The roles of ATF3, an adaptive-response gene, in high-fat-diet-induced diabetes and pancreatic beta-cell dysfunction.
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.
Zmuda
Erik J
EJ
Molecular, Cellular and Developmental Biology Program, Department of Molecular and Cellular Biochemistry, Center for Molecular Neurobiology, Ohio State University, Columbus, Ohio 43210, USA.
Qi
Ling
L
Zhu
Michael X
MX
Mirmira
Raghavendra G
RG
Montminy
Marc R
MR
Hai
Tsonwin
T
D051700:Activating Transcription Factor 3 / Q000235:genetics / Q000502:physiology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D004041:Dietary Fats / Q000009:adverse effects; D004797:Enzyme-Linked Immunosorbent Assay; D005951:Glucose Tolerance Test; D015151:Immunoblotting; D007150:Immunohistochemistry; D007328:Insulin / Q000097:blood; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051381:Rats
D051700:Activating Transcription Factor 3; C103002:Atf3 protein, mouse; D004041:Dietary Fats; D007328:Insulin