Hatanaka, MasayukiAnderson-Baucum, EmilyLakhter, AlexanderKono, TatsuyoshiMaier, BernhardTersey, Sarah A.Tanizawa, YukioEvans-Molina, CarmellaMirmira, Raghavendra G.Sims, Emily K.2017-11-162017-11-162017-06-19Hatanaka, M., Anderson-Baucum, E., Lakhter, A., Kono, T., Maier, B., Tersey, S. A., … Sims, E. K. (2017). Chronic high fat feeding restricts islet mRNA translation initiation independently of ER stress via DNA damage and p53 activation. Scientific Reports, 7, 3758. http://doi.org/10.1038/s41598-017-03869-5https://hdl.handle.net/1805/14575Under conditions of high fat diet (HFD) consumption, glucose dyshomeostasis develops when β-cells are unable to adapt to peripheral insulin demands. Few studies have interrogated the molecular mechanisms of β-cell dysfunction at the level of mRNA translation under such conditions. We sought to address this issue through polyribosome profile analysis of islets from mice fed 16-weeks of 42% HFD. HFD-islet analysis revealed clear trends toward global reductions in mRNA translation with a significant reduction in the polyribosome/monoribosome ratio for Pdx1 mRNA. Transcriptional and translational analyses revealed endoplasmic reticulum stress was not the etiology of our findings. HFD-islets demonstrated evidence of oxidative stress and DNA damage, as well as activation of p53. Experiments in MIN-6 β-cells revealed that treatment with doxorubicin to directly induce DNA damage mimicked our observed effects in islets. Islets from animals treated with pioglitazone concurrently with HFD demonstrated a reversal of effects observed from HFD alone. Finally, HFD-islets demonstrated reduced expression of multiple ribosome biogenesis genes and the key translation initiation factor eIF4E. We propose a heretofore unappreciated effect of chronic HFD on β-cells, wherein continued DNA damage owing to persistent oxidative stress results in p53 activation and a resultant inhibition of mRNA translation.en-USAttribution 3.0 United StatesDNA damage responseTranslationType 2 diabetesArticle