title: Atf6α-null mice are glucose intolerant due to pancreatic β-cell failure on a high-fat diet but partially resistant to diet-induced insulin resistance.
abstract: Activating transcription factor 6α (ATF6α) is essential for the endoplasmic reticulum (ER) stress response. Since recent studies suggested that ER stress is involved in the pathogenesis of type 2 diabetes mellitus, we have analyzed Atf6α-null (Atf6α(-/-)) mice challenged with metabolic overload or genetic manipulations. Atf6α(-/-) mice were fed a high-fat diet to create diet-induced obese (DO) mice, and were subjected to examination of glucose homeostasis with biochemical and morphological analysis of the pancreatic β-cell and liver tissues. Atf6α-null mice were also crossed with genetic models of diabetes caused either by insulin resistance (Agouti obese mice) or by impaired insulin secretion (Ins2(WT/C96Y) mice). Atf6α(-/-) DO mice were less glucose tolerant with blunted insulin secretion compared to littermates on a high-fat diet. Pancreatic insulin content was lower in Atf6α(-/-) DO mice with the swollen β-cell ER, a typical feature of cells with ER stress. In the liver of Atf6α(-/-) DO mice, XBP-1 splicing was increased, suggesting that higher ER stress was present. ATF6-deficient mice showed increased mRNA expressions of glucose-6-phosphatase and SREBP1c associated with a tendency for a higher degree of steatosis in the liver. However, Atf6α(-/-) DO mice exhibited higher insulin sensitivity with lower serum triglyceride levels. Similar phenotypes were observed in ATF6α-deficient Agouti mice. In addition, ATF6α-deficiency accelerated reduction in pancreatic insulin content in Ins2(WT/C96Y) mice. These data suggested that ATF6α contributes to both prevention and promotion of diabetes; it protects β-cells from ER stress and suppresses hepatosteatosis, but plays a role in the development of hyperlipidemia and insulin resistance.
authors.affiliation: Division of Molecular Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Usui
authors.forename: Suguru
authors.initials: S
authors.lastname: Yamaguchi
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Tanji
authors.forename: Ryu
authors.initials: R
authors.lastname: Tominaga
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Ishigaki
authors.forename: Manabu
authors.initials: M
authors.lastname: Fukumoto
authors.forename: Hideki
authors.initials: H
authors.lastname: Katagiri
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Mori
authors.forename: Yoshitomo
authors.initials: Y
authors.lastname: Oka
authors.forename: Hisamitsu
authors.initials: H
authors.lastname: Ishihara
mesh_terms: D051702:Activating Transcription Factor 6 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D003920:Diabetes Mellitus / Q000209:etiology / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D059305:Diet, High-Fat / Q000009:adverse effects; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005234:Fatty Liver / Q000378:metabolism*; D005260:Female; D005952:Glucose-6-Phosphatase / Q000235:genetics / Q000378:metabolism; D006706:Homeostasis; D006949:Hyperlipidemias / Q000097:blood / Q000378:metabolism*; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000648:ultrastructure; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009765:Obesity / Q000209:etiology / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000097:blood
chemical_list: D051702:Activating Transcription Factor 6; C497112:Atf6 protein, mouse; D001786:Blood Glucose; D012333:RNA, Messenger; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D014280:Triglycerides; D005952:Glucose-6-Phosphatase