Concurrently, miR-126, which targets IRS-1, was up-regulated (p<0.05). These two features were maintained in isolated primary pre-adipocytes and differentiated adipocytes in-vitro. We have therefore established that maternal diet-induced obesity programs adipose tissue insulin resistance. We hypothesise that maintenance of the phenotype in-vitro strongly suggests that this mechanism is cell autonomous and may drive insulin resistance in later life.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Bushell, Professor Martin
• Authors: Fernandez-Twinn, D. S., Alfaradhi, M. Z., Martin-Gronert, M. S., Duque-Guimaraes, D. E., Piekarz, A., Ferland-McCollough, D., Bushell, M., and Ozanne, S. E.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Molecular Metabolism
• Publisher: Elsevier
• ISSN: 2212-8778
• ISSN (Online): 2212-8778
• Published Online: 20 January 2014
• Copyright Holders: Copyright © 2014 The Authors
• First Published: First published in Molecular Metabolism 3(3): 325-333
• Publisher Policy: Reproduced under a Creative Commons License