| First Author | Usui M | Year | 2012 |
| Journal | Metabolism | Volume | 61 |
| Issue | 8 | Pages | 1118-28 |
| PubMed ID | 22386934 | Mgi Jnum | J:319483 |
| Mgi Id | MGI:6861890 | Doi | 10.1016/j.metabol.2012.01.004 |
| Citation | Usui M, et al. (2012) Atf6alpha-null mice are glucose intolerant due to pancreatic beta-cell failure on a high-fat diet but partially resistant to diet-induced insulin resistance. Metabolism 61(8):1118-28 |
| abstractText | Activating transcription factor 6alpha (ATF6alpha) 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 Atf6alpha-null (Atf6alpha(-/-)) mice challenged with metabolic overload or genetic manipulations. Atf6alpha(-/-) 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. Atf6alpha-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). Atf6alpha(-/-) DO mice were less glucose tolerant with blunted insulin secretion compared to littermates on a high-fat diet. Pancreatic insulin content was lower in Atf6alpha(-/-) DO mice with the swollen beta-cell ER, a typical feature of cells with ER stress. In the liver of Atf6alpha(-/-) 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, Atf6alpha(-/-) DO mice exhibited higher insulin sensitivity with lower serum triglyceride levels. Similar phenotypes were observed in ATF6alpha-deficient Agouti mice. In addition, ATF6alpha-deficiency accelerated reduction in pancreatic insulin content in Ins2(WT/C96Y) mice. These data suggested that ATF6alpha 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. |
