10.17863/CAM.10498
Martin-Gronert, Malgorzata
Fernandez-Twinn, Denise
0000-0003-2610-277X
Bushell, Martin
Siddle, Kenneth
Ozanne, Susan
0000-0001-8753-5144
Cell-autonomous programming of rat adipose tissue insulin signalling proteins by maternal nutrition
Apollo - University of Cambridge Repository (staging)
2016
adipose tissue
cell autonomous mechanisms
developmental programming
insulin signalling
low birthweight
maternal diet
protein restriction
type 2 diabetes
Apollo - University of Cambridge Repository (staging)
Apollo - University of Cambridge Repository (staging)
2016
Article
0012-186X
1432-0428
Attribution 4.0 International
Aims/hypothesis Individuals with low birth-weight have increased risk of developing type 2 diabetes mellitus in adulthood. This is associated with peripheral insulin resistance. Here we aim to determine whether changes in insulin signalling proteins in white adipose tissue (WAT) can be detected prior to the onset of impaired glucose tolerance, if these changes are cell autonomous and to identify underlying mechanisms involved. Methods 14-month-old male rat offspring, born to dams fed a standard protein (20%) diet or a low (8%) protein (LP) diet throughout gestation and lactation, were studied. Fat distribution and adipocyte size were determined. Protein and mRNA expression of key insulin signalling molecules were analysed in epididymal WAT and pre-adipocytes that were differentiated in vitro. Results 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 protein expression of IRS1, PI3K p110β, AKT1, PKCζ and phospho-AKT Ser473. Corresponding mRNA transcript levels were unchanged. Similarly, pre-adipocytes from LP offspring differentiated in vitro showed reduced protein levels of IRβ, IRS1, PI3K p85α and p110β subunits, and AKT1. Phosphorylation of AKT Ser473 and IRS1 Tyr612 was reduced while phosphorylation of IRS1 Ser307 was increased. Conclusions/interpretation Maternal protein restriction during gestation and lactation causes changes in distribution and morphology of WAT and reductions in protein levels of key insulin signalling molecules in the male offspring. This phenotype is retained in adipocytes differentiated in vitro suggesting programming by cell autonomous mechanism(s).
This work was supported by Diabetes UK (M.S.M-G 12/0004508) the British Heart Foundation (S.E.O. FS/09/029/27902), the UK Medical Research Council (S.E.O MC_UU_12012/4).
This is the accepted manuscript. It is currently embargoed pending publication.