Programming of adipose tissue miR-483-3p and GDF-3 expression by maternal diet in type 2 diabetes.
Nutrition during early mammalian development permanently influences health of the adult, including increasing the risk of type 2 diabetes and coronary heart disease. However, the molecular mechanisms underlying such programming are poorly defined. Here we demonstrate that programmed changes in miRNA expression link early-life nutrition to long-term health. Specifically, we show that miR-483-3p is upregulated in adipose tissue from low-birth-weight adult humans and prediabetic adult rats exposed to suboptimal nutrition in early life. We demonstrate that manipulation of miR-483-3p levels in vitro substantially modulates the capacity of adipocytes to differentiate and store lipids. We show that some of these effects are mediated by translational repression of growth/differentiation factor-3, a target of miR-483-3p. We propose that increased miR-483-3p expression in vivo, programmed by early-life nutrition, limits storage of lipids in adipose tissue, causing lipotoxicity and insulin resistance and thus increasing susceptibility to metabolic disease.
MRC Toxicology Unit, Lancaster Road, Leicester LE1 9HN, UK.
D
D
Ferland-McCollough
D S
DS
Fernandez-Twinn
I G
IG
Cannell
H
H
David
M
M
Warner
A A
AA
Vaag
J
J
Bork-Jensen
C
C
Brøns
T W
TW
Gant
A E
AE
Willis
K
K
Siddle
M
M
Bushell
S E
SE
Ozanne
D020413:3' Untranslated Regions; D000273:Adipose Tissue / Q000378:metabolism*; D000328:Adult; D000818:Animals; D000831:Animals, Newborn; D001483:Base Sequence; D002454:Cell Differentiation; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000473:pathology; D004032:Diet; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D055451:Growth Differentiation Factor 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D050356:Lipid Metabolism; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D020413:3' Untranslated Regions; D055451:Growth Differentiation Factor 3; D035683:MicroRNAs; D034741:RNA, Small Interfering