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Transcriptome profiling of white adipose tissue in a mouse model for 15q duplication syndrome.

ABSTRACT: Obesity is not only associated with unhealthy lifestyles, but also linked to genetic predisposition. Previously, we generated an autism mouse model (patDp/+) that carries a 6.3 Mb paternal duplication homologous to the human 15q11-q13 locus. Chromosomal abnormalities in this region are known to cause autism spectrum disorder, Prader-Willi syndrome, and Angelman syndrome in humans. We found that, in addition to autistic-like behaviors, patDp/+ mice display late-onset obesity and hypersensitivity to a high-fat diet. These phenotypes are likely to be the results of genetic perturbations since the energy expenditures and food intakes of patDp/+ mice do not significantly differ from those of wild-type mice. Intriguingly, we found that an enlargement of adipose cells precedes the onset of obesity in patDp/+ mice. To understand the underlying molecular networks responsible for this pre-obese phenotype, we performed transcriptome profiling of white adipose tissue from patDp/+ and wild-type mice using microarray. We identified 230 genes as differentially expressed genes. Sfrp5 - a gene whose expression is positively correlated with adipocyte size, was found to be up-regulated, and Fndc5, a potent inducer of brown adipogenesis was identified to be the top down-regulated gene. Subsequent pathway analysis highlighted a set of 35 molecules involved in energy production, lipid metabolism, and small molecule biochemistry as the top candidate biological network responsible for the pre-obese phenotype of patDp/+. The microarray data were deposited in NCBI Gene Expression Omnibus database with accession number GSE58191. Ultimately, our dataset provides novel insights into the molecular mechanism of obesity and demonstrated that patDp/+ is a valuable mouse model for obesity research.

SUBMITTER: Liu X

PROVIDER: S-EPMC4583688 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Transcriptome profiling of white adipose tissue in a mouse model for 15q duplication syndrome.

Liu Xiaoxi X Tamada Kota K Kishimoto Rui R Okubo Hiroko H Ise Satoko S Ohta Hisashi H Ruf Sandra S Nakatani Jin J Kohno Nobuoki N Spitz François F Takumi Toru T

Genomics data 20150710

Obesity is not only associated with unhealthy lifestyles, but also linked to genetic predisposition. Previously, we generated an autism mouse model (patDp/+) that carries a 6.3 Mb paternal duplication homologous to the human 15q11-q13 locus. Chromosomal abnormalities in this region are known to cause autism spectrum disorder, Prader-Willi syndrome, and Angelman syndrome in humans. We found that, in addition to autistic-like behaviors, patDp/+ mice display late-onset obesity and hypersensitivity ...[more]

PMID: 26484295

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Project description:Huntington's disease (HD) is a fatal, autosomal dominantly inherited neurodegenerative disorder, characterised not only by progressive cognitive, motor and psychiatric impairments, but also of peripheral pathology. In both human HD and in mouse models of HD there is evidence of increased energy expenditure and weight loss, alongside altered body composition. Unlike white adipose tissue (WAT), brown adipose tissue (BAT), as well as brown-like cells within WAT, expresses the mitochondrial protein, uncoupling protein 1 (UCP1). UCP1 enables dissociation of cellular respiration from ATP utilization, resulting in the release of stored energy as heat. Hyperplasia of brown/beige cells in WAT has been suggested to enhance energy expenditure. In this study, we therefore investigated the gene expression profile, histological appearance, response to cold challenge and functional aspects of WAT in the R6/2 HD mouse model and selected WAT gene expression in the full-length Q175 mouse model of HD. WAT from R6/2 mice contained significantly more brown-like adipocyte regions and had a gene profile suggestive of the presence of brown-like adipocytes, such as higher Ucp1 expression. Cold exposure induced Ucp1 expression in R6/2 inguinal WAT to a markedly higher degree as compared to the thermogenic response in WT WAT. Alongside this, gene expression of transcription factors (Zfp516 and Pparα), important inducers of WAT browning, were increased in R6/2 inguinal WAT, and Creb1 was highlighted as a key transcription factor in HD. In addition to increased WAT Ucp1 expression, a trend towards increased mitochondrial oxygen consumption due to enhanced uncoupling activity was found in inguinal R6/2 WAT. Key gene expressional changes (increased expression of (Zfp516 and Pparα)) were replicated in inguinal WAT obtained from Q175 mice. In summary, for the first time, we here show that HD mouse WAT undergoes a process of browning, resulting in molecular and functional alterations that may contribute to the weight loss and altered metabolism observed with disease progression.

Dataset Information

Transcriptome profiling of white adipose tissue in a mouse model for 15q duplication syndrome.

Publications

Transcriptome profiling of white adipose tissue in a mouse model for 15q duplication syndrome.

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