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

Masahiro Usui, Suguru Yamaguchi, Yasuhiro Tanji, Ryu Tominaga, Yasushi Ishigaki, Manabu Fukumoto, Hideki Katagiri, Kazutoshi Mori, Yoshitomo Oka, Hisamitsu Ishihara

Research output: Contribution to journalArticlepeer-review

80 Citations (Scopus)

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 Ins2WT/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.

Original languageEnglish
Pages (from-to)1118-1128
Number of pages11
JournalMetabolism: Clinical and Experimental
Volume61
Issue number8
DOIs
Publication statusPublished - 2012 Aug
Externally publishedYes

Keywords

  • 78 kDa glucose-regulated protein
  • ATF6α
  • BW
  • DO
  • ER
  • G6Pase
  • GRP78
  • HFD
  • IPGTT
  • IRE1
  • ITT
  • PERK
  • PKR (double-stranded-RNA-dependent protein kinase)-like ER kinase
  • TG
  • UPR
  • VLDL
  • WT
  • X-box binding protein.
  • XBP
  • activating transcription factor 6α
  • body weight
  • cDNA
  • complementary DNA
  • diet-induced obese
  • eIF2α
  • endoplasmic reticulum
  • eukaryotic initiation factor 2
  • glucose-6-phosphatase
  • high-fat diet
  • inositol requiring enzyme 1
  • intraperitoneal glucose tolerance test
  • intraperitoneal insulin tolerance test
  • triglyceride
  • unfolded protein response
  • very low-density lipoprotein
  • wild-type

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

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