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Epigenetic epidemiology of obesity: application of epigenomic technology

Robert A Waterland
DOI: http://dx.doi.org/10.1111/j.1753-4887.2008.00060.x S21-S23 First published online: 1 August 2008

Compelling human epidemiologic and animal model data indicate that during critical periods of prenatal and postnatal mammalian development, nutrition and other environmental stimuli influence developmental pathways and thereby induce permanent changes in metabolism and chronic disease susceptibility. The biologic mechanisms underlying such ‘metabolic imprinting’ are poorly understood, but epigenetic mechanisms are likely involved.1 Epigenetics is the study of mitotically heritable alterations in gene expression potential that are not caused by changes in DNA sequence.2 Transient environmental influences during development can cause permanent changes in epigenetic gene regulation, and accumulating evidence links epigenetic dysregulation to human disease.3

The worldwide increase in the prevalence of obesity in recent decades has occurred too rapidly to be explained completely by genetic variation, suggesting the involvement of epigenetic mechanisms. Indeed, data from animal models and humans demonstrate that epigenetic dysregulation can cause obesity.4 Several years ago Levin5 proposed that maternal obesity during pregnancy and lactation might cause metabolic imprinting of neural networks in the offspring, perpetuating, or even amplifying, obesity susceptibility across generations.5 This postulate is supported by recent studies in the mouse, which demonstrate that the formation of hypothalamic projections during early postnatal development is dependent upon cues from outside the brain.6 Leptin-deficient (ob/ob) mice fail to form hypothalamic connections necessary for normal energy homeostasis. Remarkably, transient administration of exogenous leptin during postnatal development rescues hypothalamic innervation and normalizes adult body weight.6 Analogously, maternal obesity during pregnancy …

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