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Cell-autonomous programming of rat adipose tissue insulin signalling proteins by maternal nutrition.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Martin-Gronert, Malgorzata S 
Fernandez-Twinn, Denise S 
Bushell, Martin 
Siddle, Kenneth 
Ozanne, Susan E 

Abstract

AIMS/HYPOTHESIS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS/INTERPRETATION: 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).

Description

Keywords

Adipose tissue, Cell-autonomous mechanisms, Developmental programming, Insulin signalling, Low birthweight, Maternal diet, Protein restriction, Type 2 diabetes, Adipocytes, Adipose Tissue, Animals, Cell Size, Cells, Cultured, Diet, Protein-Restricted, Female, Insulin, Insulin Resistance, Male, Maternal Nutritional Physiological Phenomena, MicroRNAs, Pregnancy, Rats, Signal Transduction

Journal Title

Diabetologia

Conference Name

Journal ISSN

0012-186X
1432-0428

Volume Title

Publisher

Springer Link
Sponsorship
Medical Research Council (MC_UU_12012/4)
British Heart Foundation (None)
Medical Research Council (MC_UU_12012/5)
Diabetes UK (None)
Medical Research Council (MC_PC_12012)
This work was supported by Diabetes UK (MSM-G; no. 12/0004508), the British Heart Foundation (SEO; no. FS/09/029/27902) and the UK Medical Research Council (SEO; no. MC_UU_12012/4)