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Circulating adipocyte-derived extracellular vesicles are novel markers of metabolic stress

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Abstract

We recently reported that stressed adipocytes release extracellular vesicles (EVs) that act as “find-me” signals to promote macrophage migration and activation. In this study, we performed a comprehensive characterization of stressed adipocyte-derived EVs, assessing their antigenic composition, lipidomics, and RNA profiles. Perilipin A was identified as one of the adipose-specific proteins and studied as a potential novel biomarker to detect adipocyte-derived EVs in circulation. Circulating EVs were significantly increased in mice with diet-induced obesity (DIO) and in obese humans with metabolic syndrome compared to lean controls. This increase was associated with decreased glucose tolerance in the DIO mice and metabolic dysfunction, elevated insulin, and homeostatic model assessment of insulin resistance (HOMA-IR) in the obese humans. EVs from both DIO mice and obese humans were enriched in perilipin A, a central gatekeeper of the adipocyte lipid storehouse and a marker of adipocyte differentiation. In obese humans, circulating levels of EVs enriched in perilipin A were dynamic, decreasing 35 % (p < 0.05) after a 3-month reduced calorie diet intervention. This translational study provides an extensive characterization of adipocyte-derived EVs. The findings identify perilipin A as a novel biomarker of circulating EVs of adipocyte origin and support the development of circulating perilipin A-positive EVs as indicators of adipose tissue health.

Key message

• Extensive characterization of 3T3L1 EVs identified perilipin A in their composition.

• Circulating EVs are elevated in obese mice and associated with glucose intolerance.

• Circulating EVs are elevated in obese human and correlated with metabolic factors.

• Perilipin A and EV levels are increased in the circulation of obese mice and human.

• Circulating EV and perilipin A levels decrease with low calorie intervention.

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Acknowledgments

The authors would like to thank Dr. Marilyn Farquhar (University of California, San Diego, UCSD) for the use of the electron microscopy facility; Timo Meerloo for electron microscopy sample preparation; Dr. Majid Ghassemian of the Biomolecular and Proteomics Mass Spectrometry facility (UCSD) for the proteomics study; Dr. Gary Hardiman, director of UCSD Biomedical Genomics Facility (BIOGEM); and Dr. Roman Sasik for analysis of the sequencing study. We acknowledge One World Lab for the assistance with selecting antibodies and providing test size quantities. This work was supported by NIH grant (U01 AA022489) and (DK082451) to AEF, Gilead research scholars program in liver disease to AE, and P. Robert Majumder Charitable Foundation to DDS.

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Authors and Affiliations

  1. Department of Pediatrics, University of California San Diego (UCSD), La Jolla, CA, 92093, USA

    Akiko Eguchi, Milos Lazic, Susan A. Phillips & Ariel E. Feldstein

  2. Department of Pharmacology, University of California San Diego (UCSD), La Jolla, CA, 92093, USA

    Aaron M. Armando & Oswald Quehenberger

  3. Department of Pediatrics, Mount Sinai Hospital, Chicago, IL, 60608, USA

    Roia Katebian

  4. Department of Internal Medicine, University of Connecticut School of Medicine, Farmington, CT, 06030, USA

    Spyridoula Maraka

  5. Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, MN, 55905, USA

    Spyridoula Maraka

  6. Department of Medicine, University of California San Diego (UCSD), La Jolla, CA, 92093, USA

    Oswald Quehenberger

  7. Division of Endocrinology and Metabolism, University of California San Diego (UCSD), La Jolla, CA, 92093, USA

    Dorothy D. Sears

  8. Division of Pediatric Gastroenterology, Hepatology, and Nutrition, UCSD, 3020 Children’s Way, MC 5030, San Diego, CA, 92103-8450, USA

    Ariel E. Feldstein

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  1. Akiko Eguchi
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Corresponding author

Correspondence to Ariel E. Feldstein.

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Conflict of interest

DDS was a paid consultant of Zone Labs, Inc. prior to the initiation of the human diet intervention study for which Zone Labs, Inc. donated food supplies.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Table 1

Proteomic analysis of total protein composition in palmitic-acid induced sadEV. (XLSX 22 kb)

Supplementary Table 2

Complete list of fatty acids and their bioactive lipid mediators in sadEVs. Unit: pmol/106 sadEV (XLSX 47 kb)

Supplementary Table 3

Complete list of miRNAs in sadEVs and control sadEVs and their respective parent adipocytes by RNA sequencing. (with a lower threshold of >5 raw counts for positive results). (XLS 82 kb)

Supplementary Table 4

Metabolic parameters at baseline and post-calorie restriction. (DOCX 16 kb)

ESM 5

(DOCX 479 kb)

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Eguchi, A., Lazic, M., Armando, A.M. et al. Circulating adipocyte-derived extracellular vesicles are novel markers of metabolic stress. J Mol Med 94, 1241–1253 (2016). https://doi.org/10.1007/s00109-016-1446-8

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  • DOI: https://doi.org/10.1007/s00109-016-1446-8

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