Chronic high fat feeding restricts islet mRNA translation initiation independently of ER stress via DNA damage and p53 activation

Masayuki Hatanaka, Emily Anderson-Baucum, Alexander Lakhter, Tatsuyoshi Kono, Bernhard Maier, Sarah A. Tersey, Yukio Tanizawa, Carmella Evans-Molina, Raghavendra G. Mirmira, Emily K. Sims

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Under 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.

Original languageEnglish (US)
Article number3758
JournalScientific reports
Issue number1
StatePublished - Dec 1 2017


ASJC Scopus subject areas

  • General

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