title: Maternal obesity and diabetes induces latent metabolic defects and widespread epigenetic changes in isogenic mice.
abstract: Intrauterine nutrition can program metabolism, creating stable changes in physiology that may have significant health consequences. The mechanism underlying these changes is widely assumed to involve epigenetic changes to the expression of metabolic genes, but evidence supporting this idea is limited. Here we have performed the first study of the epigenomic consequences of exposure to maternal obesity and diabetes. We used a mouse model of natural-onset obesity that allows comparison of genetically identical mice whose mothers were either obese and diabetic or lean with a normal metabolism. We find that the offspring of obese mothers have a latent metabolic phenotype that is unmasked by exposure to a Western-style diet, resulting in glucose intolerance, insulin resistance and hepatic steatosis. The offspring show changes in hepatic gene expression and widespread but subtle alterations in cytosine methylation. Contrary to expectation, these molecular changes do not point to metabolic pathways but instead reside in broadly developmental ontologies. We propose that, rather than being adaptive, these changes may simply produce an inappropriate response to suboptimal environments; maladaptive phenotypes may be avoidable if postnatal nutrition is carefully controlled.
authors.affiliation: Molecular Genetics Division; Victor Chang Cardiac Research Institute; Darlinghurst, NSW Australia.
authors.forename: Cheryl C Y
authors.initials: CC
authors.lastname: Li
authors.forename: Paul E
authors.initials: PE
authors.lastname: Young
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Maloney
authors.forename: Sally A
authors.initials: SA
authors.lastname: Eaton
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Cowley
authors.forename: Michael E
authors.initials: ME
authors.lastname: Buckland
authors.forename: Thomas
authors.initials: T
authors.lastname: Preiss
authors.forename: Darren C
authors.initials: DC
authors.lastname: Henstridge
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Cooney
authors.forename: Mark A
authors.initials: MA
authors.lastname: Febbraio
authors.forename: David I K
authors.initials: DI
authors.lastname: Martin
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Cropley
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Suter
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism*; D004032:Diet; D044127:Epigenesis, Genetic; D005260:Female; D047109:Fetal Development; D015870:Gene Expression; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008930:Mitochondria, Liver / Q000235:genetics / Q000378:metabolism; D009765:Obesity / Q000378:metabolism*; D011247:Pregnancy; D011248:Pregnancy Complications / Q000378:metabolism*; D011254:Pregnancy in Diabetics / Q000378:metabolism
keywords: Avy; cytosine methylation; diabetes; epigenetic programming; fetal programming; obesity