title: Administration of progranulin (PGRN) triggers ER stress and impairs insulin sensitivity via PERK-eIF2α-dependent manner.
abstract: Progranulin (PGRN) has recently emerged as an important regulator for glucose metabolism and insulin sensitivity. However, the direct effects of PGRN in vivo and the underlying mechanisms between PGRN and impaired insulin sensitivity are not fully understood. In this study, mice treated with PGRN for 21 d exhibited the impaired glucose tolerance and insulin sensitivity, remarkable ER stress as well as attenuated insulin signaling in liver and adipose tissue but not in skeletal muscle. Furthermore, treatment of mice with phenyl butyric acid (PBA), a chemical chaperone alleviating ER stress, resulted in a significant restoration of systemic insulin sensitivity and recovery of insulin signaling induced by PGRN. Consistent with these findings in vivo, we also observed that PGRN treatment induced ER stress, impaired insulin signaling in cultured hepatocytes and adipocytes, with such effects being partially nullified by blockade of PERK. Whereas PGRN-deficient hepatocytes and adipocytes were more refractory to palmitate-induced insulin resistance, indicating the causative role of the PERK-eIF2α axis of the ER stress response in action of PGRN. Collectively, our findings supported the notion that PGRN is a key regulator of insulin resistance and that PGRN may mediate its effects, at least in part, by inducing ER stress via the PERK-eIF2α dependent pathway.
authors.affiliation: a First Affiliated Hospital; Key Laboratory of Environment and Genes Related to Diseases; Ministry of Education; Medical School of Xi'an Jiaotong University ; Xi'an , Shaanxi , China.
authors.forename: Huixia
authors.initials: H
authors.lastname: Li
authors.forename: Bo
authors.initials: B
authors.lastname: Zhou
authors.forename: Jiali
authors.initials: J
authors.lastname: Liu
authors.forename: Fang
authors.initials: F
authors.lastname: Li
authors.forename: Yulong
authors.initials: Y
authors.lastname: Li
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Kang
authors.forename: Hongzhi
authors.initials: H
authors.lastname: Sun
authors.forename: Shufang
authors.initials: S
authors.lastname: Wu
mesh_terms: D016475:3T3 Cells; D017667:Adipocytes / Q000166:cytology; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D020148:Butyric Acid / Q000737:chemistry; D004721:Endoplasmic Reticulum / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D005227:Fatty Acids / Q000737:chemistry; D020868:Gene Silencing; D005947:Glucose / Q000378:metabolism; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D000077155:Granulins; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018832:Molecular Chaperones / Q000378:metabolism; D009132:Muscles / Q000378:metabolism; D000077153:Progranulins; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism
chemical_list: D015852:Eukaryotic Initiation Factor-2; D005227:Fatty Acids; D000077155:Granulins; C120204:Grn protein, mouse; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; D018832:Molecular Chaperones; D000077153:Progranulins; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; C506236:Tnfrsf1a protein, mouse; D020148:Butyric Acid; D005947:Glucose
keywords: ER stress; TNFR; insulin resistance; progranulin