title: Mangiferin suppresses endoplasmic reticulum stress in perivascular adipose tissue and prevents insulin resistance in the endothelium.
abstract: OBJECTIVE
  Mangiferin is a naturally occurring glucosylxanthone with beneficial effects on glucose and lipid homeostasis. This study investigates the potential therapeutic effect of Mangiferin in perivascular adipose tissue (PVAT) and whether it contributes to regulating insulin action in the endothelium.
  
  
  METHODS
  Palmitate challenge evoked ROS-associated endoplasmic reticulum stress (ER stress) and NLRP3 inflammasome activation in PVAT. The conditioned medium from PA-stimulated PVAT was prepared to induce endothelial insulin resistance, and improved endothelium-dependent vasodilation in response to insulin was detected in vitro and in vivo.
  
  
  RESULTS
  Mangiferin treatment enhanced LKB1-dependent AMPK activity and suppressed ER stress with downregulation of TXNIP induction, leading to the inhibition of NLRP3 inflammasome activation evidenced by attenuated NLRP3 and cleaved caspase-1 expression as well as reduced IL-1β secretion. Moreover, Mangiferin restored insulin-mediated Akt and eNOS phosphorylations with increased NO production, immunohistochemistry examination of adipocytes, and endothelial tissue in high-fat diet-fed mice also showed that oral administration of Mangiferin inhibited ER stress and NLRP3 induction in PVAT, and then effectively prevented insulin resistance in the vessel endothelium.
  
  
  CONCLUSIONS
  Taken together, these results revealed that Mangiferin suppressed ER stress-associated NLRP3 inflammasome activation in PVAT through regulation of AMPK activity, which prevented endothelial insulin resistance. These findings suggested that the amelioration of PVAT dysfunction may be a therapeutic strategy for the prevention of endothelial insulin resistance.
authors.affiliation: Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 639 Longmian Road, 211198, Nanjing, China.
authors.forename: Xiaoshan
authors.initials: X
authors.lastname: Xu
authors.affiliation: Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 639 Longmian Road, 211198, Nanjing, China.
authors.forename: Yupeng
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Hebei University of Chinese Medicine, Pharmaceutical Botany Office, Hebei, China.
authors.forename: Junna
authors.initials: J
authors.lastname: Song
authors.affiliation: Hebei University of Chinese Medicine, Pharmacognosy Office, Hebei, China.
authors.forename: Fangjie
authors.initials: F
authors.lastname: Hou
authors.affiliation: Scientific Research Center of Hebei University of Chinese Medicine, Hebei, China.
authors.forename: Xuelian
authors.initials: X
authors.lastname: Ma
authors.affiliation: Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 639 Longmian Road, 211198, Nanjing, China.
authors.forename: Baolin
authors.initials: B
authors.lastname: Liu
authors.affiliation: Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 639 Longmian Road, 211198, Nanjing, China. njhuangfang@163.com.
authors.forename: Fang
authors.initials: F
authors.lastname: Huang
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D044004:Xanthones / Q000494:pharmacology*
chemical_list: D044004:Xanthones; C013592:mangiferin
keywords: ER stress; Inflammasome; Insulin resistance; Mangiferin