期刊
HUMAN MOLECULAR GENETICS
卷 24, 期 16, 页码 4559-4572出版社
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddv187
关键词
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资金
- KAKENHI, Japan Society of Promotion of Science
- Ministry of Education, Culture, Sports, Science and Technology, Strategic International Cooperative Program (SICP)
- CREST, Japan Science and Technology Agency
- Intramural Research Grant for Neurological and Psychiatric Disorders of NCNP
- Takeda Science Foundation
- Takeda Pharmaceutical Co. Ltd.
- Grants-in-Aid for Scientific Research [26670165, 25242077] Funding Source: KAKEN
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 showthat 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.
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