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Genetic interaction of DGAT2 and FAAH in the development of human obesity

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Abstract

Purpose

DGAT2 is the critical catalyzing enzyme for triglyceride biosynthesis, and excess triglyceride accumulation in fat tissues is a fundamental process for obesity. Mutations in DGAT2 or other genes interacting with DGAT2 associated with adiposity have not been reported in human to date.

Methods

DGAT2 mutation was identified based on our in-home database-exome sequencing 227 young obese subjects (body-mass index (BMI), 35.1–61.7 kg/m2) and 219 lean controls (BMI, 17.5–23.0 kg/m2), further validated in 1190 lean subjects and the pedigree of the proband. The trios of the proband were further subjected to whole-exome sequencing to explore the candidate genes for obesity. The mutations in DGAT2 and FAAH were functionally evaluated in vitro.

Results

We detected two rare variants in DGAT2 with no significant difference between obese and lean individuals. One novel heterozygous nonsense variant c.382C > T (p.R128*) was identified in one obese subject but not in 219 lean subjects and another 1190 lean subjects. Notably, in vitro study showed that R128* mutation severely damaged the TG-biosynthesis ability of DGAT2, and all other R128* carriers in the pedigree were lean. Thus, we further identified a loss-of-function variant c. 944G > T (p.R315I) in FAAH in the proband inheriting from his obese father. Importantly, FAAH overexpression inhibited DGAT2 expression and TG synthesis, while R315I mutant largely eliminated this inhibitory effect.

Summary

We first report loss-of-function mutations in DGAT2 and FAAH in one obese subject, which may interact with each other to affect the adiposity penetrance, providing a model of genetic interaction associated with human obesity.

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Acknowledgements

We thank all the staff and participants for their contributions. This study was funded by grants from the National Natural Science Foundation of China (81522011, 81570757, 81370963, 81370949, 81500651), National Basic Research Program of China (2015CB553601), National International Science Cooperation Foundation (2015DFA30560).

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Authors and Affiliations

  1. Institute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS) & Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, 200025, China

    Tinglu Ning, Yaoyu Zou, Qianqian Lu & Guang Ning

  2. Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolism, National Key Laboratory for Medical Genomes, China National Research Center for Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, 200025, China

    Minglan Yang, Maopei Chen, Wen Liu, Shaoqian Zhao, Yingkai Sun, Juan Shi, Qinyun Ma, Jie Hong, Ruixin Liu, Jiqiu Wang & Guang Ning

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  1. Tinglu Ning
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Correspondence to Jiqiu Wang or Guang Ning.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. And all applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

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Ning, T., Zou, Y., Yang, M. et al. Genetic interaction of DGAT2 and FAAH in the development of human obesity. Endocrine 56, 366–378 (2017). https://doi.org/10.1007/s12020-017-1261-1

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