title: Circulating adipocyte-derived extracellular vesicles are novel markers of metabolic stress.
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.
  
  
  
  • 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.
authors.affiliation: Department of Pediatrics, University of California San Diego (UCSD), La Jolla, CA, 92093, USA.
authors.forename: Akiko
authors.initials: A
authors.lastname: Eguchi
authors.affiliation: Department of Pediatrics, University of California San Diego (UCSD), La Jolla, CA, 92093, USA.
authors.forename: Milos
authors.initials: M
authors.lastname: Lazic
authors.affiliation: Department of Pharmacology, University of California San Diego (UCSD), La Jolla, CA, 92093, USA.
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Armando
authors.affiliation: Department of Pediatrics, University of California San Diego (UCSD), La Jolla, CA, 92093, USA.
authors.forename: Susan A
authors.initials: SA
authors.lastname: Phillips
authors.affiliation: Department of Pediatrics, Mount Sinai Hospital, Chicago, IL, 60608, USA.
authors.forename: Roia
authors.initials: R
authors.lastname: Katebian
authors.affiliation: Department of Internal Medicine, University of Connecticut School of Medicine, Farmington, CT, 06030, USA.|Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, MN, 55905, USA.
authors.forename: Spyridoula
authors.initials: S
authors.lastname: Maraka
authors.affiliation: Department of Pharmacology, University of California San Diego (UCSD), La Jolla, CA, 92093, USA.|Department of Medicine, University of California San Diego (UCSD), La Jolla, CA, 92093, USA.
authors.forename: Oswald
authors.initials: O
authors.lastname: Quehenberger
authors.affiliation: Division of Endocrinology and Metabolism, University of California San Diego (UCSD), La Jolla, CA, 92093, USA.
authors.forename: Dorothy D
authors.initials: DD
authors.lastname: Sears
authors.affiliation: Department of Pediatrics, University of California San Diego (UCSD), La Jolla, CA, 92093, USA. afeldstein@ucsd.edu.|Division of Pediatric Gastroenterology, Hepatology, and Nutrition, UCSD, 3020 Children's Way, MC 5030, San Diego, CA, 92103-8450, USA. afeldstein@ucsd.edu.
authors.forename: Ariel E
authors.initials: AE
authors.lastname: Feldstein
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism*; D000328:Adult; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D031204:Caloric Restriction; D002478:Cells, Cultured; D000067128:Extracellular Vesicles / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000097:blood / Q000494:pharmacology; D007333:Insulin Resistance; D008055:Lipids / Q000032:analysis; D055432:Metabolomics; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism; D009765:Obesity / Q000097:blood / Q000378:metabolism / Q000473:pathology; D000070778:Perilipin-1 / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D040901:Proteomics; D017423:Sequence Analysis, RNA; D013312:Stress, Physiological / Q000187:drug effects
chemical_list: D015415:Biomarkers; D007328:Insulin; D008055:Lipids; D035683:MicroRNAs; D000070778:Perilipin-1; D011506:Proteins
keywords: Adipocyte stress and hypertrophy; Extracellular vesicles; Noninvasive biomarker; Obesity