title: Cell-autonomous programming of rat adipose tissue insulin signalling proteins by maternal nutrition.
abstract: Individuals with a low birthweight have an increased risk of developing type 2 diabetes mellitus in adulthood. This is associated with peripheral insulin resistance. Here, we aimed to determine whether changes in insulin signalling proteins in white adipose tissue (WAT) can be detected prior to the onset of impaired glucose tolerance, determine whether these changes are cell-autonomous and identify the underlying mechanisms involved.
  
  
  
  Fourteen-month-old male rat offspring born to dams fed a standard protein (20%) diet or a low (8%) protein diet throughout gestation and lactation were studied. Fat distribution and adipocyte size were determined. Protein content and mRNA expression of key insulin signalling molecules were analysed in epididymal WAT and in pre-adipocytes that had undergone in vitro differentiation.
  
  
  
  The offspring of low protein fed dams (LP offspring) had reduced visceral WAT mass, altered fat distribution and a higher percentage of small adipocytes in epididymal WAT. This was associated with reduced levels of IRS1, PI3K p110β, Akt1 and PKCζ proteins and of phospho-Akt Ser473. Corresponding mRNA transcript levels were unchanged. Similarly, in vitro differentiated adipocytes from LP offspring showed reduced protein levels of IRβ, IRS1, PI3K p85α and p110β subunits, and Akt1. Levels of Akt Ser473 and IRS1 Tyr612 phosphorylation were reduced, while IRS1 Ser307 phosphorylation was increased.
  
  
  
  Maternal protein restriction during gestation and lactation changes the distribution and morphology of WAT and reduces the levels of key insulin signalling proteins in the male offspring. This phenotype is retained in in vitro differentiated adipocytes, suggesting that programming occurs via cell-autonomous mechanism(s).
authors.affiliation: University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Box 289, Cambridge, CB2 OQQ, UK. msm32@cam.ac.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, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Box 289, Cambridge, CB2 OQQ, UK.
authors.forename: Denise S
authors.initials: DS
authors.lastname: Fernandez-Twinn
authors.affiliation: MRC Toxicology Unit, University of Leicester, Hodgkin Building, Leicester, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Bushell
authors.affiliation: University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Box 289, Cambridge, CB2 OQQ, UK.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Siddle
authors.affiliation: University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Box 289, Cambridge, CB2 OQQ, UK.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Ozanne
mesh_terms: D017667:Adipocytes / Q000166:cytology* / Q000378:metabolism*; D000273:Adipose Tissue / Q000166:cytology*; D000818:Animals; D048429:Cell Size; D002478:Cells, Cultured; D018753:Diet, Protein-Restricted; D005260:Female; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology; D008297:Male; D039382:Maternal Nutritional Physiological Phenomena / Q000502:physiology; D035683:MicroRNAs / Q000235:genetics; D011247:Pregnancy; D051381:Rats; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D007328:Insulin; D035683:MicroRNAs
keywords: Adipose tissue; Cell-autonomous mechanisms; Developmental programming; Insulin signalling; Low birthweight; Maternal diet; Protein restriction; Type 2 diabetes