title: In vivo activating transcription factor 3 silencing ameliorates the AMPK compensatory effects for ER stress-mediated β-cell dysfunction during the progression of type-2 diabetes.
abstract: In obese Zucker diabetic fatty (ZDF) rats, ER stress is associated with insulin resistance and pancreatic β-cell dysfunction; however the exact mechanisms by which ER stress drives type-2 diabetes remain uncertain. Here, we investigated the role of ATF3 on the preventive regulation of AMPK against ER stress-mediated β-cell dysfunction during the end-stage progression of hyperglycemia in ZDF rats. The impaired glucose metabolism and β-cell dysfunction were significantly increased in late-diabetic phase 19-week-old ZDF rats. Although AMPK phosphorylation reduced in 6- and 12-week-old ZDF rats was remarkably increased at 19weeks, the increases of lipogenice genes, ATF3, and ER stress or ROS-mediated β-cell dysfunction were still remained, which were attenuated by in vivo-injection of chemical chaperon tauroursodeoxycholate (TUDCA), chronic AICAR, or antioxidants. ATF3 did not directly affect AMPK phosphorylation, but counteracts the preventive effects of AMPK for high glucose-induced β-cell dysfunction. Moreover, knockdown of ATF3 by delivery of in vivo-jetPEI ATF3 siRNA attenuated ER stress-mediated β-cell dysfunction and enhanced the beneficial effect of AICAR. Our data suggest that ATF3 may play as a counteracting regulator of AMPK and thus promote β-cell dysfunction and the development of type-2 diabetes and could be a potential therapeutic target in treating type-2 diabetes.
authors.affiliation: Division of Metabolic Disease, Center for Biomedical Science, National Institutes of Health, #187 Osong Saengmyeong2-ro, Osong-eup, Cheongwon-gun, Chungbuk, Republic of Korea.
authors.forename: Ji Yeon
authors.initials: JY
authors.lastname: Kim
authors.forename: Keun Jae
authors.initials: KJ
authors.lastname: Park
authors.forename: Gyu Hee
authors.initials: GH
authors.lastname: Kim
authors.forename: Eun Ae
authors.initials: EA
authors.lastname: Jeong
authors.forename: Dae Yeon
authors.initials: DY
authors.lastname: Lee
authors.forename: Seong Su
authors.initials: SS
authors.lastname: Lee
authors.forename: Dae Jin
authors.initials: DJ
authors.lastname: Kim
authors.forename: Gu Seob
authors.initials: GS
authors.lastname: Roh
authors.forename: Jihyun
authors.initials: J
authors.lastname: Song
authors.forename: Sung Hwan
authors.initials: SH
authors.lastname: Ki
authors.forename: Won-Ho
authors.initials: WH
authors.lastname: Kim
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D051700:Activating Transcription Factor 3 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D059865:Endoplasmic Reticulum Stress; D004789:Enzyme Activation; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D008297:Male; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D011924:Rats, Zucker
chemical_list: D051700:Activating Transcription Factor 3; D007328:Insulin; D034741:RNA, Small Interfering; D055372:AMP-Activated Protein Kinases
keywords: AMPK; ATF3; ER stress; In vivo knockdown; Pancreatic β-cells; Type 2 diabetes