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Neprilysin facilitates adipogenesis through potentiation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway

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Abstract

Neprilysin (NEP) is a zinc metallopeptidase that cleaves a number of small peptides into inactive forms. Despite the recent evidence of a significant correlation between the levels of NEP in plasma and the severity of obesity in humans, a cause-and-effect relationship or a functional role of NEP in obesity has remained uncertain. In this study, we show that NEP has a positive regulatory effect on fat cell formation from precursor cells. NEP increases the accumulation of cytoplasmic triglycerides in 3T3-L1 preadipocytes or the C3H10T1/2 mesenchymal stem cell line in differentiation conditions. Consistently, cells expressing NEP showed an increase in mRNA expression of adipogenic transcription factors, peroxisome proliferator-activated receptor γ (PPARγ), CCAAT/enhancer binding protein α (C/EBPα), and the adipocyte markers aP2 and adipsin. Furthermore, this NEP-enhanced induction of adipogenesis was found to require the enzymatic activity of NEP, leading to augmentation of the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt) signaling pathway. In summary, our results indicate that NEP accelerates adipogenesis through enhancement of insulin-mediated PI3K-Akt activation and imply a high therapeutic value of NEP in treating obesity and obesity-related disorders.

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Abbreviations

AD:

Alzheimer’s disease

Akt:

Protein kinase B

aP2:

Adipocyte protein 2

C/EBPα:

CCAAT-enhancer-binding protein α

DMI:

Dexamethasone, 1-methyl-3-isobutylxanthine and insulin

HFD:

High-fat diet

IRES:

Internal ribosome entry sequence

MMPs:

Matrix metalloproteinases

NEP:

Neprilysin, neutral endopeptidase, EC3.4.24.11

PI3K:

Phosphatidylinositol 3-kinase

PPARγ:

Peroxisome proliferator-activated receptor γ

qRT-PCR:

Quantitative real-time PCR

SD:

Standard chow diet

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Acknowledgements

This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (#2015R1A2A2A01005687).

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Authors and Affiliations

  1. College of Biotechnology and Bioengineering, Sungkyunkwan University, Suwon, Gyeonggi-do, 16419, South Korea

    Juwan Kim, Dasol Han, Sung-Hyun Byun, Mookwang Kwon & Keejung Yoon

  2. Division of Brain Diseases, Center for Biomedical Sciences, Korea National Institute of Health, Osong, Chungcheongbuk-do, 28159, South Korea

    Sun-Jung Cho & Young Ho Koh

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  1. Juwan Kim
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Correspondence to Keejung Yoon.

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Kim, J., Han, D., Byun, SH. et al. Neprilysin facilitates adipogenesis through potentiation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway. Mol Cell Biochem 430, 1–9 (2017). https://doi.org/10.1007/s11010-017-2948-6

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