Multigenerational mistimed feeding drives circadian reprogramming with an impaired unfolded protein response

Front Endocrinol (Lausanne). 2023 Mar 6:14:1157165. doi: 10.3389/fendo.2023.1157165. eCollection 2023.

Abstract

Mistimed food intake in relation to the day/night cycle disrupts the synchrony of circadian rhythms in peripheral tissues and increases the risk of metabolic diseases. However, the health effects over generations have seldom been explored. Here, we established a 10-generation mouse model that was continuously fed with daytime-restricted feeding (DRF). We performed RNA-seq analysis of mouse liver samples obtained every 4 h over a 24 h period from F2, F5 and F10 generations exposed to DRF. Multigenerational DRF programs the diurnal rhythmic transcriptome through a gain or loss of diurnal rhythmicity over generations. Gene ontology (GO) analysis of the differential rhythmic transcriptome revealed that adaptation to persistent DRF is accompanied by impaired endoplasmic reticulum (ER) stress. Consistently, a substantially higher level of folding-deficient proinsulin was observed in F10 liver tissues than in F2 and F5 liver tissues following tail vein injection. Subsequently, tunicamycin induced more hepatocyte death in F10 samples than in F2 and F5 samples. These data demonstrate that mistimed food intake could produce cumulative effects over generations on ER stress sensitivity in mice.

Keywords: ER stress; mistimed feeding; multigenerational effect; rhythm reprogramming; unfolded protein response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Circadian Rhythm* / genetics
  • Mice
  • Transcriptome*
  • Unfolded Protein Response / genetics

Grants and funding

This work was supported by grants from National Key R&D Program of China (2018YFA0801100 to YX), the National Natural Science Foundation of China (31630091, 32100931, 31601022), Lingang Laboratory & National Key Laboratory of Human Factors Engineering Joint Grant (LG-TKN-202203-01), Science and Technology Project of Jiangsu Province (Grant Nos. BZ2020067), Academic Program Development of the Jiangsu Higher Education Institutes (PAPD) and National Center for International Research (2017B01012) and Livelihood and Technology Program of Suzhou City (N324560122).