title: Model mice for 15q11-13 duplication syndrome exhibit late-onset obesity and altered lipid metabolism.
abstract: Copy number variations on human chromosome 15q11-q13 have been implicated in several neurodevelopmental disorders. A paternal loss or duplication of the Prader-Willi syndrome/Angelman syndrome (PWS/AS) region confers a risk of obesity, although the mechanism remains a mystery due to a lack of an animal model that accurately recreates the obesity phenotype. We performed detailed analyses of mice with duplication of PWS/AS locus (6 Mb) generated by chromosome engineering and found that animals with a paternal duplication of this region (patDp/+) show late-onset obesity, high sensitivity for high-fat diet, high levels of blood leptin and insulin without an increase in food intake. We show that prior to becoming obese, young patDp/+ mice already had enlarged white adipocytes. Transcriptome analysis of adipose tissue revealed an up-regulation of Secreted frizzled-related protein 5 (Sfrp5), known to promote adipogenesis. We additionally generated a new mouse model of paternal duplication focusing on a 3 Mb region (3 Mb patDp/+) within the PWS/AS locus. These mice recapitulate the obese phenotypes including expansion of visceral adipose tissue. Our results suggest paternally expressed genes in PWS/AS locus play a significant role for the obesity and identify new potential targets for future research and treatment of obesity.
authors.affiliation: RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan, Graduate School of Biomedical Sciences, Hiroshima University, Minami, Hiroshima 734-8553, Japan.
authors.forename: Rui
authors.initials: R
authors.lastname: Kishimoto
authors.affiliation: RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan, Graduate School of Biomedical Sciences, Hiroshima University, Minami, Hiroshima 734-8553, Japan.
authors.forename: Kota
authors.initials: K
authors.lastname: Tamada
authors.affiliation: RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan.
authors.forename: Xiaoxi
authors.initials: X
authors.lastname: Liu
authors.affiliation: RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Okubo
authors.affiliation: Banyu Tsukuba Research Institute, Tsukuba, Ibaraki 300-2611, Japan.
authors.forename: Satoko
authors.initials: S
authors.lastname: Ise
authors.affiliation: Banyu Tsukuba Research Institute, Tsukuba, Ibaraki 300-2611, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Ohta
authors.affiliation: Developmental Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Ruf
authors.affiliation: Molecular Neuroscience Research Center, Shiga University of Medical Science, Ohtsu, Shiga 520-2192, Japan and.
authors.forename: Jin
authors.initials: J
authors.lastname: Nakatani
authors.affiliation: Graduate School of Biomedical Sciences, Hiroshima University, Minami, Hiroshima 734-8553, Japan.
authors.forename: Nobuoki
authors.initials: N
authors.lastname: Kohno
authors.affiliation: Developmental Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany.
authors.forename: François
authors.initials: F
authors.lastname: Spitz
authors.affiliation: RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan, Graduate School of Biomedical Sciences, Hiroshima University, Minami, Hiroshima 734-8553, Japan, JST, CREST, Tokyo, Japan toru.takumi@riken.jp.
authors.forename: Toru
authors.initials: T
authors.lastname: Takumi
mesh_terms: D000818:Animals; D058674:Chromosome Duplication; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics*; D004195:Disease Models, Animal; D056426:Genetic Loci; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics*; D051379:Mice; D009765:Obesity / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D013577:Syndrome