Epigenetic regulation of metabolism in children born small for gestational age.
OBJECTIVE
Epigenetic alterations are responsible for modulation of tissue-specific gene expression and genomic imprinting. Mechanisms include posttranslational modifications of core histones and DNA methylation. The review focuses on emerging data highlighting the potential for epigenetic modulation of gene expression in mediating early-life programming of increased risk of adult-onset disease. To illustrate these concepts, we focus on epigenetic programming of insulin resistance, obesity and type 2 diabetes, with emphasis on the potential role of the adipocyte and three of its products, fatty acids, leptin and tumour necrosis factor alpha.


RESULTS
Recent studies have highlighted potential mechanisms underlying epigenetic modification of tissue function that may predispose to later development of insulin resistance. These include altered regulation of adipocyte clonal expansion and terminal differentiation via epigenetic modification of peroxisome proliferator-activated receptor gamma, Foxo1 or cyclin D1 expression and signalling that, via altered adipocyte lipid sequestration, alters lipid delivery to nonadipose tissue and, therefore, insulin action or modification of adipokine or cytokine expression and signalling. Direct epigenetic modification of insulin action in muscle may be achieved through altered stearoyl-CoA desaturase 1 expression, which correlates with low fatty acid oxidation.


CONCLUSIONS
While poor early growth and an increased risk of type 2 diabetes in adulthood are undisputedly linked, the relative impact of environment or genotype remains unclear. Altered DNA methylation patterns could, potentially, serve as biomarkers for assessment of prognosis and could help in the development of prophylactic strategies.
Holness
Mark J
MJ
Centre for Diabetes and Metabolic Medicine, Institute of Cell and Molecular Science, Bart's and the London, Queen Mary's School of Medicine and Dentistry, London, UK. m.j.holness@qmul.ac.uk
Sugden
Mary C
MC
D000273:Adipose Tissue / Q000378:metabolism; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006801:Humans; D007231:Infant, Newborn; D007236:Infant, Small for Gestational Age / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D009765:Obesity / Q000235:genetics* / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
D007328:Insulin; D018160:Receptors, Cytoplasmic and Nuclear