Dataset Information

Microduplication of 16p11.2 locus Potentiates Hypertrophic Obesity in Association with Imbalanced Triglyceride Metabolism in White Adipose Tissue.

ABSTRACT:

Scope

Copy number variation (CNV) of 16p11.2 is a common genetic factor contributing to the etiology of abnormal weight status, while the underlying mechanism is not fully elucidated yet.

Methods and results

The 16p11.2 CNV mouse model with microduplication of the 7Slx1b-Sept1 region (dp/+) is evaluated under normal chow conditions. Compared to the wild type littermates (WT), the dp/+ mice exhibit obvious obese phenotype characterized by significant increase in body mass index, fat pad mass, and fat ratio, with visceral-dominant fat deposits at 12-week age. White adipose tissue (WAT), liver tissue, and plasma are sampled to assess the comorbid metabolic syndrome. In dp/+ mice, histopathologic analyses reveal hypertrophic adipocytes and hepatic steatosis; serological examinations show hyperlipemia and hyperinsulinemia. Further, by comparing lipidomic and transcriptomic profiling of epididymal WAT between dp/+ and WT mice, the study finds the triglyceride (TG) accumulation in dp/+ mice in association with the dysfunction of lipid droplets. Validation of TG-metabolism-associated genes in WAT and in primary cultured adipocytes show enhanced TG synthesis and declined TG hydrolysis in the dp/+ model.

Conclusion

This study elucidates that the imbalanced TG synthesis/hydrolysis in adipocytic lipid droplets may contribute to the hypertrophic obesity and metabolic disorders in mice with 16p11.2 microduplication.

SUBMITTER: Wang D

PROVIDER: S-EPMC9286681 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: Chromosomal 16p11.2 deletions and duplications are genomic disorders which are characterized by neurobehavioral abnormalities, obesity, congenital abnormalities and so on. However, the prenatal phenotypes of 16p11.2 copy number variations (CNVs) are still not well described till now. This study aimed to provide an elaborate summary of intrauterine phenotypic features for such genomic disorders. Methods: Twenty prenatal amniotic fluid samples diagnosed with 16p11.2 microdeletions/microduplications were obtained from pregnant women who opted for invasive prenatal testing. Karyotypic analysis and chromosomal microarray analysis (CMA) were performed in parallel. The pregnancy outcomes and health conditions after birth for all cases were followed up. Meanwhile, we made a pooled analysis on the prenatal phenotypes for the published cases carrying 16p11.2 CNVs. Results: 20 fetuses (20/20884, 0.10%) with 16p11.2 CNVs were identified: five 16p11.2 BP2-BP3 deletion, ten 16p11.2 BP4-BP5 deletion and five 16p11.2 BP4-BP5 duplication. Abnormal ultrasound findings were recorded in ten participants with 16p11.2 deletions.Various degrees of intrauterine phenotypic features, ranging from normal to abnormal, were observed. No ultrasound abnormalities were observed for all 16p11.2 duplication cases during the pregnancy period. For 16p11.2 deletions, eleven cases terminated their pregnancies. For 16p11.2 duplications, four cases gave birth to healthy neonates except one was lost to follow up. Conclusions: Diverse prenatal phenotypes were presented in 16p11.2 CNVs, ranging from normal to abnormal. For 16p11.2 BP4-BP5 deletion, the most common structural and non-structural abnormalities were the abnormality of the vertebral column or rib and thickened nuchal translucency, respectively. 16p11.2 BP2-BP3 deletion might be closely associated with fetal growth restriction and single umbilical artery. No representative ultrasound findings for 16p11.2 duplication were observed till now. Considering the variable expressivity and incomplete penetrance of 16p11.2 CNVs, long term follow up after birth should be carried out for these cases. We identified 20 fetuses carrying the 16p11.2 microdeletions and microduplications using chromosomal microarray analysis. And diverse prenatal phenotypes and the critical genes involved in the deleted/duplicated regions were described in this study.