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

Activating transcription factor 6 alpha (ATF6 alpha) 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 Atf6 alpha-null (Atf6 alpha(-/-)) mice challenged with metabolic overload or genetic manipulations. Atf6 alpha(-/-) 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 beta-cell and liver tissues. Atf6 alpha-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). Atf6 alpha(-/-) DO mice were less glucose tolerant with blunted insulin secretion compared to littermates on a high-fat diet. Pancreatic insulin content was lower in Atf6 alpha(-/-) DO mice with the swollen beta-cell ER, a typical feature of cells with ER stress. In the liver of Atf6 alpha(-/-) 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, Atf6 alpha(-/-) DO mice exhibited higher insulin sensitivity with lower serum triglyceride levels. Similar phenotypes were observed in ATF6 alpha-deficient Agouti mice. In addition, ATF6 alpha-deficiency accelerated reduction in pancreatic insulin content in Ins2(WT/C96Y) mice. These data suggested that ATF6 alpha contributes to both prevention and promotion of diabetes; it protects beta-cells from ER stress and suppresses hepatosteatosis, but plays a role in the development of hyperlipidemia and insulin resistance. (C) 2012 Elsevier Inc. All rights reserved.