title: In utero undernutrition in male mice programs liver lipid metabolism in the second-generation offspring involving altered Lxra DNA methylation.
abstract: Obesity and type 2 diabetes have a heritable component that is not attributable to genetic factors. Instead, epigenetic mechanisms may play a role. We have developed a mouse model of intrauterine growth restriction (IUGR) by in utero malnutrition. IUGR mice developed obesity and glucose intolerance with aging. Strikingly, offspring of IUGR male mice also developed glucose intolerance. Here, we show that in utero malnutrition of F1 males influenced the expression of lipogenic genes in livers of F2 mice, partly due to altered expression of Lxra. In turn, Lxra expression is attributed to altered DNA methylation of its 5' UTR region. We found the same epigenetic signature in the sperm of their progenitors, F1 males. Our data indicate that in utero malnutrition results in epigenetic modifications in germ cells (F1) that are subsequently transmitted and maintained in somatic cells of the F2, thereby influencing health and disease risk of the offspring.
authors.affiliation: Hospital Sant Joan de Deu, Pediatric Endocrinology, Esplugues de Llobregat, Barcelona 08950, Spain.
authors.forename: Débora
authors.initials: D
authors.lastname: Martínez
authors.affiliation: Hospital Sant Joan de Deu, Pediatric Endocrinology, Esplugues de Llobregat, Barcelona 08950, Spain.
authors.forename: Thais
authors.initials: T
authors.lastname: Pentinat
authors.affiliation: Hospital Sant Joan de Deu, Pediatric Endocrinology, Esplugues de Llobregat, Barcelona 08950, Spain.
authors.forename: Sílvia
authors.initials: S
authors.lastname: Ribó
authors.affiliation: Laboratory for Epigenetics and Environment, Centre National de Génotypage, CEA-Institute de Génomique, 91057 Evry CEDEX, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Daviaud
authors.affiliation: Department of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, University Medical Center Groningen, University of Groningen, Groningen 9713 GZ, the Netherlands.
authors.forename: Vincent W
authors.initials: VW
authors.lastname: Bloks
authors.affiliation: Hospital Sant Joan de Deu, Pediatric Endocrinology, Esplugues de Llobregat, Barcelona 08950, Spain.
authors.forename: Judith
authors.initials: J
authors.lastname: Cebrià
authors.affiliation: Hospital Sant Joan de Deu, Pediatric Endocrinology, Esplugues de Llobregat, Barcelona 08950, Spain.
authors.forename: Nuria
authors.initials: N
authors.lastname: Villalmanzo
authors.affiliation: Bioinformatics Core Facility, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Universitat de Barcelona (UB), Barcelona 08036, Spain.
authors.forename: Susana G
authors.initials: SG
authors.lastname: Kalko
authors.affiliation: Hospital Sant Joan de Deu, Pediatric Endocrinology, Esplugues de Llobregat, Barcelona 08950, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Ramón-Krauel
authors.affiliation: Hospital Sant Joan de Deu, Pediatric Endocrinology, Esplugues de Llobregat, Barcelona 08950, Spain; Facultat de Medicina, Universitat de Barcelona (UB), Barcelona 08950, Spain.
authors.forename: Rubén
authors.initials: R
authors.lastname: Díaz
authors.affiliation: Department of Obstetrics and Gynaecology, University Medical Center Groningen, University of Groningen, Groningen 9713 GZ, the Netherlands.
authors.forename: Torsten
authors.initials: T
authors.lastname: Plösch
authors.affiliation: Laboratory for Epigenetics and Environment, Centre National de Génotypage, CEA-Institute de Génomique, 91057 Evry CEDEX, France.
authors.forename: Jörg
authors.initials: J
authors.lastname: Tost
authors.affiliation: Hospital Sant Joan de Deu, Pediatric Endocrinology, Esplugues de Llobregat, Barcelona 08950, Spain. Electronic address: jjimenezc@fsjd.org.
authors.forename: Josep C
authors.initials: JC
authors.lastname: Jiménez-Chillarón
mesh_terms: D000375:Aging; D000818:Animals; D002478:Cells, Cultured; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D005317:Fetal Growth Retardation / Q000378:metabolism; D018149:Glucose Intolerance / Q000235:genetics; D050356:Lipid Metabolism / Q000502:physiology*; D050155:Lipogenesis / Q000235:genetics; D008099:Liver / Q000378:metabolism*; D000071518:Liver X Receptors; D008297:Male; D044342:Malnutrition / Q000378:metabolism*; D051379:Mice; D008813:Mice, Inbred ICR; D009765:Obesity / Q000235:genetics; D057093:Orphan Nuclear Receptors / Q000096:biosynthesis / Q000235:genetics*; D011247:Pregnancy; D013094:Spermatozoa / Q000166:cytology; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics
chemical_list: D000071518:Liver X Receptors; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1