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Cited by 114Birth, Development, and HealthAdipokines, Inflammation, and Metabolic DiseasesMetabolism, Diabetes, and Cancer

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

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Fernandez-Twinn, Denise S., Alfaradhi, Maria Z., Martin-Gronert, Malgorzata S., Duque-Guimaraes, Daniella E., Piekarz, Ana, Ferland-McCollough, David, Bushell, Martin, Ozanne, Susan E.·2014·Molecular Metabolism
DOI 10.1016/j.molmet.2014.01.007PMC PMC3986586
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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.

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Authors
Fernandez-Twinn, D. S., Alfaradhi, M. Z., Martin-Gronert, M. S., Duque-Guimaraes, D. E., Piekarz, A., Ferland-McCollough, D., Bushell, M., & Ozanne, S. E.
Affiliations
  • University of Cambridge (GB)
  • University of Leicester (GB)
ORCID
Venue
Molecular Metabolism
Publisher
Elsevier BV
Published
2014-06
Volume
3
Issue
3
Pages
325-333
ISSN
2212-8778 (ISSN-L)
DOI
10.1016/j.molmet.2014.01.007
PMC
PMC3986586
OpenAlex
W2066279727
Cited by
114
References
4
Citations by year
2026: 1 · 2025: 6 · 2024: 7 · 2023: 10 · 2022: 16 · 2021: 11 · 2020: 8 · 2019: 14 · 2018: 7 · 2017: 9 · 2016: 13 · 2015: 9 · 2014: 3
FWCI
10.67
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Metabolism (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion)
  • Apollo (University of Cambridge) (submittedVersion, cc-by)
  • Apollo (cc-by)
Funders
  • Wellcome Trust (FP7/2007–2013)
  • British Heart Foundation (FS/09/029/27902)
  • European Commission (2007–2013, FP7 2007-2013, FP7/2007, 289346)
  • Conselho Nacional de Desenvolvimento Científico e Tecnológico
  • Medical Research Council (FP7/20072013, MC_EX_G0902052)
Topics
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
  • Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords
IRS-1, offspring, insulin resistance, miR-126, microRNA, post-transcriptional regulation, phosphatidylinositol 3-kinase, Akt, insulin receptor, preadipocytes, adipocytes, epigenetic programming, glucose tolerance

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