The roles of ATF3, an adaptive-response gene, in high-fat-diet-induced diabetes and pancreatic beta-cell dysfunction

Mol Endocrinol. 2010 Jul;24(7):1423-33. doi: 10.1210/me.2009-0463. Epub 2010 Jun 2.


Most people with type 2 diabetes (T2D) have reduced beta-cell mass, and apoptosis is a key factor for this reduction. Previously, we showed that ATF3, an adaptive-response gene, is induced by various stress signals relevant to T2D, such as high glucose and high fatty acid. Because ATF3 is proapoptotic in beta-cells, we tested the hypothesis that ATF3 plays a detrimental role and contributes to the development of T2D. We compared wild-type (WT) and ATF3 knockout (KO) mice in an animal model for T2D, high-fat diet-induced diabetes. We also used INS-1 beta-cells and primary islets to analyze the roles of ATF3 in beta-cell function, including insulin gene expression and glucose-induced insulin secretion. Surprisingly, WT mice performed better in glucose tolerance test than KO mice, suggesting a protective, rather than detrimental, role of ATF3. At 12 wk on high-fat diet, no beta-cell apoptosis was observed, and the WT and KO mice had comparable beta-cell areas. However, ATF3 deficiency significantly reduced serum insulin levels in the KO mice without affecting insulin sensitivity, suggesting reduced beta-cell function in the KO mice. Analyses using INS-1 cells and primary islets support the notion that this defect is due, at least partly, to reduced insulin gene transcription in the KO islets without detectable reduction in glucose-induced calcium influx, a critical step for insulin secretion. In conclusion, our results support a model in which, before apoptosis becomes obvious, expression of ATF3 can be beneficial by helping beta-cells to cope with higher metabolic demand.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Activating Transcription Factor 3 / genetics
  • Activating Transcription Factor 3 / physiology*
  • Animals
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Chromatin Immunoprecipitation
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / genetics
  • Diabetes Mellitus, Type 2 / metabolism*
  • Dietary Fats / adverse effects
  • Enzyme-Linked Immunosorbent Assay
  • Glucose Tolerance Test
  • Immunoblotting
  • Immunohistochemistry
  • Insulin / blood
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / metabolism*
  • Insulin-Secreting Cells / pathology*
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Rats


  • Activating Transcription Factor 3
  • Atf3 protein, mouse
  • Dietary Fats
  • Insulin