title: Downregulation of IRS-1 in adipose tissue of offspring of obese mice is programmed cell-autonomously through post-transcriptional mechanisms.
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.
authors.affiliation: University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Institute of Metabolic Science, Level 4, Box 289, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
authors.forename: Denise S
authors.initials: DS
authors.lastname: Fernandez-Twinn
authors.affiliation: University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Institute of Metabolic Science, Level 4, Box 289, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
authors.forename: Maria Z
authors.initials: MZ
authors.lastname: Alfaradhi
authors.affiliation: University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Institute of Metabolic Science, Level 4, Box 289, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
authors.forename: Malgorzata S
authors.initials: MS
authors.lastname: Martin-Gronert
authors.affiliation: University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Institute of Metabolic Science, Level 4, Box 289, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
authors.forename: Daniella E
authors.initials: DE
authors.lastname: Duque-Guimaraes
authors.affiliation: University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Institute of Metabolic Science, Level 4, Box 289, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
authors.forename: Ana
authors.initials: A
authors.lastname: Piekarz
authors.affiliation: MRC Toxicology Unit, Hodgkin Building, PO Box 138, University of Leicester, Lancaster Road, Leicester LE1 9HN, UK.
authors.forename: David
authors.initials: D
authors.lastname: Ferland-McCollough
authors.affiliation: MRC Toxicology Unit, Hodgkin Building, PO Box 138, University of Leicester, Lancaster Road, Leicester LE1 9HN, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Bushell
authors.affiliation: University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Institute of Metabolic Science, Level 4, Box 289, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Ozanne
keywords: Adipose tissue; DEXA, dual energy X-ray absorptiometry; Hyperinsulinemia; IRS1; IRβ, insulin receptor-beta; Maternal obesity; PI3K, phosphotidylinositol 3-kinase; UTR, untranslated region; miRNA, microRNA; microRNAs
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