Introduction and Objective: With half the global population predicted to be obese by 2035, understanding the role of adiposity on obesity-associated comorbidities is critical. Adipose tissue (AT) inflammation negatively affects atherosclerosis, insulin resistance, and metabolic-associated fatty liver disease, but the mechanism behind interorgan signaling remains a mystery. Extracellular vesicles (EVs) deliver bioactive cargo to alter recipient cell function. With over 65% of circulating EV-miRNAs originating from adipocytes, we hypothesize that diet regulates adipocyte EV (AdEV) cargo trafficked to tissue-resident cells, dictating local inflammatory responses.Methods: We harvested AdEVs from the visceral AT of lean and obese C57BL/6J mice and lean and obese bariatric surgery patients who gave informed consent. Mouse AdEVs were administered in middle-aged Ldlr-/- mice, and human AdEVs were used for single-EV profiling, transcriptomics, and co-culturing.Results: Weight-matched middle-aged Ldlr-/- mice receiving obese AdEVs had increased en-face atherosclerosis (p<0.0001), insulin resistance (p<0.05), and hepatic steatosis (p<0.05), while lean AdEVs had no effect. The immune milieu in the aorta, liver, and spleen internalized AdEVs (p<0.05). Macrophages endocytosed human AdEVs into endosomal/lysosomal compartments with obese AdEVs colocalizing more with the latter (p<0.0001) and induced heightened pro-inflammatory responses, including IL12B(>250-fold; p<0.001) and IL1B(60-fold; p<0.01). AdEVs from lean and obese patients contained differential miRNA cargo (p<0.05) mirrored in AdEVs from lean and obese mice. Classical EV and adipocyte-specific biomarkers on the single-AdEV surface revealed more AdEVs in obese subjects’ plasma (p<0.05).Conclusion: In obesity, AdEVs accelerate atherosclerosis, insulin resistance, and hepatic steatosis through uptake, internalization, cargo delivery, and increased production of circulating AdEVs, suggesting AdEVs are a major mechanism.
X.Y. Rima: None. D. Shantaram: None. J.Z. Liu: None. V.P. Wright: None. A. Amari: None. J. Doon-Ralls: None. T.K. Nguyen: None. J. Rottinghaus: None. J.M. Fernandes: None. D.S. Patel: None. A.D. Jalilvand: None. B.J. Needleman: Speaker’s Bureau; Intuitive Surgical, Medtronic. S. Noria: None. S. Brethauer: None. K.A. Perry: None. E. Reategui: None. W. Hsueh: None.
National Institutes of Health (5T32HL149637); Burroughs Wellcome Fund (1285320)
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