4.7 Article

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

Journal

MOLECULAR NUTRITION & FOOD RESEARCH
Volume 66, Issue 5, Pages -

Publisher

WILEY
DOI: 10.1002/mnfr.202100241

Keywords

16p11; 2 microduplication; adipogenesis; lipid droplet; metabolic disorder; obesity

Funding

  1. Sanming Project of Medicine in Shenzhen [SZSM201911003]
  2. Research Start-up Fund of the Seventh Affiliated Hospital, Sun Yat-Sen University [ZSQYBRJH0001, ZSQYBRJH0007]
  3. Science and Technology Planning Project of Guangdong Province [2019B030316031]

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This study investigates the role of imbalanced TG synthesis/hydrolysis in adipocytic lipid droplets in contributing to hypertrophic obesity and metabolic disorders in mice with 16p11.2 microduplication.
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 characterize 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.

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