title: Progranulin causes adipose insulin resistance via increased autophagy resulting from activated oxidative stress and endoplasmic reticulum stress.
abstract: BACKGROUND
  Progranulin (PGRN) has recently emerged as an important regulator for insulin resistance. However, the direct effect of progranulin in adipose insulin resistance associated with the autophagy mechanism is not fully understood.
  
  
  METHODS
  In the present study, progranulin was administered to 3T3-L1 adipocytes and C57BL/6 J mice with/without specific inhibitors of oxidative stress and endoplasmic reticulum stress, and metabolic parameters, oxidative stress, endoplasmic reticulum stress and autophagy markers were assessed.
  
  
  RESULTS
  Progranulin treatment increased iNOS expression, NO synthesis and ROS generation, and elevated protein expressions of CHOP, GRP78 and the phosphorylation of PERK, and caused a significant increase in Atg7 and LC3-II protein expression and a decreased p62 expression, and decreased insulin-stimulated tyrosine phosphorylation of IRS-1 and glucose uptake, demonstrating that progranulin activated oxidative stress and ER stress, elevated autophagy and induced insulin insensitivity in adipocytes and adipose tissue of mice. Interestingly, inhibition of iNOS and ER stress both reversed progranulin-induced stress response and increased autophagy, protecting against insulin resistance in adipocytes. Furthermore, the administration of the ER stress inhibitor 4-phenyl butyric acid reversed the negative effect of progranulin in vivo.
  
  
  CONCLUSIONS
  Our findings showed the clinical potential of the novel adipokine progranulin in the regulation of insulin resistance, suggesting that progranulin might mediate adipose insulin resistance, at least in part, by inducing autophagy via activated oxidative stress and ER stress.
authors.affiliation: Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an, Shaanxi, 710061, China.
authors.forename: Qinyue
authors.initials: Q
authors.lastname: Guo
authors.affiliation: Department of Endocrinology, the Affiliated Guangren Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710004, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Xu
authors.affiliation: Key Laboratory of Environment and Genes Related to Diseases, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China.
authors.forename: Huixia
authors.initials: H
authors.lastname: Li
authors.affiliation: Key Laboratory of Environment and Genes Related to Diseases, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China.
authors.forename: Hongzhi
authors.initials: H
authors.lastname: Sun
authors.affiliation: Clinical Laboratory, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China.
authors.forename: Jiali
authors.initials: J
authors.lastname: Liu
authors.affiliation: Center for Translational Medicine, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China.
authors.forename: Shufang
authors.initials: S
authors.lastname: Wu
authors.affiliation: Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an, Shaanxi, 710061, China. zb_bob@stu.xjtu.edu.cn.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhou
mesh_terms: D041721:3T3-L1 Cells; D000273:Adipose Tissue / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D000071193:Autophagy-Related Protein 7 / Q000235:genetics / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D000077155:Granulins; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D007274:Injections, Intraperitoneal; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism; D007333:Insulin Resistance; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D009569:Nitric Oxide / Q000819:agonists* / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010654:Phenylbutyrates / Q000494:pharmacology; D000077153:Progranulins; D017382:Reactive Oxygen Species / Q000819:agonists* / Q000378:metabolism; D000071456:Sequestosome-1 Protein / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism
chemical_list: D000071193:Autophagy-Related Protein 7; D000091342:Endoplasmic Reticulum Chaperone BiP; D005947:Glucose; D000077155:Granulins; D006360:Heat-Shock Proteins; D055504:Insulin Receptor Substrate Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008869:Microtubule-Associated Proteins; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D010654:Phenylbutyrates; D000077153:Progranulins; D017382:Reactive Oxygen Species; D000071456:Sequestosome-1 Protein; D051742:Transcription Factor CHOP; D019892:eIF-2 Kinase; C502661:Atg7 protein, mouse; C497250:Ddit3 protein, mouse; C120204:Grn protein, mouse; C000717248:Hspa5 protein, mouse; C526295:Irs1 protein, mouse; C480860:Map1lc3b protein, mouse; C101343:Sqstm1 protein, mouse; C075773:4-phenylbutyric acid; C496317:Nos2 protein, mouse
keywords: Autophagy; Endoplasmic reticulum stress; Insulin resistance; Oxidative stress; Progranulin